1
|
Sun Q, Cheng Y, Huang Y, Li S, Li Y, Fu Q. Neferine inhibits PRRSV infection by disrupting p65 nuclear translocation. Microb Pathog 2025; 205:107648. [PMID: 40311944 DOI: 10.1016/j.micpath.2025.107648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 04/26/2025] [Accepted: 04/28/2025] [Indexed: 05/03/2025]
Abstract
Porcine reproductive and respiratory syndrome (PRRS), caused by the PRRS virus (PRRSV), imposes substantial economic losses on the global swine industry due to its profound impact on pig health and production efficiency. The main clinical manifestations are reproductive disorders such as miscarriage, stillbirth or weak foetuses in sows, as well as severe respiratory diseases in pigs of all ages. Currently, due to the high genomic diversity, antigen heterogeneity, and antibody-dependent enhancement effects of PRRSV, vaccination strategies cannot effectively control PRRSV infection. It is also difficult to control these viral infectious diseases with antiviral drugs. In this study, we demonstrate that neferine (Nef), a natural compound derived from lotus seeds, inhibits NF-κB activation during PRRSV infection. Consequently, Nef effectively suppresses PRRSV gene expression and virion replication in the PRRSV-infected Marc-145 cell line. Further studies demonstrated that Nef attenuates the nuclear translocation of p65 triggered by PRRSV infection, consequently mitigating the excessive production of inflammatory cytokines in infected cells. This anti-inflammatory mechanism may contribute to its observed antiviral efficacy against PRRSV. As a result, we conclude that Nef may be an effective clinical treatment for the acute occurrence and transmission of PRRSV infections. Furthermore, PRRSV is thought to be responsible for an increase in proinflammatory cytokines.
Collapse
Affiliation(s)
- Qinqin Sun
- School of Animal Science and Technology, Foshan University, Foshan, PR China; Foshan University Veterinary Teaching Hospital, Foshan University, Foshan, PR China
| | - Yun Cheng
- School of Animal Science and Technology, Foshan University, Foshan, PR China
| | - Yunfei Huang
- School of Animal Science and Technology, Foshan University, Foshan, PR China
| | - Shun Li
- School of Animal Science and Technology, Foshan University, Foshan, PR China
| | - Yajuan Li
- School of Animal Science and Technology, Foshan University, Foshan, PR China
| | - Qiang Fu
- School of Animal Science and Technology, Foshan University, Foshan, PR China; Foshan University Veterinary Teaching Hospital, Foshan University, Foshan, PR China.
| |
Collapse
|
2
|
Cao D, Tian M, Liu Z, Guo K, Peng J, Ravichandra A, Ferrell C, Dong Y. Unlock the sustained therapeutic efficacy of mRNA. J Control Release 2025; 383:113837. [PMID: 40368188 PMCID: PMC12145234 DOI: 10.1016/j.jconrel.2025.113837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 05/01/2025] [Accepted: 05/10/2025] [Indexed: 05/16/2025]
Abstract
mRNA therapies have emerged as a transformative class of medicines, offering immense potential across a diverse array of applications. This progress has been particularly evident in the wake of the success of lipid nanoparticle (LNP)-based mRNA vaccines during the COVID-19 pandemic. As these applications expand, the demand for sustained protein production has become increasingly critical. However, conventional mRNA therapies face significant challenges, including inherent RNA instability and suboptimal expression efficiency, often requiring repeated dosing to maintain therapeutic efficacy over time. This review highlights recent advances in strategies to prolong the therapeutic efficacy of LNP-mRNA systems. We focus on preclinical and emerging approaches aimed at extending the period of protein translation by engineering both the mRNA molecule and the LNP delivery system. Sustained protein expression is a cornerstone of mRNA-based therapeutics, and addressing this challenge is vital for unlocking their therapeutic potential. We hope this review provides valuable insights to guide the development of optimized delivery platforms for LNP-mRNA therapeutics.
Collapse
Affiliation(s)
- Dinglingge Cao
- Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Meng Tian
- Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Zhengwei Liu
- Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kaiyuan Guo
- Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jonathan Peng
- Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Anjali Ravichandra
- Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Caroline Ferrell
- Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yizhou Dong
- Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| |
Collapse
|
3
|
Azcarate D, Olasagasti Arsuaga F, Granizo Rodriguez E, Arana-Arri E, España PP, Intxausti M, Sancho C, García de Vicuña Meléndez A, Ibarrondo O, M de Pancorbo M. Human-genetic variants associated with susceptibility to SARS-CoV-2 infection. Gene 2025; 953:149423. [PMID: 40120867 DOI: 10.1016/j.gene.2025.149423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 03/13/2025] [Accepted: 03/15/2025] [Indexed: 03/25/2025]
Abstract
SARS-CoV-2, the third major coronavirus of the 21st century, causing COVID-19 disease, profoundly impacts public health and workforces worldwide. Identifying individuals at heightened risk of SARS-CoV-2 infection is crucial for targeted interventions and preparedness. This study investigated 35 SNVs within viral infection-associated genes in SARS-CoV-2 patients and uninfected controls from the Basque Country (March 2020-July 2021). Its primary aim was to uncover genetic markers indicative of SARS-CoV-2 susceptibility and explore genetic predispositions to infection. Association analyses revealed previously unreported associations between SNVs and susceptibility. Haplotype analyses uncovered novel links between haplotypes and susceptibility, surpassing individual SNV associations. Descriptive modelling identified key susceptibility factors, with rs11246068-CC (IFITM3), rs5742933-GG (ORMDL1), rs35337543-CG (IFIH1), and GGGCT (rs2070788, rs2298659, rs17854725, rs12329760, rs3787950) variation in TMPRSS2 emerging as main infection-susceptibility indicators for a COVID-19 pandemic situation. These findings underscore the importance of integrated SNV and haplotype analyses in delineating susceptibility to SARS-CoV-2 and informing proactive prevention strategies. The genetic markers profiled in this study offer valuable insights for future pandemic preparedness.
Collapse
Affiliation(s)
- Daniel Azcarate
- BIOMICs Research Group (BIOMICS and Microfluidics cluster), Zoology and animal cellular biology department, Faculty of Science and Technology (UPV/EHU), 48940 Leioa, Biscay (Basque Country), Spain
| | - Felix Olasagasti Arsuaga
- BIOMICs Research Group (BIOMICS and Microfluidics cluster), Biochemistry and molecular biology department, Faculty of Pharmacy (UPV/EHU), 01006 Vitoria-Gasteiz, Alava (Basque Country), Spain.
| | - Eva Granizo Rodriguez
- BIOMICs Research Group (BIOMICS and Microfluidics cluster), Zoology and animal cellular biology department, Faculty of Science and Technology (UPV/EHU), 48940 Leioa, Biscay (Basque Country), Spain
| | - Eunate Arana-Arri
- Clinical Epidemiology Unit, Cruces University Hospital, 48903 Barakaldo, Biscay (Basque Country), Spain
| | - Pedro Pablo España
- Pulmonology Service, Galdakao-Usansolo University Hospital, 48960 Galdakao, Biscay (Basque Country), Spain
| | - Maider Intxausti
- Pulmonology Service, Alava University Hospital - Txagorritxu, 01009 Vitoria-Gasteiz, Álava (Basque Country), Spain
| | - Cristina Sancho
- Department of Pneumology, Basurto University Hospital, 48013 Bilbao, Biscay (Basque Country), Spain
| | | | - Oliver Ibarrondo
- Consultant in Statistics and Health Economics Research, Debagoiena AP-OSI Research Unit, 20500 Arrasate, Gipuzkoa (Basque Country), Spain
| | - Marian M de Pancorbo
- BIOMICs Research Group (BIOMICS and Microfluidics cluster), Zoology and animal cellular biology department, Faculty of Science and Technology (UPV/EHU), 48940 Leioa, Biscay (Basque Country), Spain.
| |
Collapse
|
4
|
Mishra Y, Kumar A, Kaundal RK. Mitochondrial Dysfunction is a Crucial Immune Checkpoint for Neuroinflammation and Neurodegeneration: mtDAMPs in Focus. Mol Neurobiol 2025; 62:6715-6747. [PMID: 39115673 DOI: 10.1007/s12035-024-04412-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 07/30/2024] [Indexed: 01/03/2025]
Abstract
Neuroinflammation is a pivotal factor in the progression of both age-related and acute neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Mitochondria, essential for neuronal health due to their roles in energy production, calcium buffering, and oxidative stress regulation, become increasingly susceptible to dysfunction under conditions of metabolic stress, aging, or injury. Impaired mitophagy in aged or injured neurons leads to the accumulation of dysfunctional mitochondria, which release mitochondrial-derived damage-associated molecular patterns (mtDAMPs). These mtDAMPs act as immune checkpoints, activating pattern recognition receptors (PRRs) and triggering innate immune signaling pathways. This activation initiates inflammatory responses in neurons and brain-resident immune cells, releasing cytokines and chemokines that damage adjacent healthy neurons and recruit peripheral immune cells, further amplifying neuroinflammation and neurodegeneration. Long-term mitochondrial dysfunction perpetuates a chronic inflammatory state, exacerbating neuronal injury and contributing additional immunogenic components to the extracellular environment. Emerging evidence highlights the critical role of mtDAMPs in initiating and sustaining neuroinflammation, with circulating levels of these molecules potentially serving as biomarkers for disease progression. This review explores the mechanisms of mtDAMP release due to mitochondrial dysfunction, their interaction with PRRs, and the subsequent activation of inflammatory pathways. We also discuss the role of mtDAMP-triggered innate immune responses in exacerbating both acute and chronic neuroinflammation and neurodegeneration. Targeting dysfunctional mitochondria and mtDAMPs with pharmacological agents presents a promising strategy for mitigating the initiation and progression of neuropathological conditions.
Collapse
Affiliation(s)
- Yogesh Mishra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) - SAS Nagar, SAS Nagar, Punjab, India
| | - Ashutosh Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) - SAS Nagar, SAS Nagar, Punjab, India.
| | - Ravinder Kumar Kaundal
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) - Raebareli, Lucknow, Uttar Pradesh, India.
| |
Collapse
|
5
|
Joshi G, Décembre E, Brocard J, Montpellier C, Ferrié M, Allatif O, Mehnert AK, Pons J, Galiana D, Dao Thi VL, Jouvenet N, Cocquerel L, Dreux M. Plasmacytoid dendritic cell sensing of hepatitis E virus is shaped by both viral and host factors. Life Sci Alliance 2025; 8:e202503256. [PMID: 40175091 PMCID: PMC11966012 DOI: 10.26508/lsa.202503256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/14/2025] [Accepted: 03/14/2025] [Indexed: 04/04/2025] Open
Abstract
Type I and III interferons critically protect the host against viral infection. Previous studies showed that IFN responses are suppressed in cells infected by hepatitis E virus (HEV). Here, we studied the anti-HEV function of IFN secreted by plasmacytoid dendritic cells (pDCs), specialized producers of IFNs. We showed that pDCs co-cultured with HEV-replicating cells secreted IFN in a cell contact-dependent manner. This pDC response required the endosomal nucleic acid sensor TLR7 and adhesion molecules. IFNs secreted by pDCs reduced viral spread. Intriguingly, ORF2, the capsid protein of HEV, can be produced in various forms by the infected cells, and we wanted to study their role in anti-HEV immune response. During infection, a fraction of ORF2 localizes into the nucleus, and glycosylated forms of ORF2 are massively secreted by infected cells. We showed that glycosylated ORF2 potentiates the recognition of infected cells by pDCs, by regulating cell contacts. On the other hand, nuclear ORF2 triggers immune response by IRF3 activation. Together, our results suggest that pDCs may be essential to control HEV replication.
Collapse
Affiliation(s)
- Garima Joshi
- CIRI, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, University Lyon, Lyon, France
| | - Elodie Décembre
- CIRI, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, University Lyon, Lyon, France
| | - Jacques Brocard
- Université Claude Bernard Lyon 1, CNRS UAR3444, INSERMUS8, ENS de Lyon, SFR Biosciences, Lyon, France
| | - Claire Montpellier
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
| | - Martin Ferrié
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
| | - Omran Allatif
- CIRI, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, University Lyon, Lyon, France
| | - Ann-Kathrin Mehnert
- Department of Infectious Diseases, Virology, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany and German Centre for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany
| | - Johann Pons
- Sup'biotech, École Des Ingénieurs En Biotechnologies, Villejuif, Paris
| | - Delphine Galiana
- CIRI, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, University Lyon, Lyon, France
| | - Viet Loan Dao Thi
- Department of Infectious Diseases, Virology, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany and German Centre for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany
| | - Nolwenn Jouvenet
- Institut Pasteur, Université de Paris, CNRS UMR 3569, Virus sensing and signaling Unit, Paris, France
| | - Laurence Cocquerel
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
| | - Marlène Dreux
- CIRI, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, University Lyon, Lyon, France
| |
Collapse
|
6
|
Wang C, Jiang X, Li HY, Hu J, Ji Q, Wang Q, Liu X, Huang D, Yan K, Zhao L, Fan Y, Wang S, Ma S, Belmonte JCI, Qu J, Liu GH, Zhang W. RIG-I-driven CDKN1A stabilization reinforces cellular senescence. SCIENCE CHINA. LIFE SCIENCES 2025; 68:1646-1661. [PMID: 40133712 DOI: 10.1007/s11427-024-2844-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 01/17/2025] [Indexed: 03/27/2025]
Abstract
The innate immune signaling network follows a canonical format for signal transmission. The innate immune pathway is crucial for defense against pathogens, yet its mechanistic crosstalk with aging processes remains largely unexplored. Retinoic acid-inducible gene-I (RIG-I), a key mediator of antiviral immunity within this pathway, has an enigmatic role in stem cell senescence. Our study reveals that RIG-I levels increase in human genetic and physiological cellular aging models, and its accumulation drives cellular senescence. Conversely, CRISPR/Cas9-mediated RIG-I deletion or pharmacological inhibition in human mesenchymal stem cells (hMSCs) confers resistance to senescence. Mechanistically, RIG-I binds to endogenous mRNAs, with CDKN1A mRNA being a prominent target. Specifically, RIG-I stabilizes CDKN1A mRNA, resulting in elevated CDKN1A transcript levels and increased p21Cip1 protein expression, which precipitates senescence. Collectively, our findings establish RIG-I as a post-transcriptional regulator of senescence and suggest potential targets for the mitigation of aging-related diseases.
Collapse
Affiliation(s)
- Cui Wang
- China National Center for Bioinformation, Beijing, 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaoyu Jiang
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Hong-Yu Li
- Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jianli Hu
- China National Center for Bioinformation, Beijing, 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Qianzhao Ji
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Qiaoran Wang
- China National Center for Bioinformation, Beijing, 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaoqian Liu
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Daoyuan Huang
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
| | - Kaowen Yan
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Liyun Zhao
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
| | - Yanling Fan
- China National Center for Bioinformation, Beijing, 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Si Wang
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
- Aging Biomarker Consortium, Beijing, 100101, China
| | - Shuai Ma
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Aging Biomarker Consortium, Beijing, 100101, China
| | | | - Jing Qu
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
- Aging Biomarker Consortium, Beijing, 100101, China.
| | - Guang-Hui Liu
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
- Aging Biomarker Consortium, Beijing, 100101, China.
| | - Weiqi Zhang
- China National Center for Bioinformation, Beijing, 100101, China.
