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Akter D, Biswas J, Moradpour S, Carter MF, Miller MJ, Thiele DJ, Murphy EA, O'Connor CM, Moffat JF, Chan GC. Targeting the host transcription factor HSF1 prevents human cytomegalovirus replication in vitro and in vivo. Antiviral Res 2025; 237:106150. [PMID: 40147538 DOI: 10.1016/j.antiviral.2025.106150] [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: 10/24/2024] [Revised: 03/06/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025]
Abstract
FDA-approved antivirals against HCMV have several limitations, including only targeting the later stages of the viral replication cycle, adverse side effects, and the emergence of drug-resistant strains. Antivirals targeting host factors specifically activated within infected cells and necessary for viral replication could address the current drawbacks of anti-HCMV standard-of-care drugs. In this study, we found HCMV infection stimulated the activation of the stress response transcription factor heat shock transcription factor 1 (HSF1). HCMV entry into fibroblasts rapidly increased HSF1 activity and subsequent relocalization from the cytoplasm to the nucleus, which was maintained throughout viral replication and in contrast to the transient burst of activity induced by canonical heat shock. Prophylactic pharmacological inhibition or genetic depletion of HSF1 prior to HCMV infection attenuated the expression of all classes of viral genes, including immediate early (IE) genes, and virus production, suggesting HSF1 promotes the earliest stages of the viral replication cycle. Therapeutic treatment with SISU-102, an HSF1 inhibitor tool compound, after IE expression also reduced the levels of L proteins and progeny production, suggesting HSF1 regulates multiple steps along the HCMV replication cycle. Leveraging a newly developed human skin xenograft transplant murine model, we found prophylactic treatment with SISU-102 significantly attenuated viral replication in transplanted human skin xenografts as well as viral dissemination to distal sites. These data demonstrate HCMV infection rapidly activates and relocalizes HSF1 to the nucleus to promote viral replication, which can be exploited as a host-directed antiviral strategy.
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Affiliation(s)
- Dilruba Akter
- Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA
| | - Juthi Biswas
- Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA
| | - Shima Moradpour
- Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA
| | - Meghan F Carter
- Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA
| | - Michael J Miller
- Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA
| | | | - Eain A Murphy
- Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA
| | - Christine M O'Connor
- Infection Biology, Lerner Research Institute, Sheikha Fatima bint Mubarak Global Center for Pathogen & Human Health Research, Cleveland Clinic, Cleveland, OH, 44195, USA; Case Comprehensive Cancer Center, Cleveland, OH, 44106, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, 44195, USA
| | - Jennifer F Moffat
- Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA
| | - Gary C Chan
- Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA.
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Alasady MJ, Mendillo ML. The heat shock factor code: Specifying a diversity of transcriptional regulatory programs broadly promoting stress resilience. Cell Stress Chaperones 2024; 29:735-749. [PMID: 39454718 PMCID: PMC11570959 DOI: 10.1016/j.cstres.2024.10.006] [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: 09/05/2024] [Revised: 10/19/2024] [Accepted: 10/19/2024] [Indexed: 10/28/2024] Open
Abstract
The heat shock factor (HSF) family of transcription factors drives gene expression programs that maintain cytosolic protein homeostasis (proteostasis) in response to a vast array of physiological and exogenous stressors. The importance of HSF function has been demonstrated in numerous physiological and pathological contexts. Evidence accumulating over the last two decades has revealed that the regulatory programs driven by the HSF family can vary dramatically depending on the context in which it is activated. To broadly maintain proteostasis across these contexts, HSFs must bind and appropriately regulate the correct target genes at the correct time. Here, we discuss "the heat shock factor code"-our current understanding of how human cells use HSF paralog diversification and interplay, local concentration, post-translational modifications, and interactions with other proteins to enable the functional plasticity required for cellular resilience across a multitude of environments.
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Affiliation(s)
- Milad J Alasady
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Marc L Mendillo
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
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3
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Akter D, Biswas J, Miller MJ, Thiele DJ, Murphy EA, O'Connor CM, Moffat JF, Chan GC. Targeting the host transcription factor HSF1 prevents human cytomegalovirus replication in vitro and in vivo. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.23.614483. [PMID: 39386472 PMCID: PMC11463536 DOI: 10.1101/2024.09.23.614483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
FDA-approved antivirals against HCMV have several limitations, including only targeting the later stages of the viral replication cycle, adverse side effects, and the emergence of drug-resistant strains. Antivirals targeting host factors specifically activated within infected cells and necessary for viral replication could address the current drawbacks of anti-HCMV standard-of-care drugs. In this study, we found HCMV infection stimulated the activation of the stress response transcription factor heat shock transcription factor 1 (HSF1). HCMV entry into fibroblasts rapidly increased HSF1 activity and subsequent relocalization from the cytoplasm to the nucleus, which was maintained throughout viral replication and in contrast to the transient burst of activity induced by canonical heat shock. Prophylactic pharmacological inhibition or genetic depletion of HSF1 prior to HCMV infection attenuated the expression of all classes of viral genes, including immediate early (IE) genes, and virus production, suggesting HSF1 promotes the earliest stages of the viral replication cycle. Therapeutic treatment with SISU-102, an HSF1 inhibitor tool compound, after IE expression also reduced the levels of L proteins and progeny production, suggesting HSF1 regulates multiple steps along the HCMV replication cycle. Leveraging a newly developed human skin xenograft transplant murine model, we found prophylactic treatment with SISU-102 significantly attenuated viral replication in transplanted human skin xenografts as well as viral dissemination to distal sites. These data demonstrate HCMV infection rapidly activates and relocalizes HSF1 to the nucleus to promote viral replication, which can be exploited as a host-directed antiviral strategy. One Sentence Summary Inhibiting of HSF1 as a host-directed antiviral therapy attenuates HCMV replication in vitro and in vivo.