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Aging Biomarker Consortium, Beijing, 100101, China.
| |
Collapse
|
7
|
Baral H, Kaundal RK. Novel insights into neuroinflammatory mechanisms in traumatic brain injury: Focus on pattern recognition receptors as therapeutic targets. Cytokine Growth Factor Rev 2025; 83:18-34. [PMID: 40169306 DOI: 10.1016/j.cytogfr.2025.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 03/14/2025] [Indexed: 04/03/2025]
Abstract
Traumatic brain injury (TBI) is a major global health concern and a leading cause of morbidity and mortality. Neuroinflammation is a pivotal driver of both the acute and chronic phases of TBI, with pattern recognition receptors (PRRs) playing a central role in detecting damage-associated molecular patterns (DAMPs) and initiating immune responses. Key PRR subclasses, including Toll-like receptors (TLRs), NOD-like receptors (NLRs), and cGAS-like receptors (cGLRs), are abundantly expressed in central nervous system (CNS) cells and infiltrating immune cells, where they mediate immune activation, amplify neuroinflammatory cascades, and exacerbate secondary injury mechanisms. This review provides a comprehensive analysis of these PRR subclasses, detailing their distinct structural characteristics, expression patterns, and roles in post-TBI immune responses. We critically examine the molecular mechanisms underlying PRR-mediated signaling and explore their contributions to neuroinflammatory pathways and secondary injury processes. Additionally, preclinical and clinical evidence supporting the therapeutic potential of targeting PRRs to mitigate neuroinflammation and improve neurological outcomes is discussed. By integrating recent advancements, this review offers an in-depth understanding of the role of PRRs in TBI pathobiology and underscores the potential of PRR-targeted therapies in mitigating TBI-associated neurological deficits.
Collapse
Affiliation(s)
- Harapriya Baral
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP 226002, India
| | - Ravinder K Kaundal
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP 226002, India.
| |
Collapse
|
8
|
Zhang A, Luo S, Li P, Meng L, Huang L, Cheng H, Zhao C, Tu H, Gong X. Urolithin A alleviates radiation pneumonitis by activating PINK1/PRKN-mediated Mitophagy. Int Immunopharmacol 2025; 156:114671. [PMID: 40253768 DOI: 10.1016/j.intimp.2025.114671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 04/05/2025] [Accepted: 04/11/2025] [Indexed: 04/22/2025]
Abstract
BACKGROUND Radiation pneumonitis (RP) is a common and severe complication of radiotherapy, whose pathogenesis involves complex inflammatory responses and cellular damage. Despite its clinical significance, effective treatments remain limited. This study investigates the role of radiation-induced PINK1/PRKN-mediated mitophagy and type I interferon responses in RP and evaluates the therapeutic potential of Urolithin A (UA) in regulating inflammation through mitophagy activation. METHODS We established RP mouse models (20 Gy thoracic irradiation) and radiation-induced BEAS-2B cell models (6 Gy). We systematically investigated mitochondrial damage, mtRNA release, RIG-I/MDA5-MAVS pathway activation, and PINK1/PRKN-mediated mitophagy changes. Moreover, the effects of UA and the mitophagy inhibitor Mdivi-1 on inflammation and lung injury were analyzed. RESULTS Radiation significantly caused mitochondrial damage in lung tissues, inducing mtRNA release and RIG-I/MDA5-MAVS-mediated type I interferon response. PINK1/PRKN-mediated mitophagy was significantly enhanced, clearing damaged mitochondria and reducing cytosolic mtRNA release, thereby suppressing inflammation. Pharmacological activation of mitophagy with UA markedly improved lung pathology, reduced inflammatory cytokine levels, and inhibited excessive activation of the RIG-I/MDA5-MAVS pathway. Conversely, the knockdown of PINK1 or PRKN weakened the protective effects of UA. Both in vitro and in vivo, UA reduced radiation-induced inflammation and improved lung tissue structure and function through mitophagy. CONCLUSIONS Radiation-induced mtRNA release activates the RIG-I/MDA5-MAVS-mediated type I interferon response, driving inflammation in RP. PINK1/PRKN-mediated mitophagy significantly alleviates inflammation by reducing cytosolic mtRNA release. As a mitophagy inducer, UA demonstrates therapeutic potential for RP, providing a new direction for the development of anti-inflammatory strategies.
Collapse
Affiliation(s)
- Anqi Zhang
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shilan Luo
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Peng Li
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lu Meng
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Litang Huang
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hongxia Cheng
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Chenhui Zhao
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hongbin Tu
- Department of Integrated TCM & Western Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaomei Gong
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
| |
Collapse
|
9
|
Tonutti A, Motta F, Isailovic N, Selmi C, Timilsina S, Eric Gershwin M, De Santis M. Mechanistic considerations linking SARS-CoV-2 infection, inflammation, and the loss of immune tolerance. Curr Opin Immunol 2025; 95:102567. [PMID: 40412200 DOI: 10.1016/j.coi.2025.102567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 04/27/2025] [Accepted: 05/08/2025] [Indexed: 05/27/2025]
Abstract
The immune response to SARS-CoV-2 has been implicated in the onset of multiple, seemingly unrelated, autoimmune diseases. The immune response to SARS-CoV-2 has also been implicated in the unmasking and/or production of multiple autoantibodies, even in the absence of clinical disease. Despite such data, it remains unclear whether antibodies targeting antiviral signaling proteins and mitochondrial antigens reflect bystander activation or alternatively contribute to de novo viral immune escape mechanisms. With these comments in mind, a variety of professional antibody presenting cells and including lung resident macrophages of COVID-19 infected patients are impacted and dependent on the uptake of antibody-opsonized virus by Fcγ receptors; yet infection is aborted via antibody-dependent effector mechanisms or pyroptosis, possibly leading to autoantibody production, and autoinflammatory manifestations, respectively. TRIM21/Ro52, a cytosolic E3-ubiquitin ligase with an Fc-gamma receptor domain, functions as an intracytoplasmic antibody receptor, directs immune complexes binding virions but also autoantigens to autophagy. During autophagy, Ig-virions-TRIM21/Ro52-autoantigens complexes bind directly to class II human leukocyte antigen in lysosomal compartment, leading to subsequent presentation on the cell surface. This process favors the development of a specific humoral immune response but has the potential to lead to loss of tolerance. Interestingly, TRIM21/Ro52 can also contribute to pyroptosis. We propose that TRIM21/Ro52 is well-placed at the crossroad between the inflammatory response and clinical autoimmunity.
Collapse
Affiliation(s)
- Antonio Tonutti
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy; Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | - Francesca Motta
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy; Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | - Natasa Isailovic
- Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | - Carlo Selmi
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy; Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy.
| | - Suraj Timilsina
- Division of Rheumatology, Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA, USA
| | - Merrill Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA, USA
| | - Maria De Santis
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy; Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| |
Collapse
|
10
|
Gehlhausen JR, Kong Y, Baker E, Ramachandran S, Koumpouras F, Ko CJ, Vesely M, Little AJ, Damsky W, King B, Iwasaki A. Cutaneous lupus features specialized stromal niches and altered retroelement expression. J Invest Dermatol 2025:S0022-202X(25)00488-9. [PMID: 40409678 DOI: 10.1016/j.jid.2025.04.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 04/10/2025] [Accepted: 04/17/2025] [Indexed: 05/25/2025]
Abstract
Cutaneous Lupus is an inflammatory skin disease causing highly morbid inflamed skin and hair loss. In order to investigate the pathophysiology of cutaneous lupus, we performed single-cell RNA and spatial sequencing of lesional and non-lesional cutaneous lupus skin compared to healthy controls. Pathway enrichment analyses of lesional keratinocytes revealed elevated responses to type I interferon, type II interferon, tumor necrosis factor, and apoptotic signaling. Detailed clustering demonstrated unique fibroblasts specific to lupus skin with likely roles in inflammatory cell recruitment and fibrosis. We also evaluated the association of retroelement expression with type I interferons in the skin. We observed increased retroelement expression which correlated with interferon-stimulated genes across multiple cell types. Moreover, we saw elevated expression of genes involved in RIG-I and cGAS-STING pathways, which transduce elevated nucleic acid signals. Treatment of active cutaneous lupus with Anifrolumab reduced RIG-I and cGAS-STING pathways in addition to the most abundant retroelement family, L2b. Our studies better define type I interferon-mediated immunopathology in cutaneous lupus and identify an association between retroelement expression and interferon signatures in cutaneous lupus.
Collapse
Affiliation(s)
| | - Yong Kong
- Yale School of Public Health; New Haven, CT, USA
| | - Emily Baker
- Yale Department of Dermatology; New Haven, CT, USA
| | | | | | - Christine J Ko
- Yale Department of Dermatology; New Haven, CT, USA; Yale Department of Pathology; New Haven, CT, USA
| | | | | | - William Damsky
- Yale Department of Dermatology; New Haven, CT, USA; Yale Department of Pathology; New Haven, CT, USA
| | - Brett King
- Yale Department of Dermatology; New Haven, CT, USA
| | - Akiko Iwasaki
- Yale Department of Dermatology; New Haven, CT, USA; Yale Department of Immunobiology; New Haven, CT, USA; Department of Molecular Cellular and Developmental Biology, Yale University; New Haven, CT, USA; Howard Hughes Medical Institute; Chevy Chase, MD, USA.
| |
Collapse
|
11
|
Madej M, Ngoc PCT, Muthukumar S, Konturek-Cieśla A, Tucciarone S, Germanos A, Ashworth C, Kotarsky K, Ghosh S, Fan Z, Fritz H, Pascual-Gonzalez I, Huerta A, Guzzi N, Colazzo A, Beneventi G, Lee HM, Cieśla M, Douse C, Kato H, Swaminathan V, Agace WW, Castellanos-Rubio A, Salomoni P, Bryder D, Bellodi C. PUS10-induced tRNA fragmentation impacts retrotransposon-driven inflammation. Cell Rep 2025; 44:115735. [PMID: 40402745 DOI: 10.1016/j.celrep.2025.115735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 02/28/2025] [Accepted: 05/02/2025] [Indexed: 05/24/2025] Open
Abstract
Pseudouridine synthases (PUSs) catalyze the isomerization of uridine (U)-to-pseudouridine (Ψ) and have emerging roles in development and disease. How PUSs adapt gene expression under stress remains mostly unexplored. We identify an unconventional role for the Ψ "writer" PUS10 impacting intracellular innate immunity. Using Pus10 knockout mice, we uncover cell-intrinsic upregulation of interferon (IFN) signaling, conferring resistance to inflammation in vivo. Pus10 loss alters tRNA-derived small RNAs (tdRs) abundance, perturbing translation and endogenous retroelements expression. These alterations promote proinflammatory RNA-DNA hybrids accumulation, potentially activating cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING). Supplementation with selected tdR pools partly rescues these effects through interactions with RNA processing factors that modulate immune responses, revealing a regulatory circuit that counteracts cell-intrinsic inflammation. By extension, we define a PUS10-specific molecular fingerprint linking its dysregulation to human autoimmune disorders, including inflammatory bowel diseases. Collectively, these findings establish PUS10 as a viral mimicry modulator, with broad implications for innate immune homeostasis and autoimmunity.
Collapse
Affiliation(s)
- Magdalena Madej
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden
| | - Phuong Cao Thi Ngoc
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden
| | - Sowndarya Muthukumar
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden
| | - Anna Konturek-Cieśla
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
| | - Silvia Tucciarone
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden
| | - Alexandre Germanos
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden
| | - Christian Ashworth
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Knut Kotarsky
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Sudip Ghosh
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Zhimeng Fan
- Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Helena Fritz
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden
| | | | - Alain Huerta
- University of the Basque Country, UPV-EHU, Leioa, Spain; Biobizkaia Research Institute, Cruces-Barakaldo, Spain; Galdakao University Hospital, Galdakao, Spain
| | - Nicola Guzzi
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden
| | - Anita Colazzo
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden
| | - Giulia Beneventi
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden
| | - Hang-Mao Lee
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Maciej Cieśla
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden; International Institute of Molecular Mechanisms and Machines, Polish Academy of Sciences, Warsaw, Poland
| | - Christopher Douse
- Epigenetics and Chromatin Dynamics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Hiroki Kato
- Institute of Cardiovascular Immunology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Vinay Swaminathan
- Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden; Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
| | - William W Agace
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark; Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Ainara Castellanos-Rubio
- University of the Basque Country, UPV-EHU, Leioa, Spain; Biobizkaia Research Institute, Cruces-Barakaldo, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Paolo Salomoni
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - David Bryder
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden
| | - Cristian Bellodi
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden; Biotech Research Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
| |
Collapse
|
12
|
Wang Y, Li Z, Li Z, Song Y, Li J, Yuan L, Wang C, Lai F, Yan R, Xiao W, Wang J. Zebrafish fkbp5 attenuates antiviral innate immunity by autophagic degradation of transcription factor irf7. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025:vkaf089. [PMID: 40391431 DOI: 10.1093/jimmun/vkaf089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 03/25/2025] [Indexed: 05/21/2025]
Abstract
Activation of the type I interferon (IFN-I) signaling pathway is crucial for protecting host cells against viral infections. IFN-I production requires the transcription factors IFN regulatory factor 3 (IRF3) and IRF7, and its regulation must be finely tuned to both combat infection effectively and prevent excessive immunopathology. Here, we report that selective autophagy mediated by zebrafish FK506-binding protein 5 (Fkbp5), a PPIase (peptidyl-prolyl isomerase) promotes the degradation of Irf7 and Irf3, thereby inhibiting virus-induced type I IFN production. Quantitative real-time reverse-transcription polymerase chain reaction experiments indicate that zebrafish fkbp5 is induced by viral infection. Moreover, disrupting fkbp5 in AB-line zebrafish using CRISPR/Cas9 enhances survival rates and reduces viral messenger RNA levels compared with wild-type zebrafish. In cell culture, using promoter analysis and quantitative real-time reverse-transcription polymerase chain reaction, we found fkbp5 overexpression significantly attenuates cellular antiviral capacity and facilitates viral proliferation. Mechanistically, we found that fkbp5 inhibits Irf3/7-induced IFN activation, which depends on the binding of Fkbp5 to the Irf3 or IRF association domain of Irf7 via co-immunoprecipitation and Western blot assays. Furthermore, Fkbp5 induces the autophagic degradation of Irf3 and Irf7 independent of its PPIase activity. Blocking autophagy in vivo and in vitro restores the regulation of the RLR (RIG-I-like receptor) pathway by fkbp5. These findings reveal a critical role for zebrafish fkbp5 in suppressing the activation of Irf7 and Irf3 for IFN signaling and antiviral immune responses.
Collapse
Affiliation(s)
- Yanyi Wang
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, P. R. China
- Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, P. R. China
- University of Chinese Academy of Sciences, Beijing, P. R. China
| | - Zhi Li
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, P. R. China
- Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, P. R. China
- University of Chinese Academy of Sciences, Beijing, P. R. China
| | - Ziyi Li
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, P. R. China
- Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, P. R. China
- University of Chinese Academy of Sciences, Beijing, P. R. China
| | - Yanan Song
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, P. R. China
- Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, P. R. China
- University of Chinese Academy of Sciences, Beijing, P. R. China
| | - Jun Li
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, P. R. China
- Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, P. R. China
- University of Chinese Academy of Sciences, Beijing, P. R. China
| | - Le Yuan
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, P. R. China
- Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, P. R. China
- University of Chinese Academy of Sciences, Beijing, P. R. China
| | - Chunling Wang
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, P. R. China
| | - Fuxiang Lai
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, P. R. China
- Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, P. R. China
- University of Chinese Academy of Sciences, Beijing, P. R. China
| | - Runkun Yan
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, P. R. China
- Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, P. R. China
- University of Chinese Academy of Sciences, Beijing, P. R. China
| | - Wuhan Xiao
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, P. R. China
- Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, P. R. China
- University of Chinese Academy of Sciences, Beijing, P. R. China
- Innovation of Seed Design, Chinese Academy of Sciences, Wuhan, P. R. China
| | - Jing Wang
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, P. R. China
- Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, P. R. China
- University of Chinese Academy of Sciences, Beijing, P. R. China
- Innovation of Seed Design, Chinese Academy of Sciences, Wuhan, P. R. China
| |
Collapse
|
13
|
Agrawal R, Pal VK, K S S, Menon GJ, Singh IR, Malhotra N, C S N, Ganesh K, Rajmani RS, Narain Seshasayee AS, Chandra N, Joshi MB, Singh A. Hydrogen sulfide (H2S) coordinates redox balance, carbon metabolism, and mitochondrial bioenergetics to suppress SARS-CoV-2 infection. PLoS Pathog 2025; 21:e1013164. [PMID: 40388397 DOI: 10.1371/journal.ppat.1013164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 04/28/2025] [Indexed: 05/21/2025] Open
Abstract
Viruses modulate various aspects of host physiology, including carbon metabolism, redox balance, and mitochondrial bioenergetics to acquire the building blocks for replication and regulation of the immune response. Understanding how SARS-CoV-2 alters the host metabolism may lead to treatments for COVID-19. We report that a ubiquitous gaseous molecule, hydrogen sulfide (H2S), regulates redox, metabolism, and mitochondrial bioenergetics to control SARS-CoV-2. Virus replication is associated with down-regulation of the H2S-producing enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CTH), and 3-mercaptopyruvate sulfurtransferase (3-MST) in multiple cell lines and nasopharyngeal swabs of symptomatic COVID-19 patients. Consequently, SARS-CoV-2-infected cells showed diminished endogenous H2S levels and a protein modification (S-sulfhydration) caused by H2S. Genetic silencing or chemical inhibition of CTH resulted in SARS-CoV-2 proliferation. Chemical supplementation of H2S using a slow-releasing H2S donor, GYY4137, diminished virus replication. Using a redox biosensor, metabolomics, transcriptomics, and XF-flux analyzer, we showed that GYY4137 blocked SARS-CoV-2 replication by inducing the Nrf2/Keap1 pathway, restoring redox balance and carbon metabolites and potentiating mitochondrial oxidative phosphorylation. Treatment of SARS-CoV-2-infected mice or hamsters with GYY4137 suppressed viral replication and ameliorated lung pathology. GYY4137 treatment reduced the expression of inflammatory cytokines and re-established the expression of Nrf2-dependent antioxidant genes in the lungs of SARS-CoV-2-infected mice. Notably, non-invasive measurement of respiratory functions using unrestrained whole-body plethysmography (uWBP) of SARS-CoV-2-infected mice showed improved pulmonary function variables, including pulmonary obstruction (Penh), end-expiratory pause (EEP), and relaxation time (RT) upon GYY4137 treatment. Together, our findings significantly extend our understanding of H2S-mediated regulation of viral infections and open new avenues for investigating the pathogenic mechanisms and therapeutic opportunities for coronavirus-associated disorders.
Collapse
Affiliation(s)
- Ragini Agrawal
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka, India
- Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, Karnataka, India
- Department of Aging Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Udupi, Karnataka, India
| | - Virender Kumar Pal
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka, India
- Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, Karnataka, India
| | - Suhas K S
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka, India
- Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, Karnataka, India
| | - Gopika Jayan Menon
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka, India
- Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, Karnataka, India
| | - Inder Raj Singh
- National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru, Karnataka, India
| | - Nitish Malhotra
- National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru, Karnataka, India
| | - Naren C S
- Department of Biochemistry, Indian Institute of Science, Bengaluru, Karnataka, India
| | - Kailash Ganesh
- Department of Aging Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Udupi, Karnataka, India
| | - Raju S Rajmani
- Molecular Biophysics Unit, Indian Institute of Science, Bengaluru, Karnataka, India
| | - Aswin Sai Narain Seshasayee
- National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru, Karnataka, India
| | - Nagasuma Chandra
- Department of Biochemistry, Indian Institute of Science, Bengaluru, Karnataka, India
| | - Manjunath B Joshi
- Department of Aging Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Udupi, Karnataka, India
| | - Amit Singh
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka, India
- Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, Karnataka, India
| |
Collapse
|
14
|
Antonello J, Roy P. Damage-Associated Molecular Patterns (DAMPs) In Vascular Diseases. J Biol Chem 2025:110241. [PMID: 40381697 DOI: 10.1016/j.jbc.2025.110241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 05/02/2025] [Accepted: 05/07/2025] [Indexed: 05/20/2025] Open
Abstract
Research into the role of chronic sterile inflammation (i.e. a prolonged inflammatory state not caused by an infectious agent), in vascular disease progression has continued to grow over the last few decades. DAMPs have a critical role in this research due to their ability to link stress-causing cardiovascular risk factors to inflammatory phenotypes seen in vascular disease. In this mini-review, we will briefly summarize the DAMPs and receptor signaling pathways that have been extensively studied in the context of vascular disease, including TLRs, RAGE, cGAS-STING, and the NLRP3 inflammasome. In particular, we will discuss how these pathways can promote the release of pro-inflammatory cytokines and chemokines as well as vascular remodeling. Next, we will summarize the results of studies which have linked the various pro-inflammatory effects of DAMPs with the phenotypes in the context of vascular diseases including atherosclerosis, fibrosis, aneurysm, ischemia, and hypertension. Finally, we will discuss some pre-clinical and clinical trials that have targeted DAMPs, their receptors, or the products of their signaling pathways, and discuss the outlook and future directions for the field at large.
Collapse
Affiliation(s)
| | - Partha Roy
- Bioengineering, University of Pittsburgh; Pathology, University of Pittsburgh.
| |
Collapse
|
15
|
Castillo-Galán S, Grünenwald F, Hidalgo Y, Cárdenas JC, Cadiz MI, Alcayaga-Miranda F, Khoury M, Cuenca J. Mitochondrial Antiviral Signaling Protein Activation by Retinoic Acid-Inducible Gene I Agonist Triggers Potent Antiviral Defense in Umbilical Cord Mesenchymal Stromal Cells Without Compromising Mitochondrial Function. Int J Mol Sci 2025; 26:4686. [PMID: 40429828 PMCID: PMC12111392 DOI: 10.3390/ijms26104686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Revised: 05/02/2025] [Accepted: 05/06/2025] [Indexed: 05/29/2025] Open
Abstract
Mesenchymal stromal cells (MSCs) represent a promising therapeutic approach in viral infection management. However, their interaction with viruses remains poorly understood. MSCs can support antiviral immune responses and act as viral reservoirs, potentially compromising their therapeutic potential. Innate immune system recognition of viral pathogens involves pattern recognition receptors (PRRs), including RIG-I-like receptors (RLRs), which activate mitochondrial antiviral signaling protein (MAVS). MAVS triggers antiviral pathways like IRF3 and NF-κB, leading to interferon (IFN) production and pro-inflammatory responses. This study explores the antiviral response in umbilical cord-derived MSCs (UC-MSCs) through targeted stimulation with influenza A virus-derived 5'triphosphate-RNA (3p-hpRNA), a RIG-I agonist. By investigating MAVS activation, we provide mechanistic insights into the immune response at the molecular level. Our findings reveal that 3p-hpRNA stimulation triggers immune activation of the IRF3 and NF-κB pathways through MAVS. Subsequently, this leads to the induction of type I and III IFNs, IFN-stimulated genes (ISGs), and pro-inflammatory cytokines. Critically, this immune activation occurs without compromising mitochondrial integrity. UC-MSCs retain their capacity for mitochondrial transfer to recipient cells. These results highlight the adaptability of UC-MSCs, offering a nuanced understanding of immune responses balancing activation with metabolic integrity. Finally, our research provides mechanistic evidence for MSC-based interventions against viral infections.
Collapse
Affiliation(s)
- Sebastián Castillo-Galán
- Centro de Investigación e Innovación Biomédica (CIIB), Universidad de los Andes, Santiago 7550000, Chile; (S.C.-G.); (F.G.); (Y.H.); (F.A.-M.); (M.K.)
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago 7550000, Chile
| | - Felipe Grünenwald
- Centro de Investigación e Innovación Biomédica (CIIB), Universidad de los Andes, Santiago 7550000, Chile; (S.C.-G.); (F.G.); (Y.H.); (F.A.-M.); (M.K.)
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago 7550000, Chile
| | - Yessia Hidalgo
- Centro de Investigación e Innovación Biomédica (CIIB), Universidad de los Andes, Santiago 7550000, Chile; (S.C.-G.); (F.G.); (Y.H.); (F.A.-M.); (M.K.)
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago 7550000, Chile
| | - J César Cárdenas
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 750000, Chile;
- Geroscience Center for Brain Health and Metabolism, Santiago 7750000, Chile
- Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93101, USA
| | - Maria Ignacia Cadiz
- Cells for Cells, Santiago 7550000, Chile;
- Consorcio REGENERO, The Chilean Consortium for Regenerative Medicine, Santiago 8330024, Chile
| | - Francisca Alcayaga-Miranda
- Centro de Investigación e Innovación Biomédica (CIIB), Universidad de los Andes, Santiago 7550000, Chile; (S.C.-G.); (F.G.); (Y.H.); (F.A.-M.); (M.K.)
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago 7550000, Chile
- Cells for Cells, Santiago 7550000, Chile;
- Consorcio REGENERO, The Chilean Consortium for Regenerative Medicine, Santiago 8330024, Chile
| | - Maroun Khoury
- Centro de Investigación e Innovación Biomédica (CIIB), Universidad de los Andes, Santiago 7550000, Chile; (S.C.-G.); (F.G.); (Y.H.); (F.A.-M.); (M.K.)
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago 7550000, Chile
- Cells for Cells, Santiago 7550000, Chile;
- Consorcio REGENERO, The Chilean Consortium for Regenerative Medicine, Santiago 8330024, Chile
| | - Jimena Cuenca
- Centro de Investigación e Innovación Biomédica (CIIB), Universidad de los Andes, Santiago 7550000, Chile; (S.C.-G.); (F.G.); (Y.H.); (F.A.-M.); (M.K.)
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago 7550000, Chile
- Cells for Cells, Santiago 7550000, Chile;
- Consorcio REGENERO, The Chilean Consortium for Regenerative Medicine, Santiago 8330024, Chile
| |
Collapse
|
16
|
Huang W, Wang Y, Ji N, Xiao H, Chen K, Guo J, Feng J, Mustafa N, Wang J, Feng H, Zou J. Zebrafish TRIM2a promotes virus replication via ubiquitination of IRF3 and autophagic cargo receptor p62. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025:vkaf064. [PMID: 40359380 DOI: 10.1093/jimmun/vkaf064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 02/24/2025] [Indexed: 05/15/2025]
Abstract
A balanced IFN response, tightly regulated at multiple levels, is essential for host defense against viral infection. Tripartite motif-containing (TRIM) proteins are a large group of E3 ubiquitin ligases, and have been shown to be involved in the regulation of IFN response. However, the regulatory functions of individual TRIM proteins remain controversial. Here, we show that a virus-inducible TRIM2 homolog acts as a negative regulator for IFN production in zebrafish. Zebrafish Trim2a was upregulated in response to spring viremia of carp virus (SVCV) infection, and knockout of Trim2a significantly increased the expression of antiviral genes, leading to enhanced resistance to SVCV. Overexpression of Trim2a resulted in pronounced ubiquitination of IFN regulatory factor 3 (IRF3) via K11, K27, K29, and K48, promoting IRF3 degradation and stability of SVCV phosphoprotein to favor viral replication. Moreover, TRIM2a induced ubiquitination of autophagic cargo receptor p62, which then interacted with IRF3, instigating IRF3 degradation. Further, the inhibitory effects of TRIM2a on IFN production were also observed in human HEK293 cells, suggesting that the regulatory functions of TRIM2 are likely to be conserved during evolution. Collectively, our findings demonstrate that TRIM2a is a negative regulator of IFN production, and could serve as a potential target to dampen exacerbated IFN response triggered by aberrant activation of retinoic acid-inducible gene 1 (RIG-I)-like receptors. Our study provides insights into a previously uncharacterized role of TRIM2 in the regulation of IFN signaling.
Collapse
Affiliation(s)
- Wenji Huang
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China
- Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Yafang Wang
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Ning Ji
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Hehe Xiao
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Kangyong Chen
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Jiahong Guo
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Jianhua Feng
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Nageen Mustafa
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Junya Wang
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Hao Feng
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, China
| | - Jun Zou
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China
- Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, China
| |
Collapse
|
17
|
Giram P, Md Mahabubur Rahman K, Aqel O, You Y. In Situ Cancer Vaccines: Redefining Immune Activation in the Tumor Microenvironment. ACS Biomater Sci Eng 2025; 11:2550-2583. [PMID: 40223683 DOI: 10.1021/acsbiomaterials.5c00121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/15/2025]
Abstract
Cancer is one of the leading causes of mortality worldwide. Nanomedicines have significantly improved life expectancy and survival rates for cancer patients in current standard care. However, recurrence of cancer due to metastasis remains a significant challenge. Vaccines can provide long-term protection and are ideal for preventing bacterial and viral infections. Cancer vaccines, however, have shown limited therapeutic efficacy and raised safety concerns despite extensive research. Cancer vaccines target and stimulate responses against tumor-specific antigens and have demonstrated great potential for cancer treatment in preclinical studies. However, tumor-associated immunosuppression and immune tolerance driven by immunoediting pose significant challenges for vaccine design. In situ vaccination represents an alternative approach to traditional cancer vaccines. This strategy involves the intratumoral administration of immunostimulants to modulate the growth and differentiation of innate immune cells, such as dendritic cells, macrophages, and neutrophils, and restore T-cell activity. Currently approved in situ vaccines, such as T-VEC, have demonstrated clinical promise, while ongoing clinical trials continue to explore novel strategies for broader efficacy. Despite these advancements, failures in vaccine research highlight the need to address tumor-associated immune suppression and immune escape mechanisms. In situ vaccination strategies combine innate and adaptive immune stimulation, leveraging tumor-associated antigens to activate dendritic cells and cross-prime CD8+ T cells. Various vaccine modalities, such as nucleotide-based vaccines (e.g., RNA and DNA vaccines), peptide-based vaccines, and cell-based vaccines (including dendritic, T-cell, and B-cell approaches), show significant potential. Plant-based viral approaches, including cowpea mosaic virus and Newcastle disease virus, further expand the toolkit for in situ vaccination. Therapeutic modalities such as chemotherapy, radiation, photodynamic therapy, photothermal therapy, and Checkpoint blockade inhibitors contribute to enhanced antigen presentation and immune activation. Adjuvants like CpG-ODN and PRR agonists further enhance immune modulation and vaccine efficacy. The advantages of in situ vaccination include patient specificity, personalization, minimized antigen immune escape, and reduced logistical costs. However, significant barriers such as tumor heterogeneity, immune evasion, and logistical challenges remain. This review explores strategies for developing potent cancer vaccines, examines ongoing clinical trials, evaluates immune stimulation methods, and discusses prospects for advancing in situ cancer vaccination.
Collapse
Affiliation(s)
- Prabhanjan Giram
- Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14214, United States
| | - Kazi Md Mahabubur Rahman
- Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14214, United States
| | - Osama Aqel
- Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14214, United States
| | - Youngjae You
- Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14214, United States
| |
Collapse
|
18
|
Dixon LK. Advances in African swine fever virus molecular biology and host interactions contributing to new tools for control. J Virol 2025:e0093224. [PMID: 40340396 DOI: 10.1128/jvi.00932-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2025] Open
Abstract
African swine fever virus (ASFV) causes a frequently fatal hemorrhagic disease in domestic pigs and wild boar. The spread from Africa to Georgia in 2007 initiated a pandemic affecting many European and most Asian countries. This has had a very high socio-economic impact and threatens global food security. The virus is a large, complex, cytoplasmic DNA virus, the only member of the Asfarviridae family and codes for 170-190 proteins. Many of these have unknown functions and do not resemble other viruses or host proteins. This complexity has hindered the development of vaccines and other tools for control. The intensity of research has increased since the spread of ASFV in Europe and Asia, leading to rapid advances in knowledge. This review summarizes recent research, including the determination by cryogenic electron microscopy of the virus capsid structure and virion proteome. Novel information on the virus replication cycle, including mechanisms of virus entry into cells and the identification of host endosomal proteins important for entry, is summarized. Multiple, novel virus immune evasion proteins and their targets in the type I interferon response and inflammation pathways have been identified. The potential for the application of this knowledge to developing novel control tools, including modified live vaccines and other interventions targeting critical virus processes or host interactions, is discussed.
Collapse
Affiliation(s)
- Linda K Dixon
- The Pirbright Institute, Pirbright, Woking, Surrey, United Kingdom
| |
Collapse
|
19
|
Bertram JF, Cullen-McEwen LA, Andrade-Oliveira V, Câmara NOS. The intelligent podocyte: sensing and responding to a complex microenvironment. Nat Rev Nephrol 2025:10.1038/s41581-025-00965-y. [PMID: 40341763 DOI: 10.1038/s41581-025-00965-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2025] [Indexed: 05/11/2025]
Abstract
Podocytes are key components of the glomerular filtration barrier - a specialized structure that is responsible for the filtration of blood by the kidneys. They therefore exist in a unique microenvironment exposed to mechanical force and the myriad molecules that cross the filtration barrier. To survive and thrive, podocytes must continually sense and respond to their ever-changing microenvironment. Sensing is achieved by interactions with the surrounding extracellular matrix and neighbouring cells, through a variety of pathways, to sense changes in environmental factors such as nutrient levels including glucose and lipids, oxygen levels, pH and pressure. The response mechanisms similarly involve a range of processes, including signalling pathways and the actions of specific organelles that initiate and regulate appropriate responses, including alterations in cell metabolism, immune regulation and changes in podocyte structure and cognate functions. These functions ultimately affect glomerular and kidney health. Imbalances in these processes can lead to inflammation, podocyte loss and glomerular disease.
Collapse
Affiliation(s)
- John F Bertram
- Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
- Australian Research Council Training Centre for Cell and Tissue Engineering Technologies, Brisbane, Queensland, Australia
| | - Luise A Cullen-McEwen
- Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Vinicius Andrade-Oliveira
- Center for Natural and Human Sciences, Federal University of ABC, Sao Paulo, Brazil.
- Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
| | | |
Collapse
|
20
|
De Chiara A, Falanga AP, Froechlich G, Borbone N, Campanile A, Pellino E, Piccialli G, Nicosia A, Oliviero G, Sasso E. Peptide nucleic acid-mediated circularization of target RNA as tool to inhibit translation. Int J Biol Macromol 2025; 308:142230. [PMID: 40118420 DOI: 10.1016/j.ijbiomac.2025.142230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 03/12/2025] [Accepted: 03/16/2025] [Indexed: 03/23/2025]
Abstract
Antisense oligonucleotides (ASOs) are short, synthetic sequences designed to specifically target RNA target molecules to modulate their translation and protein expression. To enhance their stability, chemically modified ASOs have been developed. Over the decades, peptide nucleic acids (PNAs) have emerged as powerful tools in molecular biology, proving their ability in gene knockdown, as well as therapeutic or diagnostic applications. In this study, we sought to explore the potential of PNAs to inhibit RNA translation through a novel mechanism of action. To enhance translation inhibition, we designed a new class of PNAs able to mediate target RNA circularization. These PNAs bind the 5' end of the RNA, interacting with CAP and 5'UTR structures, while simultaneously binding to the poly-A tail at the opposite end of the same RNA molecule. Our findings suggest target RNA circularization and inhibition of protein translation across multiple models. We established a dose-dependent effect of the circularizing PNAs on target RNA translation. Overall, our results reveal that this dual-targeting approach strongly inhibits RNA translation compared to binding solely to the 5'UTR, paving the way to the potential development and therapeutic application of this novel class of ASO PNAs.
Collapse
Affiliation(s)
- Arianna De Chiara
- Ceinge-Biotecnologie Avanzate S.c.a.r.l., Via Gaetano Salvatore 486, 80145 Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy
| | - Andrea Patrizia Falanga
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
| | - Guendalina Froechlich
- Ceinge-Biotecnologie Avanzate S.c.a.r.l., Via Gaetano Salvatore 486, 80145 Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy
| | - Nicola Borbone
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
| | - Andrea Campanile
- Ceinge-Biotecnologie Avanzate S.c.a.r.l., Via Gaetano Salvatore 486, 80145 Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy
| | - Emilio Pellino
- Ceinge-Biotecnologie Avanzate S.c.a.r.l., Via Gaetano Salvatore 486, 80145 Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy
| | - Gennaro Piccialli
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
| | - Alfredo Nicosia
- Ceinge-Biotecnologie Avanzate S.c.a.r.l., Via Gaetano Salvatore 486, 80145 Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy; ImGen-T Srl, Viale del Parco Carelli, Napoli, NA, Italy.
| | - Giorgia Oliviero
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy.
| | - Emanuele Sasso
- Ceinge-Biotecnologie Avanzate S.c.a.r.l., Via Gaetano Salvatore 486, 80145 Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy; ImGen-T Srl, Viale del Parco Carelli, Napoli, NA, Italy.
| |
Collapse
|
21
|
Lewash SA, McKenney VR, Wuebben C, Ludwig J, Hosni R, Radzey D, Toma MI, Bartok E, Schlee M, Zillinger T, Heckel A, Hartmann G. Immunoengineering of a Photocaged 5´-triphosphate Oligoribonucleotide Ligand for Spatiotemporal Control of RIG-I Activation in Cancer. Angew Chem Int Ed Engl 2025; 64:e202423321. [PMID: 40095771 PMCID: PMC12087816 DOI: 10.1002/anie.202423321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 02/22/2025] [Accepted: 02/27/2025] [Indexed: 03/19/2025]
Abstract
Photochemical control of oligonucleotides bears great potential for the spatio-temporal control of therapeutic targets, such as immune sensing receptors. Retinoic acid-inducible gene I (RIG-I) is a cytoplasmic receptor of the innate immune system that triggers antiviral responses upon detection of viral RNA. RIG-I can be specifically activated by short double-stranded (ds) RNA with a blunt 5' end bearing a triphosphate, mimicking nascent viral transcripts. Tumor cells are specifically sensitive to RIG-I-induced cell death. Here we developed a potent oligonucleotide ligand for spatiotemporally controlled activation of RIG-I by light exposure. Through structural considerations and functional studies we identified a combination of two nucleoside positions in a RIG-I oligonucleotide ligand for which the substitution of both respective 2'-hydroxy groups of the ribose by photolabile protecting groups (2'-photocages) resulted in a complete loss of RIG-I ligand activity, whereas photocaging the individual positions was not sufficient to turn off RIG-I. Light exposure fully restored RIG-I activation by the photocaged RIG-I ligand, enabling light-controlled RIG-I-mediated cell death of human cancer cells which had internalized the photocaged RIG-I ligand prior to light exposure. This novel photoactivatable RIG-I oligonucleotide ligand may be applicable for precise light-controlled induction of tumor cell death in superficial cancer such as melanoma.
Collapse
Affiliation(s)
- Sandra Anika Lewash
- Institute of Clinical Chemistry and Clinical Pharmacology – Immunology in TranslationUniversity Hospital BonnVenusberg‐Campus 153127BonnGermany
| | - Vivien Rose McKenney
- Institute for Organic Chemistry and Chemical BiologyGoethe University FrankfurtMax‐von‐Laue‐Straße 960438Frankfurt am MainGermany
| | - Christine Wuebben
- Institute of Clinical Chemistry and Clinical Pharmacology – Immunology in TranslationUniversity Hospital BonnVenusberg‐Campus 153127BonnGermany
| | - Janos Ludwig
- Institute of Clinical Chemistry and Clinical Pharmacology – Immunology in TranslationUniversity Hospital BonnVenusberg‐Campus 153127BonnGermany
| | - Racha Hosni
- Institute of PathologyUniversity Hospital BonnVenusberg‐Campus 153127BonnGermany
| | - Dirk Radzey
- Institute of Clinical Chemistry and Clinical Pharmacology – Immunology in TranslationUniversity Hospital BonnVenusberg‐Campus 153127BonnGermany
| | - Marieta I. Toma
- Institute of PathologyUniversity Hospital BonnVenusberg‐Campus 153127BonnGermany
| | - Eva Bartok
- Institute of Experimental Haematology and Transfusion MedicineUniversity Hospital BonnVenusberg‐Campus 153127BonnGermany
| | - Martin Schlee
- Institute of Clinical Chemistry and Clinical Pharmacology – Immunology in TranslationUniversity Hospital BonnVenusberg‐Campus 153127BonnGermany
| | - Thomas Zillinger
- Institute of Clinical Chemistry and Clinical Pharmacology – Immunology in TranslationUniversity Hospital BonnVenusberg‐Campus 153127BonnGermany
- Department of BiomedicineAarhus UniversityHøegh‐Guldbergs Gade 10Aarhus8000Denmark
| | - Alexander Heckel
- Institute for Organic Chemistry and Chemical BiologyGoethe University FrankfurtMax‐von‐Laue‐Straße 960438Frankfurt am MainGermany
| | - Gunther Hartmann
- Institute of Clinical Chemistry and Clinical Pharmacology – Immunology in TranslationUniversity Hospital BonnVenusberg‐Campus 153127BonnGermany
| |
Collapse
|
22
|
Yang H, Qin B, Fu J, Zhang M, Wang H, Xiao T, Lv Z. Nuclear scaffold attachment factor A functions as a potential viral recognition receptor involved in the antiviral immunity of grass carp (Ctenopharyngodon idella). Int J Biol Macromol 2025; 308:142337. [PMID: 40120911 DOI: 10.1016/j.ijbiomac.2025.142337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 12/20/2024] [Accepted: 03/18/2025] [Indexed: 03/25/2025]
Abstract
As one of the most primitive vertebrates, fish have evolved a distinct repertoire of viral recognition receptors. However, the existence of nuclear viral recognition receptors in fish remains uncertain. In this study, we identified a scaffold attachment factor A (SAFA), CiSAFA, as a potential nuclear recognition receptor for grass carp reovirus (GCRV) in grass carp (Ctenopharyngodon idella). CiSAFA shares high amino acid sequence similarity (70.3-99.6 %) and identity (56.1-98.6 %) with its counterparts from other vertebrates and contains three conserved domains, namely, SAP, SPRY, and AAA_33. On the basis of the subcellular location analysis, CiSAFA was found to localize to the nucleus. In vitro, CiSAFA can bind to poly(I:C) and induce interferon (IFN) expression. The expression data revealed that CiSAFA exhibited ubiquitous mRNA expression across all the tissues of grass carp. After GCRV infection, CiSAFA showed significantly upregulated mRNA expression levels and exhibited an expression pattern similar to that of IFN1 in the spleen and head kidney. The results of RNA immunoprecipitation indicated that CiSAFA might interact with dsRNA segment 6 of GCRV. The overexpression of CiSAFA significantly increased the expression levels of several representative antiviral genes, including interferon regulatory factor 3 (IRF3), IRF7, IFN1, and virus-induced gene 1 (GIG1), and inhibited GCRV replication. To our knowledge, this study represents the first discovery of a potential nuclear recognition receptor, CiSAFA, for GCRV in grass carp and reveals its antiviral immune mechanism against GCRV infection, which may provide new insight into host immune recognition system-virus interactions in fish.
Collapse
Affiliation(s)
- Hong Yang
- Fisheries College, Hunan Agricultural University, Changsha 410128, China
| | - Beibei Qin
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Jiaojiao Fu
- Fisheries College, Hunan Agricultural University, Changsha 410128, China
| | - Mengyuan Zhang
- Fisheries College, Hunan Agricultural University, Changsha 410128, China
| | - Hongquan Wang
- Fisheries College, Hunan Agricultural University, Changsha 410128, China; Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha 410128, China
| | - Tiaoyi Xiao
- Fisheries College, Hunan Agricultural University, Changsha 410128, China; Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha 410128, China
| | - Zhao Lv
- Fisheries College, Hunan Agricultural University, Changsha 410128, China; Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha 410128, China.
| |
Collapse
|
23
|
Wang B, Wang Y, Pan T, Zhou L, Ran Y, Zou J, Yan X, Wen Z, Lin S, Ren A, Wang F, Liu Z, Liu T, Lu H, Yang B, Zhou F, Zhang L. Targeting a key disulfide linkage to regulate RIG-I condensation and cytosolic RNA-sensing. Nat Cell Biol 2025; 27:817-834. [PMID: 40229436 DOI: 10.1038/s41556-025-01646-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 02/25/2025] [Indexed: 04/16/2025]
Abstract
Maintaining innate immune homeostasis is critical for preventing infections and autoimmune diseases but effective interventions are lacking. Here we identified C864-C869-mediated intermolecular disulfide-linkage formation as a critical step for human RIG-I activation that can be bidirectionally regulated to control innate immune homeostasis. The viral-stimulated C864-C869 disulfide linkage mediates conjugation of an SDS-resistant RIG-I oligomer, which prevents RIG-I degradation by E3 ubiquitin-ligase MIB2 and is necessary for RIG-I to perform liquid-liquid phase separation to compartmentalize downstream signalsome, thereby stimulating type I interferon signalling. The corresponding C865S 'knock-in' caused an oligomerization defect and liquid-liquid phase separation in mouse RIG-I, which inhibited innate immunity, resulting in increased viral load and mortality in mice. Using unnatural amino acids to generate covalent C864-C869 linkage and the development of an interfering peptide to block C864-C869 residues, we bidirectionally regulated RIG-I activities in human diseases. These findings provide in-depth insights on mechanism of RIG-I activation, allowing for the development of methodologies that hold promising implications in clinics.
Collapse
Affiliation(s)
- Bin Wang
- Department of Radiation Oncology and the State Key Laboratory of Transvascular Implantation Devices, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, The First Affiliated Hospital, Jiangxi Medical College Nanchang University, Nanchang, China
| | - Yongqiang Wang
- Institutes of Biology and Medical Sciences, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, China
| | - Ting Pan
- Shenzhen Key Laboratory of Systems Medicine for Inflammatory Diseases, School of Medicine, Sun Yat-sen University, Shenzhen, China
| | - Lili Zhou
- Institutes of Biology and Medical Sciences, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, China
| | - Yu Ran
- Department of Radiation Oncology and the State Key Laboratory of Transvascular Implantation Devices, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China
- Institutes of Biology and Medical Sciences, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, China
| | - Jing Zou
- Department of Radiation Oncology and the State Key Laboratory of Transvascular Implantation Devices, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Xiaohua Yan
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, The First Affiliated Hospital, Jiangxi Medical College Nanchang University, Nanchang, China
| | - Zhenke Wen
- Institutes of Biology and Medical Sciences, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, China
| | - Shixian Lin
- Department of Radiation Oncology and the State Key Laboratory of Transvascular Implantation Devices, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Aiming Ren
- Department of Radiation Oncology and the State Key Laboratory of Transvascular Implantation Devices, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Fangwei Wang
- Department of Radiation Oncology and the State Key Laboratory of Transvascular Implantation Devices, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Zhuang Liu
- Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Institute of Functional Nano and Soft Materials (FUNSOM), Soochow University, Suzhou, China
| | - Ting Liu
- Departments of Cell Biology and General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Huasong Lu
- Department of Radiation Oncology and the State Key Laboratory of Transvascular Implantation Devices, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Bing Yang
- Department of Radiation Oncology and the State Key Laboratory of Transvascular Implantation Devices, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China.
| | - Fangfang Zhou
- Institutes of Biology and Medical Sciences, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, China.
| | - Long Zhang
- Department of Radiation Oncology and the State Key Laboratory of Transvascular Implantation Devices, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China.
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, The First Affiliated Hospital, Jiangxi Medical College Nanchang University, Nanchang, China.
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, China.
| |
Collapse
|
24
|
Zhou P, Zhang Q, Yang Y, Liu D, Wu W, Jongkaewwattana A, Jin H, Zhou H, Luo R. TRIM14 restricts tembusu virus infection through degrading viral NS1 protein and activating type I interferon signaling. PLoS Pathog 2025; 21:e1013200. [PMID: 40435148 PMCID: PMC12118852 DOI: 10.1371/journal.ppat.1013200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 05/09/2025] [Indexed: 06/01/2025] Open
Abstract
Tembusu virus (TMUV), an emerging avian orthoflavivirus, causes severe economic losses due to egg-drop syndrome and fatal encephalitis in domestic waterfowl. To combat this threat, the host immune system plays a crucial role in controlling and eliminating TMUV infection. Understanding the mechanisms of this immune response is thus vital for developing effective strategies against the virus. In this study, we investigated the antiviral activities of duck TRIM family proteins (duTRIM) against TMUV, focusing particularly on duTRIM14 as a potent host restriction factor. We showed that overexpression of duTRIM14 significantly inhibits TMUV replication, while its deficiency leads to increased viral titers. We elucidate a novel mechanism by which duTRIM14 interacts with the TMUV NS1 protein, facilitating its K27/K29-linked polyubiquitination and subsequent proteasomal degradation. The Lys141 residue on NS1 was identified as critical for this process, with its removal significantly enhancing TMUV replication both in vitro and in vivo. Furthermore, we showed that duTRIM14 interacts with duck TBK1 (duTBK1), promoting its K63-linked polyubiquitination on Lys30 and Lys401, which substantially augments IFN-β production during TMUV infection. Taken together, these results provide a novel dual-action antiviral mechanism in which duTRIM14 suppresses TMUV replication by simultaneously promoting proteasomal degradation of NS1 and enhancing the host antiviral response by modulating duTBK1 activity.
Collapse
Affiliation(s)
- Peng Zhou
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affairs of the People’s Republic of China, Wuhan, China
| | - Qingxiang Zhang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affairs of the People’s Republic of China, Wuhan, China
| | - Yueshan Yang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affairs of the People’s Republic of China, Wuhan, China
| | - Dan Liu
- China Institute of Veterinary Drug Control, Beijing, PR China
| | - Wanrong Wu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affairs of the People’s Republic of China, Wuhan, China
| | - Anan Jongkaewwattana
- Virology and Cell Technology Research Team, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Klong Nueng, Pathum Thani, Thailand
| | - Hui Jin
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affairs of the People’s Republic of China, Wuhan, China
| | - Hongbo Zhou
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affairs of the People’s Republic of China, Wuhan, China
| | - Rui Luo
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affairs of the People’s Republic of China, Wuhan, China
| |
Collapse
|
25
|
Regulation of RIG-I activity by phase separation reveals new therapeutic opportunities. Nat Cell Biol 2025; 27:718-719. [PMID: 40346350 DOI: 10.1038/s41556-025-01656-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/11/2025]
|
26
|
Chen L, Hu L, Chang H, Mao J, Ye M, Jin X. DNA-RNA hybrids in inflammation: sources, immune response, and therapeutic implications. J Mol Med (Berl) 2025; 103:511-529. [PMID: 40131443 DOI: 10.1007/s00109-025-02533-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 03/13/2025] [Accepted: 03/14/2025] [Indexed: 03/27/2025]
Abstract
Cytoplasmic DNA-RNA hybrids are emerging as important immunogenic nucleic acids, that were previously underappreciated. DNA-RNA hybrids, formed during cellular processes like transcription and replication, or by exogenous pathogens, are recognized by pattern recognition receptors (PRRs), including cGAS, DDX41, and TLR9, which trigger immune responses. Post-translational modifications (PTMs) including ubiquitination, phosphorylation, acetylation, and palmitoylation regulate the activity of PRRs and downstream signaling molecules, fine-tuning the immune response. Targeting enzymes involved in DNA-RNA hybrid metabolism and PTMs regulation offers therapeutic potential for inflammatory diseases. Herein, we discuss the sources, immune response, and therapeutic implications of DNA-RNA hybrids in inflammation, highlighting the significance of DNA-RNA hybrids as potential targets for the treatment of inflammation.
Collapse
Affiliation(s)
- Litao Chen
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Lechen Hu
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Han Chang
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Jianing Mao
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Meng Ye
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China.
| | - Xiaofeng Jin
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China.
| |
Collapse
|
27
|
Hong X, Schneider WM, Rice CM. Hepatitis B Virus Nucleocapsid Assembly. J Mol Biol 2025:169182. [PMID: 40316009 DOI: 10.1016/j.jmb.2025.169182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 04/13/2025] [Accepted: 04/28/2025] [Indexed: 05/04/2025]
Abstract
Hepatitis B virus (HBV), the prototypical member of the Hepadnaviridae family, is a DNA virus that replicates its genome through reverse transcription of a pregenomic RNA (pgRNA) precursor. The selective packaging of pgRNA and viral polymerase (Pol) into assembling capsids formed by the viral core protein-a process known as nucleocapsid assembly-is an essential step in the HBV lifecycle. Advances in cellular and cell-free systems have provided significant insights into the mechanisms underlying capsid assembly, Pol binding to pgRNA, Pol-pgRNA packaging, and initiation of genome replication. However, the absence of a cell-free system capable of reconstituting selective HBV Pol-pgRNA packaging into fully assembled capsids leaves fundamental questions about nucleocapsid assembly unanswered. This review summarizes the current knowledge of HBV nucleocapsid assembly, focusing on the interplay between Pol-pgRNA interactions, capsid formation, and regulation by host factors. It also highlights the contribution of cellular and cell-free systems to these discoveries and underscores the need for new approaches that reconstitute the complete HBV nucleocapsid assembly process. With the growing interest in developing nucleocapsid assembly inhibitors, some of which are currently in clinical trials, targeting Pol-pgRNA interactions and nucleocapsid assembly represents a promising therapeutic strategy for curing chronic hepatitis B.
Collapse
Affiliation(s)
- Xupeng Hong
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
| | - William M Schneider
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Charles M Rice
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| |
Collapse
|
28
|
Deng Y, Liang X, Zhao L, Zhou X, Liu J, Li Z, Chen S, Xiao G. Pogostemon cablin Acts as a Key Regulator of NF- κB Signaling and Has a Potent Therapeutic Effect on Intestinal Mucosal Inflammation. Mediators Inflamm 2025; 2025:9000672. [PMID: 40331148 PMCID: PMC12052453 DOI: 10.1155/mi/9000672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 03/29/2025] [Indexed: 05/08/2025] Open
Abstract
Persistent intestinal inflammation is a major contributor to various diseases, including digestive disorders, immune dysregulation, and cancer. The NF-κB signaling pathway is pivotal in the inflammatory response of intestinal cells, regulating the secretion of inflammatory factors, mediating signal transduction, and activating receptors. In colitis, NF-κB signaling and its effector molecules are excessively activated by various stimuli, leading to overexpression of inflammatory mediators and immune regulators. Colitis, an inflammation of the intestinal mucosa, underlies many intestinal diseases, with increasing incidence. Traditional treatments such as glucocorticoids and nonsteroidal antiinflammatory drugs have significant limitations and side effects. Pogostemon cablin, a traditional Chinese medicine and food, is widely used in food, spices, and pharmaceuticals. Studies have demonstrated its positive therapeutic effects on intestinal inflammation, primarily through regulation of the NF-κB signaling pathway. Moreover, P. cablin and its active components exhibit pharmacological activities such as antiapoptotic, antioxidant, and antitumor effects. This review summarizes the original research on treating intestinal mucosal inflammation via NF-κB signaling regulation using P. cablin and its active components, providing new insights for colitis treatment.
Collapse
Affiliation(s)
- Yuqing Deng
- Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Lu zhou 646000, Sichuan, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, Affiliated Traditional Medicine Hospital, Southwest Medical University, Lu Zhou 646000, China
| | - Xin Liang
- Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Lu zhou 646000, Sichuan, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, Affiliated Traditional Medicine Hospital, Southwest Medical University, Lu Zhou 646000, China
| | - Long Zhao
- Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Lu zhou 646000, Sichuan, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, Affiliated Traditional Medicine Hospital, Southwest Medical University, Lu Zhou 646000, China
| | - Xin Zhou
- Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Lu zhou 646000, Sichuan, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, Affiliated Traditional Medicine Hospital, Southwest Medical University, Lu Zhou 646000, China
| | - Jianqin Liu
- Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Lu zhou 646000, Sichuan, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, Affiliated Traditional Medicine Hospital, Southwest Medical University, Lu Zhou 646000, China
| | - Zhi Li
- Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Lu zhou 646000, Sichuan, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, Affiliated Traditional Medicine Hospital, Southwest Medical University, Lu Zhou 646000, China
- School of Integrated Traditional Chinese and Western Clinical Medicine, North Sichuan Medical College, NanChong 637100, Sichuan, China
| | - Shanshan Chen
- Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Lu zhou 646000, Sichuan, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, Affiliated Traditional Medicine Hospital, Southwest Medical University, Lu Zhou 646000, China
| | - Guohui Xiao
- Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Lu zhou 646000, Sichuan, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, Affiliated Traditional Medicine Hospital, Southwest Medical University, Lu Zhou 646000, China
| |
Collapse
|
29
|
Han D, Zhang B, Wang Z, Mi Y. Cell-Autonomous Immunity: From Cytosolic Sensing to Self-Defense. Int J Mol Sci 2025; 26:4025. [PMID: 40362284 PMCID: PMC12071787 DOI: 10.3390/ijms26094025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2025] [Revised: 04/16/2025] [Accepted: 04/22/2025] [Indexed: 05/15/2025] Open
Abstract
As an evolutionarily conserved and ubiquitous mechanism of host defense, non-immune cells in vertebrates possess the intrinsic ability to autonomously detect and combat intracellular pathogens. This process, termed cell-autonomous immunity, is distinct from classical innate immunity. In this review, we comprehensively examine the defense mechanisms employed by non-immune cells in response to intracellular pathogen invasion. We provide a detailed analysis of the cytosolic sensors that recognize aberrant nucleic acids, lipopolysaccharide (LPS), and other pathogen-associated molecular patterns (PAMPs). Specifically, we elucidate the molecular mechanisms underlying key signaling pathways, including the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs)-mitochondrial antiviral signaling (MAVS) axis, and the guanylate-binding proteins (GBPs)-mediated pathway. Furthermore, we critically evaluate the involvement of these pathways in the pathogenesis of various diseases, including autoimmune disorders, inflammatory conditions, and malignancies, while highlighting their potential as therapeutic targets.
Collapse
Affiliation(s)
- Danlin Han
- The First Clinical Medical College, Zhengzhou University, Zhengzhou 450052, China; (D.H.); (B.Z.); (Z.W.)
| | - Bozheng Zhang
- The First Clinical Medical College, Zhengzhou University, Zhengzhou 450052, China; (D.H.); (B.Z.); (Z.W.)
| | - Zhe Wang
- The First Clinical Medical College, Zhengzhou University, Zhengzhou 450052, China; (D.H.); (B.Z.); (Z.W.)
| | - Yang Mi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| |
Collapse
|
30
|
Pandey S, Gack MU. Tearing down the house of mosquito-transmitted viruses. Proc Natl Acad Sci U S A 2025; 122:e2504932122. [PMID: 40228137 PMCID: PMC12037046 DOI: 10.1073/pnas.2504932122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2025] Open
Affiliation(s)
- Shanti Pandey
- Florida Research and Innovation Center, Cleveland Clinic, FL34987
| | - Michaela U. Gack
- Florida Research and Innovation Center, Cleveland Clinic, FL34987
| |
Collapse
|
31
|
Xin X, Wu D, Zhao P, Li Y, Qin H, Dai J, Zhou Y, Lyu Y, Yang Y, Zhu Y, Shi H, Yang L, Yin L. Catch-to-Amplify Nanoparticles with Bacteria Surface for Sequential Mucosal Immune Activation for Acute Myeloid Leukemia Therapy. ACS NANO 2025; 19:14661-14679. [PMID: 40202129 DOI: 10.1021/acsnano.4c08515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/10/2025]
Abstract
Mucosal-mediated immune deficiency is associated with immune evasion and poor clinical outcomes in acute myeloid leukemia (AML). Here, we describe the elicitation of mucosal and systemic immune response by oral delivery of MDP-modified PEG-lipid (MDP-PEG-DSPE) and polylactic acid-polyhistidine (PLA-PHis) copolymer constructed nanosystem (mPOD) into Peyer's patches. To protect against gastrointestinal degradation, enteric-soluble capsules are utilized for encapsulating mPOD to promote penetration across intestinal mucus and engender robust Peyer's patch targeting initiated by MDP-PEG-DSPE. Compared with intravenous and intramuscular administration, the oral delivery of MDP-PEG-DSPE and 5'-triphosphate-modified RNA (ppp-RNA) into gut-associated lymphoid tissues reinforces dendritic cell maturation and migration, amplifies mucosal immune response, and boosts the production of secretory immunoglobulin A via retinoic acid-inducible gene I/nucleotide-binding oligomerization domain 2 (RIG-I/NOD2) signaling activation. In the AML murine model, the provoked mucosal immunity positively regulates the systemic cytotoxic immune reactions, which, in turn, eradicate disseminated malignant leukemic cells and provide defense against leukemia attacks.
Collapse
MESH Headings
- Animals
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/therapy
- Leukemia, Myeloid, Acute/pathology
- Nanoparticles/chemistry
- Mice
- Immunity, Mucosal/drug effects
- Humans
- Mice, Inbred C57BL
- Polyethylene Glycols/chemistry
Collapse
Affiliation(s)
- Xiaofei Xin
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
- NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing 210009, China
| | - Di Wu
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Pengbo Zhao
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Yuanyuan Li
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Huanyu Qin
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Jinyu Dai
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Yong Zhou
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Yifu Lyu
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Yang Yang
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Ying Zhu
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Hang Shi
- Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Lei Yang
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
- NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing 210009, China
| | - Lifang Yin
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
- NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing 210009, China
- Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 210009, China
- State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China
| |
Collapse
|
32
|
Du Q, He W, Chen X, Liu J, Guan M, Chen Y, Chen M, Yuan Y, Zuo Y, Miao Y, Wang Q, Zhou H, Liu Y, Jiang J, Zheng H. Bilirubin metabolism in the liver orchestrates antiviral innate immunity in the body. Cell Rep 2025; 44:115481. [PMID: 40153433 DOI: 10.1016/j.celrep.2025.115481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 02/09/2025] [Accepted: 03/07/2025] [Indexed: 03/30/2025] Open
Abstract
Bilirubin metabolism crucially maintains normal liver function, but whether it contributes to antiviral immunity remains unknown. Here, we reveal that the liver bilirubin metabolic pathway facilitates antiviral innate immunity of the body. We discovered that viral infection upregulates uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) expression in the liver, which in turn stabilizes IRF3 proteins to promote type I interferon (IFN-I) production. Moreover, we found that serum unconjugated bilirubin (UCB), a unique physiological substrate of UGT1A1, can competitively inhibit the binding of IFN-I to IFN-I receptor 2 (IFNAR2), thus attenuating IFN-I-induced antiviral signaling of the body. Accordingly, effective bilirubin metabolism in the liver promotes antiviral immunity of the body by specifically employing liver UGT1A1-mediated enhancement of IFN-I production and reducing serum bilirubin-mediated inhibition of IFN-I signaling. This study uncovers the significance of bilirubin metabolism in antiviral innate immunity and demonstrates that conventional IFN-I therapy is less efficient for patients with hepatitis B virus (HBV) with high levels of bilirubin.
Collapse
Affiliation(s)
- Qian Du
- The First Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences (IBMS), Collaborative Innovation Center of Hematology, MOE Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, School of Medicine, Soochow University, Suzhou, Jiangsu 215123, China
| | - Wei He
- The First Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences (IBMS), Collaborative Innovation Center of Hematology, MOE Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, School of Medicine, Soochow University, Suzhou, Jiangsu 215123, China
| | - Xiangjie Chen
- The First Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences (IBMS), Collaborative Innovation Center of Hematology, MOE Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, School of Medicine, Soochow University, Suzhou, Jiangsu 215123, China
| | - Jin Liu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu 215000, China
| | - Mingcheng Guan
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215123, China
| | - Yichang Chen
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China
| | - Meixia Chen
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China
| | - Yukang Yuan
- The First Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences (IBMS), Collaborative Innovation Center of Hematology, MOE Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, School of Medicine, Soochow University, Suzhou, Jiangsu 215123, China; Department of Laboratory Medicine, Institute of Laboratory Medicine, Translational Clinical Immunology Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 611731, China
| | - Yibo Zuo
- The First Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences (IBMS), Collaborative Innovation Center of Hematology, MOE Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, School of Medicine, Soochow University, Suzhou, Jiangsu 215123, China; Department of Laboratory Medicine, Institute of Laboratory Medicine, Translational Clinical Immunology Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 611731, China
| | - Ying Miao
- The First Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences (IBMS), Collaborative Innovation Center of Hematology, MOE Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, School of Medicine, Soochow University, Suzhou, Jiangsu 215123, China; Department of Laboratory Medicine, Institute of Laboratory Medicine, Translational Clinical Immunology Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 611731, China
| | - Qin Wang
- The First Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences (IBMS), Collaborative Innovation Center of Hematology, MOE Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, School of Medicine, Soochow University, Suzhou, Jiangsu 215123, China; Department of Laboratory Medicine, Institute of Laboratory Medicine, Translational Clinical Immunology Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 611731, China
| | - Haiyan Zhou
- Department of Laboratory Medicine, Institute of Laboratory Medicine, Translational Clinical Immunology Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 611731, China
| | - Yanli Liu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
| | - Jingting Jiang
- Department of Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China.
| | - Hui Zheng
- The First Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences (IBMS), Collaborative Innovation Center of Hematology, MOE Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, School of Medicine, Soochow University, Suzhou, Jiangsu 215123, China; Department of Laboratory Medicine, Institute of Laboratory Medicine, Translational Clinical Immunology Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 611731, China.
| |
Collapse
|
33
|
AlDaif BA, Fleming SB. Innate Immune Sensing of Parapoxvirus Orf Virus and Viral Immune Evasion. Viruses 2025; 17:587. [PMID: 40285029 PMCID: PMC12031380 DOI: 10.3390/v17040587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Revised: 04/14/2025] [Accepted: 04/17/2025] [Indexed: 04/29/2025] Open
Abstract
Orf virus (ORFV) is the type species of Parapoxvirus of the Poxviridae family that induces cutaneous pustular skin lesions in sheep and goats, and causes zoonotic infections in humans. Pattern recognition receptors (PRRs) sense pathogen-associated molecular patterns (PAMPs), leading to the triggering of the innate immune response through multiple signalling pathways involving type I interferons (IFNs). The major PAMPs generated during viral infection are nucleic acids, which are the most important molecules that are recognized by the host. The induction of type l IFNs leads to activation of the Janus kinase (JAK)-signal transducer activator of transcription (STAT) pathway, which results in the induction of hundreds of interferon-stimulated genes (ISGs), many of which encode proteins that have antiviral roles in eliminating virus infection and create an antiviral state. Genetic and functional analyses have revealed that ORFV, as found for other poxviruses, has evolved multiple immunomodulatory genes and strategies that manipulate the innate immune sensing response.
Collapse
Affiliation(s)
| | - Stephen B. Fleming
- Virus Research Unit, Department of Microbiology and Immunology, University of Otago, Dunedin 9016, New Zealand;
| |
Collapse
|
34
|
Zhang T, Pan Y, Sawa T, Akaike T, Matsunaga T. Supersulfide donors and their therapeutic targets in inflammatory diseases. Front Immunol 2025; 16:1581385. [PMID: 40308575 PMCID: PMC12040673 DOI: 10.3389/fimmu.2025.1581385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Accepted: 03/31/2025] [Indexed: 05/02/2025] Open
Abstract
Inflammation is one defense mechanism of the body that has multiple origins, ranging from physical agents to infectious agents including viruses and bacteria. The resolution of inflammation has emerged as a critical endogenous process that protects host tissues from prolonged or excessive inflammation, which can become chronic. Failure of the inflammation resolution is a key pathological mechanism that drives the progression of numerous inflammatory diseases. Owing to the various side effects of currently available drugs to control inflammation, novel therapeutic agents that can prevent or suppress inflammation are needed. Supersulfides are highly reactive and biologically potent molecules that function as antioxidants, redox regulators, and modulators of cell signaling. The catenation state of individual sulfur atoms endows supersulfides with unique biological activities. Great strides have recently been made in achieving a molecular understanding of these sulfur species, which participate in various physiological and pathological pathways. This review mainly focuses on the anti-inflammatory effects of supersulfides. The review starts with an overview of supersulfide biology and highlights the roles of supersulfides in both immune and inflammatory responses. The various donors used to generate supersulfides are assessed as research tools and potential therapeutic agents. Deeper understanding of the molecular and cellular bases of supersulfide-driven biology can help guide the development of innovative therapeutic strategies to prevent and treat diseases associated with various immune and inflammatory responses.
Collapse
Affiliation(s)
- Tianli Zhang
- Center for Integrated Control, Epidemiology and Molecular Pathophysiology of Infectious Diseases, Akita University, Akita, Japan
| | - Yuexuan Pan
- Department of Redox Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomohiro Sawa
- Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Takaaki Akaike
- Department of Redox Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
- Shimadzu × Tohoku University Supersulfides Life Science Co-creation Research Center, Sendai, Japan
| | - Tetsuro Matsunaga
- Center for Integrated Control, Epidemiology and Molecular Pathophysiology of Infectious Diseases, Akita University, Akita, Japan
- Shimadzu × Tohoku University Supersulfides Life Science Co-creation Research Center, Sendai, Japan
| |
Collapse
|
35
|
Wei W, Li H, Tian S, Zhang C, Liu J, Tao W, Cai T, Dong Y, Wang C, Lu D, Ai Y, Zhang W, Wang H, Liu K, Fan Y, Gao Y, Huang Q, Ma X, Wang B, Zhang X, Huang Y. Asparagine drives immune evasion in bladder cancer via RIG-I stability and type I IFN signaling. J Clin Invest 2025; 135:e186648. [PMID: 39964752 PMCID: PMC11996873 DOI: 10.1172/jci186648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 02/07/2025] [Indexed: 02/20/2025] Open
Abstract
Tumor cells often employ many ways to restrain type I IFN signaling to evade immune surveillance. However, whether cellular amino acid metabolism regulates this process remains unclear, and its effects on antitumor immunity are relatively unexplored. Here, we found that asparagine inhibited IFN-I signaling and promoted immune escape in bladder cancer. Depletion of asparagine synthetase (ASNS) strongly limited in vivo tumor growth in a CD8+ T cell-dependent manner and boosted immunotherapy efficacy. Moreover, clinically approved L-asparaginase (ASNase),synergized with anti-PD-1 therapy in suppressing tumor growth. Mechanistically, asparagine can directly bind to RIG-I and facilitate CBL-mediated RIG-I degradation, thereby suppressing IFN signaling and antitumor immune responses. Clinically, tumors with higher ASNS expression show decreased responsiveness to immune checkpoint inhibitor therapy. Together, our findings uncover asparagine as a natural metabolite to modulate RIG-I-mediated IFN-I signaling, providing the basis for developing the combinatorial use of ASNase and anti-PD-1 for bladder cancer.
Collapse
Affiliation(s)
- Wenjie Wei
- Department of Urology, The Third Medical Center and
- Department of Urology Laboratory, Chinese PLA General Hospital, Beijing, China
- Medical School of PLA, Beijing, China
| | - Hongzhao Li
- Department of Urology, The Third Medical Center and
| | - Shuo Tian
- Department of Urology, The Third Medical Center and
- Department of Urology Laboratory, Chinese PLA General Hospital, Beijing, China
- Medical School of PLA, Beijing, China
| | - Chi Zhang
- Department of Urology, The Third Medical Center and
- Department of Urology Laboratory, Chinese PLA General Hospital, Beijing, China
- Medical School of PLA, Beijing, China
| | - Junxiao Liu
- Department of Urology, The Third Medical Center and
- Department of Urology Laboratory, Chinese PLA General Hospital, Beijing, China
- Medical School of PLA, Beijing, China
| | - Wen Tao
- Department of Urology, The Third Medical Center and
- Department of Urology Laboratory, Chinese PLA General Hospital, Beijing, China
- Medical School of PLA, Beijing, China
| | - Tianwei Cai
- Department of Urology, The Third Medical Center and
- Department of Urology Laboratory, Chinese PLA General Hospital, Beijing, China
- Medical School of PLA, Beijing, China
| | - Yuhao Dong
- Department of Urology, The Third Medical Center and
- Department of Urology Laboratory, Chinese PLA General Hospital, Beijing, China
- Medical School of PLA, Beijing, China
| | - Chuang Wang
- Department of Urology, The Third Medical Center and
- Department of Urology Laboratory, Chinese PLA General Hospital, Beijing, China
- Medical School of PLA, Beijing, China
| | - Dingyi Lu
- State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China
| | - Yakun Ai
- Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Wanlin Zhang
- Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Hanfeng Wang
- Department of Urology, The Third Medical Center and
- Department of Urology Laboratory, Chinese PLA General Hospital, Beijing, China
- Medical School of PLA, Beijing, China
| | - Kan Liu
- Department of Urology, The Third Medical Center and
| | - Yang Fan
- Department of Urology, The Third Medical Center and
| | - Yu Gao
- Department of Urology, The Third Medical Center and
| | - Qingbo Huang
- Department of Urology, The Third Medical Center and
| | - Xin Ma
- Department of Urology, The Third Medical Center and
| | - Baojun Wang
- Department of Urology, The Third Medical Center and
| | - Xu Zhang
- Department of Urology, The Third Medical Center and
| | - Yan Huang
- Department of Urology, The Third Medical Center and
- Department of Urology Laboratory, Chinese PLA General Hospital, Beijing, China
| |
Collapse
|
36
|
Yaman Y, Bay V, Kişi YE. Discovery of host genetic factors through multi-locus GWAS against toxoplasmosis in sheep: addressing one health perspectives. BMC Vet Res 2025; 21:263. [PMID: 40221787 PMCID: PMC11992896 DOI: 10.1186/s12917-025-04719-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 03/28/2025] [Indexed: 04/14/2025] Open
Abstract
Toxoplasma gondii stands as one of the most successful pathogens, capable of infecting nearly all warm-blooded species. It is estimated that up to 50% of human population might harbor Toxoplasmosis infections. One of the primary transmission routes is the consumption of tissue cysts from infected farm animals used for food production. Thus, controlling Toxoplasmosis in farm animals is of vital importance for human health and food safety. Selective breeding in farm animals, where available, could complement classical control measures like biosecurity measures, vaccination, and test-and-cull methods. This multidisciplinary approach will make the eradication of Toxoplasmosis more effective. For this purpose, we conducted four multi-locus genome-wide association (GWA) approaches to identify the polygenic factors underlying innate resistance to Toxoplasma gondii in naturally infected sheep. Our findings indicate that 16 single nucleotide polymorphisms (SNPs), exhibiting varying degrees of statistical power, play a significant role in host immunity against T. gondii infection. We propose the genes containing these SNPs or located within 100 ± Kb of them (PLSCR5, EPHA3, DGKB, IL12B, CGA, WDR64, TMEM158, CLMP, and SIAE) as potential candidate genes. This study represents the first exploration of host genetic factors against Toxoplasmosis in livestock, utilizing the ovine paradigm as its foundation.
Collapse
Affiliation(s)
- Yalçın Yaman
- Department of Genetics, Faculty of Veterinary Medicine, Siirt University, Siirt, 56000, Turkey.
| | - Veysel Bay
- Department of Animal Science, Faculty of Agriculture, Ege University, İzmir, 35100, Turkey
| | - Yiğit Emir Kişi
- Sheep Breeding and Research Institute, Bandırma/Balıkesir, 10200, Turkey
| |
Collapse
|
37
|
Gao X, Chen K, Wang H. NicOPURE: nickless RNA circularization and one-step purification with engineered group II introns and cyclizing UTRs. Nucleic Acids Res 2025; 53:gkaf310. [PMID: 40240001 PMCID: PMC12000875 DOI: 10.1093/nar/gkaf310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 03/25/2025] [Accepted: 04/07/2025] [Indexed: 04/18/2025] Open
Abstract
Circular RNAs (circRNAs) have gained significant attention in recent years due to their diverse biological functions and potential as novel therapeutic modality. Two general mechanisms for generating circRNAs involve the utilization of group 1 and group 2 introns, which are self-splicing ribozymes found in many organisms. Although group 1 intron has been demonstrated to be highly effective in circularization, the reaction requires high temperature plus cofactors such as GTP. Consequently, undesired byproducts such as nicked RNA were generated, which requires complex purification steps before downstream applications. In this study, we have strategically designed structural elements and incorporated sequence features to enhance the efficacy of RNA circularization by group 2 introns. This innovative approach occurred at a reduced temperature and resulted in notably fewer nicks compared with group 1 introns. Furthermore, to streamline the purification process of circRNA, we incorporated two halves of streptavidin aptamer tags into the enzymatic sites of the group 2 intron. This strategic architecture guarantees the creation of a fully operational streptavidin aptamer tag solely at the circRNA junction site during in vitro circularization. This unique attribute facilitates a one-step purification process. The resulting "nickless one-step purification of engineered circular messenger RNA" system emerges as both straightforward and efficient in generating therapeutic circular messenger RNAs using simple, scalable in vitro systems.
Collapse
Affiliation(s)
- Xiang Gao
- Advanced Biomedical Pte Ltd, 160 Robinson Road, SBF Center, Singapore 068914, Singapore
| | - Kelei Chen
- N-Lab Technology Center Pte Ltd, 1 International Business Park, The Synergy, Singapore 609917, Singapore
| | - Honglei Wang
- N-Lab Technology Center Pte Ltd, 1 International Business Park, The Synergy, Singapore 609917, Singapore
| |
Collapse
|
38
|
Manivasagam S, Han J, Teghanemt A, Keen H, Sownthirarajan B, Cheng B, Singh A, Lewis A, Vogel OA, Loganathan G, Huang L, Panis M, Meyerholz DK, tenOever B, Perez JT, Manicassamy S, Issuree PD, Manicassamy B. Transcriptional repressor Capicua is a gatekeeper of cell-intrinsic interferon responses. Cell Host Microbe 2025; 33:512-528.e7. [PMID: 40132591 PMCID: PMC11985295 DOI: 10.1016/j.chom.2025.02.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 01/27/2025] [Accepted: 02/27/2025] [Indexed: 03/27/2025]
Abstract
Early detection of viral infection and rapid activation of host antiviral defenses through transcriptional upregulation of interferons (IFNs) and IFN-stimulated genes (ISGs) are critical for controlling infection. However, aberrant production of IFN in the absence of viral infection leads to auto-inflammation and can be detrimental to the host. Here, we show that the DNA-binding transcriptional repressor complex composed of Capicua (CIC) and Ataxin-1 like (ATXN1L) binds to an 8-nucleotide motif near IFN and ISG promoters and prevents erroneous expression of inflammatory genes under homeostasis in humans and mice. By contrast, during respiratory viral infection, activation of the mitogen-activated protein kinase (MAPK) pathway results in rapid degradation of the CIC-ATXN1L complex, thereby relieving repression and allowing for robust induction of IFN and ISGs. Together, our studies define a new paradigm for host regulation of IFN and ISGs through the evolutionarily conserved CIC-ATXN1L transcriptional repressor complex during homeostasis and viral infection.
Collapse
Affiliation(s)
| | - Julianna Han
- Department of Microbiology, University of Chicago, Chicago, IL, USA
| | - Athmane Teghanemt
- Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
| | - Henry Keen
- Bioinformatics Division of the Iowa Institute of Human Genetics, University of Iowa, Iowa City, IA, USA
| | | | - Boyang Cheng
- Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA
| | - Abhiraj Singh
- Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA
| | - Abigail Lewis
- Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA
| | - Olivia A Vogel
- Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA; Department of Microbiology, University of Chicago, Chicago, IL, USA
| | - Gayathri Loganathan
- Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA
| | - Lei Huang
- Center for Research Informatics, The University of Chicago, Chicago, IL 60637, USA
| | - Maryline Panis
- Department of Microbiology, New York University, New York, NY, USA
| | | | | | - Jasmine T Perez
- Department of Microbiology, University of Chicago, Chicago, IL, USA
| | | | - Priya D Issuree
- Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
| | - Balaji Manicassamy
- Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA.
| |
Collapse
|
39
|
Sarkar L, Liu G, Acharya D, Zhu J, Sayyad Z, Gack MU. MDA5 ISGylation is crucial for immune signaling to control viral replication and pathogenesis. Proc Natl Acad Sci U S A 2025; 122:e2420190122. [PMID: 40184173 PMCID: PMC12002354 DOI: 10.1073/pnas.2420190122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 03/06/2025] [Indexed: 04/05/2025] Open
Abstract
The posttranslational modification (PTM) of innate immune sensor proteins by ubiquitin or ubiquitin-like proteins is crucial for regulating antiviral host responses. The cytoplasmic dsRNA receptor melanoma differentiation-associated protein 5 (MDA5) undergoes several PTMs including ISGylation within its first caspase activation and recruitment domain (CARD), which promotes MDA5 signaling. However, the relevance of MDA5 ISGylation for antiviral immunity in an infected organism has been elusive. Here, we generated knock-in mice (MDA5K23R/K43R) in which the two major ISGylation sites, K23 and K43, in MDA5, were mutated. Primary cells derived from MDA5K23R/K43R mice exhibited abrogated endogenous MDA5 ISGylation and an impaired ability of MDA5 to form oligomeric assemblies, leading to blunted cytokine responses to MDA5 RNA-agonist stimulation or infection with encephalomyocarditis virus (EMCV) or West Nile virus. Phenocopying MDA5-/- mice, the MDA5K23R/K43R mice infected with EMCV displayed increased myocardial injury and mortality, elevated viral titers, and an ablated induction of cytokines and chemokines compared to WT mice. Molecular studies identified human HERC5 (and its functional murine homolog HERC6) as the primary E3 ligases responsible for MDA5 ISGylation and activation. Taken together, these findings establish the importance of CARD ISGylation for MDA5-mediated RNA virus restriction, promoting potential avenues for immunomodulatory drug design for antiviral or anti-inflammatory applications.
Collapse
Affiliation(s)
- Lucky Sarkar
- Florida Research and Innovation Center, Cleveland Clinic, Port St. Lucie, FL34987
| | - GuanQun Liu
- Florida Research and Innovation Center, Cleveland Clinic, Port St. Lucie, FL34987
| | - Dhiraj Acharya
- Florida Research and Innovation Center, Cleveland Clinic, Port St. Lucie, FL34987
| | - Junji Zhu
- Florida Research and Innovation Center, Cleveland Clinic, Port St. Lucie, FL34987
| | - Zuberwasim Sayyad
- Florida Research and Innovation Center, Cleveland Clinic, Port St. Lucie, FL34987
| | - Michaela U. Gack
- Florida Research and Innovation Center, Cleveland Clinic, Port St. Lucie, FL34987
| |
Collapse
|
40
|
Elrashedy A, Nayel M, Salama A, Zaghawa A, El-Shabasy RM, Hasan ME. Foot-and-mouth disease: genomic and proteomic structure, antigenic sites, serotype relationships, immune evasion, recent vaccine development strategies, and future perspectives. Vet Res 2025; 56:78. [PMID: 40197411 PMCID: PMC11974090 DOI: 10.1186/s13567-025-01485-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 12/31/2024] [Indexed: 04/10/2025] Open
Abstract
Foot-and-mouth disease (FMD) is a highly contagious and transmissible disease that can have significant economic and trade repercussions during outbreaks. In Egypt, despite efforts to mitigate FMD through mandatory immunization, the disease continues to pose a threat due to the high genetic variability and quasi-species nature of the FMD virus (FMDV). Vaccines have been crucial in preventing and managing FMD, and ongoing research focusses on developing next-generation vaccines that could provide universal protection against all FMDV serotypes. This review thoroughly examines the genetic structure of FMDV, including its polyprotein cleavage process and the roles of its structural and non-structural proteins in immune evasion. Additionally, it explores topics such as antigenic sites, specific mutations, and serotype relationships from Egypt and Ethiopia, as well as the structural changes in FMDV serotypes for vaccine development. The review also addresses the challenges associated with creating effective vaccines for controlling FMD, particularly focusing on the epitope-based vaccine. Overall, this review offers valuable insights for researchers seeking to develop effective strategies and vaccines for controlling FMD.
Collapse
Affiliation(s)
- Alyaa Elrashedy
- Department of Animal Medicine and Infectious Diseases (Infectious Diseases), Faculty of Veterinary Medicine, University of Sadat City, Sadat City, Egypt.
- Faculty of Health Science Technology, Borg Al Arab Technological University (BATU), Alexandria, Egypt.
| | - Mohamed Nayel
- Department of Animal Medicine and Infectious Diseases (Infectious Diseases), Faculty of Veterinary Medicine, University of Sadat City, Sadat City, Egypt
| | - Akram Salama
- Department of Animal Medicine and Infectious Diseases (Infectious Diseases), Faculty of Veterinary Medicine, University of Sadat City, Sadat City, Egypt
| | - Ahmed Zaghawa
- Department of Animal Medicine and Infectious Diseases (Infectious Diseases), Faculty of Veterinary Medicine, University of Sadat City, Sadat City, Egypt
| | - Rehan M El-Shabasy
- Chemistry Department, The American University in Cairo, AUC Avenue, New Cairo, 11835, Egypt
- Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Kom, 32512, Egypt
| | - Mohamed E Hasan
- Faculty of Health Science Technology, Borg Al Arab Technological University (BATU), Alexandria, Egypt
- Bioinformatics Department, Genetic Engineering and Biotechnology Research Institute, University of Sadat City, Sadat City, Egypt
| |
Collapse
|
41
|
Li F, Chan UH, Perez JG, Zeng H, Chau I, Li Y, Seitova A, Halabelian L. ATPase activity profiling of three human DExD/H-box RNA helicases. SLAS DISCOVERY : ADVANCING LIFE SCIENCES R & D 2025; 32:100229. [PMID: 40194700 DOI: 10.1016/j.slasd.2025.100229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/27/2025] [Accepted: 04/05/2025] [Indexed: 04/09/2025]
Abstract
Human DExD/H-box RNA helicases are ubiquitous molecular motors that unwind and rearrange RNA secondary structures in an ATP-dependent manner. These enzymes play essential roles in nearly all aspects of RNA metabolism. While their biological functions are well-characterized, the kinetic mechanisms remain relatively understudied in vitro. In this study, we describe the development and optimization of a bioluminescence-based assay to characterize the ATPase activity of three human RNA helicases: MDA5, LGP2, and DDX1. The assays were conducted using annealed 24-mer ds-RNA (blunt-ended double-stranded RNA) or double-stranded RNA with a 25-nt 3' overhang (partial ds-RNA). These findings establish a robust and high-throughput in vitro assay suitable for a 384-well format, enabling the discovery and characterization of inhibitors targeting MDA5, LGP2, and DDX1. This work provides a valuable resource for advancing our understanding of these helicases and their therapeutic potential in Alzheimer's disease.
Collapse
Affiliation(s)
- Fengling Li
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - U Hang Chan
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Julia Garcia Perez
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Hong Zeng
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Irene Chau
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Yanjun Li
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Almagul Seitova
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Levon Halabelian
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
| |
Collapse
|
42
|
Muhammad I, Contes K, Bility MT, Tang Q. Chasing Virus Replication and Infection: PAMP-PRR Interaction Drives Type I Interferon Production, Which in Turn Activates ISG Expression and ISGylation. Viruses 2025; 17:528. [PMID: 40284971 PMCID: PMC12031425 DOI: 10.3390/v17040528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Accepted: 04/02/2025] [Indexed: 04/29/2025] Open
Abstract
The innate immune response, particularly the interferon-mediated pathway, serves as the first line of defense against viral infections. During virus infection, viral pathogen-associated molecular patterns (PAMPs) are recognized by host pattern recognition receptors (PRRs), triggering downstream signaling pathways. This leads to the activation of transcription factors like IRF3, IRF7, and NF-κB, which translocate to the nucleus and induce the production of type I interferons (IFN-α and IFN-β). Once secreted, type I interferons bind to their receptors (IFNARs) on the surfaces of infected and neighboring cells, activating the JAK-STAT pathway. This results in the formation of the ISGF3 complex (composed of STAT1, STAT2, and IRF9), which translocates to the nucleus and drives the expression of interferon-stimulated genes (ISGs). Some ISGs exert antiviral effects by directly or indirectly blocking infection and replication. Among these ISGs, ISG15 plays a crucial role in the ISGylation process, a ubiquitin-like modification that tags viral and host proteins, regulating immune responses and inhibiting viral replication. However, viruses have evolved counteractive strategies to evade ISG15-mediated immunity and ISGylation. This review first outlines the PAMP-PRR-induced pathways leading to the production of cytokines and ISGs, followed by a summary of ISGylation's role in antiviral defense and viral evasion mechanisms targeting ISG15 and ISGYlation.
Collapse
Affiliation(s)
| | | | | | - Qiyi Tang
- Department of Microbiology, Howard University College of Medicine, Washington, DC 20059, USA; (I.M.); (K.C.); (M.T.B.)
| |
Collapse
|
43
|
Nelson KL, Reil KA, Tsuji S, Parikh AM, Robinson M, House CD, McGuire KL, Giacalone MJ. VAX014 Activates Tumor-Intrinsic STING and RIG-I to Promote the Development of Antitumor Immunity. Mol Cancer Ther 2025; 24:587-604. [PMID: 39868467 PMCID: PMC11962400 DOI: 10.1158/1535-7163.mct-24-0509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 09/06/2024] [Accepted: 01/22/2025] [Indexed: 01/28/2025]
Abstract
In situ immunization (ISI) has emerged as a promising approach to bolster early phases of the cancer immunity cycle through improved T-cell priming. One class of ISI agents, oncolytic viruses (OV), has demonstrated clinical activity, but overall benefit remains limited. Mounting evidence suggests that due to their inherent vulnerability to antiviral effects of type I IFN, OVs have limited activity in solid tumors expressing stimulator of interferon genes (STING) and/or retinoic acid-inducible gene I (RIG-I). Here, using a combination of pharmacologic, genetic, and in vivo approaches, we demonstrate that VAX014, a bacterial minicell-based oncolytic ISI agent, activates both STING and RIG-I and leverages this activity to work best in STING-positive and/or RIG-I-positive tumors. Intratumoral treatment of established syngeneic tumors expressing STING and RIG-I with VAX014 resulted in 100% tumor clearance in two mouse models. Antitumor activity of VAX014 was shown to be dependent on both tumor-intrinsic STING and RIG-I with additive activity stemming from host-intrinsic STING. Analysis of human solid tumor datasets demonstrated STING and RIG-I co-expression is prevalent in solid tumors and associates with clinical benefit in many indications, particularly those most amenable to intratumoral administration. These collective findings differentiate VAX014 from OVs by elucidating the ability of this agent to elicit antitumor activity in STING-positive and/or RIG-I-positive solid tumors and provide evidence that STING/RIG-I agonism is part of VAX014's mechanism of action. Taken together, this work supports the ongoing clinical investigation of VAX014 treatment as an alternative to OV therapy in patients with solid tumors.
Collapse
Affiliation(s)
| | | | | | | | | | - Carrie D. House
- San Diego State University, San Diego, California
- Moores Cancer Center, University of California, San Diego, California
| | | | | |
Collapse
|
44
|
Song Y, Lu J, Qin P, Chen H, Chen L. Interferon-I modulation and natural products: Unraveling mechanisms and therapeutic potential in severe COVID-19. Cytokine Growth Factor Rev 2025; 82:18-30. [PMID: 39261232 DOI: 10.1016/j.cytogfr.2024.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 08/20/2024] [Indexed: 09/13/2024]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose a significant global public health threat, particularly to older adults, pregnant women, and individuals with underlying chronic conditions. Dysregulated immune responses to SARS-CoV-2 infection are believed to contribute to the progression of COVID-19 in severe cases. Previous studies indicates that a deficiency in type I interferon (IFN-I) immunity accounts for approximately 15 %-20 % of patients with severe pneumonia caused by COVID-19, highlighting the potential therapeutic importance of modulating IFN-I signals. Natural products and their derivatives, due to their structural diversity and novel scaffolds, play a crucial role in drug discovery. Some of these natural products targeting IFN-I have demonstrated applications in infectious diseases and inflammatory conditions. However, the immunomodulatory potential of IFN-I in critical COVID-19 pneumonia and the natural compounds regulating the related signal pathway remain not fully understood. In this review, we offer a comprehensive assessment of the association between IFN-I and severe COVID-19, exploring its mechanisms and integrating information on natural compounds effective for IFN-I regulation. Focusing on the primary targets of IFN-I, we also summarize the regulatory mechanisms of natural products, their impact on IFNs, and their therapeutic roles in viral infections. Collectively, by synthesizing these findings, our goal is to provide a valuable reference for future research and to inspire innovative treatment strategies for COVID-19.
Collapse
Affiliation(s)
- Yuheng Song
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jiani Lu
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Pengcheng Qin
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; School of Pharmacy, Henan University, Kaifeng 475001, China
| | - Hongzhuan Chen
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, Fudan University, Shanghai 200032, China
| | - Lili Chen
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| |
Collapse
|
45
|
Yan T, Lu R. Shared and unique mechanisms of RNAi-mediated antiviral immunity in C. elegans. Virology 2025; 605:110459. [PMID: 40022946 PMCID: PMC11970214 DOI: 10.1016/j.virol.2025.110459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/12/2025] [Accepted: 02/20/2025] [Indexed: 03/04/2025]
Abstract
Small interfering RNAs (siRNAs), generated by Dicer proteins, play a pivotal role in antiviral immunity in eukaryotes. Dicer proteins also produce microRNAs (miRNAs), a class of endogenous small non-coding RNAs that regulate essential cellular functions through post-transcriptional mechanisms. In plants and insects, multiple Dicer proteins are produced and deployed to separately manage the biogenesis of antiviral siRNAs and miRNAs. This separation ensures that viral infections, especially the production of viral RNAi suppressors, do not severely compromise host growth or development. In contrast, nematode worms, such as Caenorhabditis elegans, rely on a single Dicer protein to produce both types of small RNAs. Probably as a strategy to mitigate the potential disruption of miRNA production by viral infections, nematodes have evolved distinct strategies for generating primary and secondary siRNAs for antiviral defense. This review explores the shared and unique features of siRNA-mediated antiviral immunity in Caenorhabditis elegans, shedding light on the specialized adaptations that enable robust antiviral defenses without compromising miRNA-mediated function.
Collapse
Affiliation(s)
- Teng Yan
- Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, 70803, USA; Key Laboratory for Northern Urban Agriculture of Ministry of Agriculture and Rural Affairs, Beijing University of Agriculture, Beijing, 102206, China
| | - Rui Lu
- Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, 70803, USA.
| |
Collapse
|
46
|
Tecle E, Warushavithana P, Li S, Blanchard MJ, Chhan CB, Bui T, Underwood RS, Bakowski MA, Troemel ER, Lažetić V. Conserved chromatin regulators control the transcriptional immune response to intracellular pathogens in Caenorhabditis elegans. PLoS Genet 2025; 21:e1011444. [PMID: 40193347 PMCID: PMC11975079 DOI: 10.1371/journal.pgen.1011444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 02/24/2025] [Indexed: 04/09/2025] Open
Abstract
Robust transcriptional responses are critical for defense against infection. However, unrestrained immune responses can cause negative impacts such as damaging inflammation and slowed development. Here, we find that a class of transcriptional regulators previously associated with regulation of development in Caenorhabditis elegans, is also involved in repressing immune responses. Specifically, through forward genetics, we find that loss of lin-15B leads to constitutive expression of Intracellular Pathogen Response (IPR) genes. lin-15B encodes a transcriptional repressor with a conserved THAP domain that is associated with the DRM chromatin remodeling complex that regulates C. elegans development. We show that lin-15B mutants have increased resistance to natural intracellular pathogens, and the induction of IPR genes in lin-15B mutants relies on the MES-4 histone methyltransferase. We extend our analyses to other DRM and NuRD chromatin remodeling factors, as well as SUMOylation histone modifiers, showing that a broad range of chromatin-related factors can repress IPR gene expression. Altogether these findings suggest that conserved chromatin regulators may facilitate development in part by repressing damaging immune responses against intracellular pathogens.
Collapse
Affiliation(s)
- Eillen Tecle
- Department of Cell and Developmental Biology, School of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Paaramitha Warushavithana
- Department of Biological Sciences, Columbian College of Arts and Sciences, The George Washington University, District of Columbia,Washington, United States of America
| | - Samuel Li
- Department of Biological Sciences, Columbian College of Arts and Sciences, The George Washington University, District of Columbia,Washington, United States of America
| | - Michael J. Blanchard
- Department of Cell and Developmental Biology, School of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America
| | - Crystal B. Chhan
- Department of Cell and Developmental Biology, School of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America
| | - Theresa Bui
- Department of Cell and Developmental Biology, School of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America
| | - Ryan S. Underwood
- Department of Cell and Developmental Biology, School of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America
| | - Malina A. Bakowski
- Department of Cell and Developmental Biology, School of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America
| | - Emily R. Troemel
- Department of Cell and Developmental Biology, School of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America
| | - Vladimir Lažetić
- Department of Cell and Developmental Biology, School of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America
- Department of Biological Sciences, Columbian College of Arts and Sciences, The George Washington University, District of Columbia,Washington, United States of America
| |
Collapse
|
47
|
Adams TJ, Schuliga M, Pearce N, Bartlett NW, Liang M. Targeting respiratory virus-induced reactive oxygen species in airways diseases. Eur Respir Rev 2025; 34:240169. [PMID: 40240057 PMCID: PMC12000908 DOI: 10.1183/16000617.0169-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 02/02/2025] [Indexed: 04/18/2025] Open
Abstract
The immune response to virus infection in the respiratory tract must be carefully balanced to achieve pathogen clearance without excessive immunopathology. For chronic respiratory diseases where there is ongoing inflammation, such as in asthma and COPD, airway immune balance is perturbed, and viral infection frequently worsens (exacerbates) these conditions. Reactive oxygen species (ROS) are critical to the induction and propagation of inflammation, and when appropriately regulated, ROS are vital cell signalling molecules and contribute to innate immunity. However, extended periods of high ROS concentration can cause excessive cellular damage that dysregulates antiviral immunity and promotes inflammation. Traditional antioxidant therapeutics have had limited success treating inflammatory diseases such as viral exacerbations of asthma or COPD, owing to nonspecific pharmacology and poorly understood pharmacokinetic properties. These drawbacks could be addressed with novel drug delivery technologies and pharmacological agents. This review summarises current research on ROS imbalances during virus infection, discusses the commercially available mitochondrial antioxidant drugs that have progressed to clinical trial and assesses novel drug delivery approaches for antioxidant delivery to the airways. Additionally, it provides a perspective on future research into pharmacological targeting of ROS for the treatment of respiratory virus infection and disease.
Collapse
Affiliation(s)
- Thomas J Adams
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia
- Infection Research Program, Hunter Medical Research Institute (HMRI), New Lambton Heights, Australia
| | - Michael Schuliga
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia
- Infection Research Program, Hunter Medical Research Institute (HMRI), New Lambton Heights, Australia
| | - Nyoaki Pearce
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia
- Infection Research Program, Hunter Medical Research Institute (HMRI), New Lambton Heights, Australia
| | - Nathan W Bartlett
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia
- Infection Research Program, Hunter Medical Research Institute (HMRI), New Lambton Heights, Australia
| | - Mingtao Liang
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia
| |
Collapse
|
48
|
Acchioni M, Acchioni C, Hiscott J, Sgarbanti M. Origin and function of anti-interferon type I viral proteins. Virology 2025; 605:110456. [PMID: 39999585 DOI: 10.1016/j.virol.2025.110456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 02/17/2025] [Accepted: 02/19/2025] [Indexed: 02/27/2025]
Abstract
Type I interferons (IFN-I) are the most important innate immune cytokines produced by vertebrate host cells following, virus infection. Broadly speaking, detection of infecting viral nucleic acids by pattern recognition receptors (PRR) and subsequent downstream signaling triggers synthesis of a large number of IFN-I-stimulated genes (ISGs), endowed with diverse antiviral effector function. The co-evolution of virus-host interactions over million years has resulted in the emergence of viral strategies that target and inhibit host PRR-mediated detection, signal transduction pathways and IFN-I-mediated stimulation of ISGs. In this review, we illustrate the multiple mechanisms of viral immune evasion and discuss the co-evolution of anti-IFN-I viral proteins by summarizing key examples from recent literature. Due to the large number of anti-IFN-I proteins described, we provide here an evaluation of the prominent examples from different virus families. Understanding the unrelenting evolution of viral evasion strategies will provide mechanistic detail concerning these evolving interactions but will further enhance the development of tailored antiviral approaches.
Collapse
Affiliation(s)
- Marta Acchioni
- Department of Infectious Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
| | - Chiara Acchioni
- Department of Infectious Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
| | - John Hiscott
- Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Viale Regina Elena 291, 00161, Rome, Italy.
| | - Marco Sgarbanti
- Department of Infectious Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
| |
Collapse
|
49
|
Muccilli SG, Schwarz B, Shue B, Jessop F, Shannon JG, Larson CL, Hage A, Hong SH, Bohrnsen E, Hsu T, Ashbrook AW, Sturdevant GL, Robertson SJ, Guarnieri JW, Lack J, Wallace DC, Bosio CM, MacDonald MR, Rice CM, Yewdell JW, Best SM. Mitochondrial hyperactivity and reactive oxygen species drive innate immunity to the yellow fever virus-17D live-attenuated vaccine. PLoS Pathog 2025; 21:e1012561. [PMID: 40258014 PMCID: PMC12052391 DOI: 10.1371/journal.ppat.1012561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 05/05/2025] [Accepted: 03/31/2025] [Indexed: 04/23/2025] Open
Abstract
The yellow fever virus 17D (YFV-17D) live attenuated vaccine is considered one of the most successful vaccines ever generated associated with high antiviral immunity, yet the signaling mechanisms that drive the response in infected cells are not understood. Here, we provide a molecular understanding of how metabolic stress and innate immune responses are linked to drive type I IFN expression in response to YFV-17D infection. Comparison of YFV-17D replication with its parental virus, YFV-Asibi, and a related dengue virus revealed that IFN expression requires RIG-I-Like Receptor signaling through MAVS, as expected. However, YFV-17D uniquely induces mitochondrial respiration and major metabolic perturbations, including hyperactivation of electron transport to fuel ATP synthase. Mitochondrial hyperactivity generates reactive oxygen species (ROS) including peroxynitrite, blocking of which abrogated MAVS oligomerization and IFN expression in non-immune cells without reducing YFV-17D replication. Scavenging ROS in YFV-17D-infected human dendritic cells increased cell viability yet globally prevented expression of IFN signaling pathways. Thus, adaptation of YFV-17D for high growth imparts mitochondrial hyperactivity to meet energy demands, resulting in generation of ROS as the critical messengers that convert a blunted IFN response into maximal activation of innate immunity essential for vaccine effectiveness.
Collapse
Affiliation(s)
- Samantha G. Muccilli
- Innate Immunity and Pathogenesis Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, United States of America
- Cellular Biology Section, Laboratory of Viral Diseases, NIAID, NIH, Bethesda, Maryland, United States of America
| | - Benjamin Schwarz
- Research Technologies Branch, NIAID, NIH, Hamilton, Montana, United States of America
| | - Byron Shue
- Innate Immunity and Pathogenesis Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, United States of America
| | - Forrest Jessop
- Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, NIAID, NIH, Hamilton, Montana, United States of America
| | - Jeffrey G. Shannon
- Innate Immunity and Pathogenesis Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, United States of America
| | - Charles L. Larson
- Innate Immunity and Pathogenesis Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, United States of America
| | - Adam Hage
- Innate Immunity and Pathogenesis Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, United States of America
| | - Seon-Hui Hong
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, United States of America
| | - Eric Bohrnsen
- Research Technologies Branch, NIAID, NIH, Hamilton, Montana, United States of America
| | - Thomas Hsu
- Innate Immunity and Pathogenesis Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, United States of America
| | - Alison W. Ashbrook
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, United States of America
| | - Gail L. Sturdevant
- Innate Immunity and Pathogenesis Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, United States of America
| | - Shelly J. Robertson
- Innate Immunity and Pathogenesis Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, United States of America
| | - Joseph W. Guarnieri
- Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Justin Lack
- Integrated Data Sciences Section, Research Technologies Branch, NIAID, NIH, Bethesda, Maryland, United States of America
| | - Douglas C. Wallace
- Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
- Division on Human Genetics, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Catharine M. Bosio
- Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, NIAID, NIH, Hamilton, Montana, United States of America
| | - Margaret R. MacDonald
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, United States of America
| | - Charles M. Rice
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, United States of America
| | - Jonathan W. Yewdell
- Cellular Biology Section, Laboratory of Viral Diseases, NIAID, NIH, Bethesda, Maryland, United States of America
| | - Sonja M. Best
- Innate Immunity and Pathogenesis Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, United States of America
| |
Collapse
|
50
|
Mukherjee S, Bayry J. The Yin and Yang of TLR4 in COVID-19. Cytokine Growth Factor Rev 2025; 82:70-85. [PMID: 39490235 DOI: 10.1016/j.cytogfr.2024.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 10/03/2024] [Accepted: 10/03/2024] [Indexed: 11/05/2024]
Abstract
Various pattern recognition receptors (PRRs), including toll-like receptors (TLRs), play a crucial role in recognizing invading pathogens as well as damage-associated molecular patterns (DAMPs) released in response to infection. The resulting signaling cascades initiate appropriate immune responses to eliminate these pathogens. Current evidence suggests that SARS-CoV-2-driven activation of TLR4, whether through direct recognition of the spike glycoprotein (alone or in combination with endotoxin) or by sensing various TLR4-activating DAMPs or alarmins released during viral infection, acts as a critical mediator of antiviral immunity. However, TLR4 exerts a dual role in COVID-19, demonstrating both beneficial and deleterious effects. Dysregulated TLR4 signaling is implicated in the proinflammatory consequences linked to the immunopathogenesis of COVID-19. Additionally, TLR4 polymorphisms contribute to severity of the disease. Given its significant immunoregulatory impact on COVID-19 immunopathology and host immunity, TLR4 has emerged as a key target for developing inhibitors and immunotherapeutic strategies to mitigate the adverse effects associated with SARS-CoV-2 and related infections. Furthermore, TLR4 agonists are also being explored as adjuvants to enhance immune responses to SARS-CoV-2 vaccines.
Collapse
Affiliation(s)
- Suprabhat Mukherjee
- Integrative Biochemistry & Immunology Laboratory (IBIL), Department of Animal Science, Kazi Nazrul University, Asansol, West Bengal 713 340, India.
| | - Jagadeesh Bayry
- Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Paris 75006, France; Department of Biological Sciences & Engineering, Indian Institute of Technology Palakkad, Palakkad 678 623, India.
| |
Collapse
|