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Alasady MJ, Koeva M, Takagishi SR, Segal D, Amici DR, Smith RS, Ansel DJ, Lindquist S, Whitesell L, Bartom ET, Taipale M, Mendillo ML. An HSF1-JMJD6-HSP feedback circuit promotes cell adaptation to proteotoxic stress. Proc Natl Acad Sci U S A 2024; 121:e2313370121. [PMID: 38985769 PMCID: PMC11260097 DOI: 10.1073/pnas.2313370121] [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: 08/10/2023] [Accepted: 05/10/2024] [Indexed: 07/12/2024] Open
Abstract
Heat Shock Factor 1 (HSF1) is best known as the master transcriptional regulator of the heat-shock response (HSR), a conserved adaptive mechanism critical for protein homeostasis (proteostasis). Combining a genome-wide RNAi library with an HSR reporter, we identified Jumonji domain-containing protein 6 (JMJD6) as an essential mediator of HSF1 activity. In follow-up studies, we found that JMJD6 is itself a noncanonical transcriptional target of HSF1 which acts as a critical regulator of proteostasis. In a positive feedback circuit, HSF1 binds and promotes JMJD6 expression, which in turn reduces heat shock protein 70 (HSP70) R469 monomethylation to disrupt HSP70-HSF1 repressive complexes resulting in enhanced HSF1 activation. Thus, JMJD6 is intricately wired into the proteostasis network where it plays a critical role in cellular adaptation to proteotoxic stress.
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Affiliation(s)
- Milad J. Alasady
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL60611
- Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL60611
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL60611
| | - Martina Koeva
- Whitehead Institute for Biomedical Research, Cambridge, MA02142
- Massachusetts Institute of Technology, Cambridge, MA02142
- HHMI, Cambridge, MA02139
| | - Seesha R. Takagishi
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL60611
- Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL60611
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL60611
| | - Dmitri Segal
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ONM5S 3E1, Canada
| | - David R. Amici
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL60611
- Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL60611
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL60611
| | - Roger S. Smith
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL60611
- Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL60611
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL60611
| | - Daniel J. Ansel
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL60611
- Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL60611
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL60611
| | - Susan Lindquist
- Whitehead Institute for Biomedical Research, Cambridge, MA02142
- Massachusetts Institute of Technology, Cambridge, MA02142
- HHMI, Cambridge, MA02139
| | - Luke Whitesell
- Whitehead Institute for Biomedical Research, Cambridge, MA02142
- Massachusetts Institute of Technology, Cambridge, MA02142
| | - Elizabeth T. Bartom
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL60611
- Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL60611
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL60611
| | - Mikko Taipale
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ONM5S 3E1, Canada
| | - Marc L. Mendillo
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL60611
- Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL60611
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL60611
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Wang XX, Zhang H, Gao J, Wang XW. Ammonia stress-induced heat shock factor 1 enhances white spot syndrome virus infection by targeting the interferon-like system in shrimp. mBio 2024; 15:e0313623. [PMID: 38358252 PMCID: PMC10936208 DOI: 10.1128/mbio.03136-23] [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: 11/21/2023] [Accepted: 01/22/2024] [Indexed: 02/16/2024] Open
Abstract
Disease emergence is the consequence of host-pathogen-environment interactions. Ammonia is a key stress factor in aquatic environments that usually increases the risk of pathogenic diseases in aquatic animals. However, the molecular regulatory mechanisms underlying the enhancement of viral infection following ammonia stress remain largely unknown. Here, we found that ammonia stress enhances white spot syndrome virus infection in kuruma shrimp (Marsupenaeus japonicus) by targeting the antiviral interferon-like system through heat shock factor 1 (Hsf1). Hsf1 is an ammonia-induced transcription factor. It regulates the expression of Cactus and Socs2, which encode negative regulators of NF-κB signaling and Jak/Stat signaling, respectively. By inhibiting these two pathways, ammonia-induced Hsf1 suppressed the production and function of MjVago-L, an arthropod interferon analog. Therefore, this study revealed that Hsf1 is a central regulator of suppressed antiviral immunity after ammonia stress and provides new insights into the molecular regulation of immunity in stressful environments. IMPORTANCE Ammonia is the end product of protein catabolism and is derived from feces and unconsumed foods. It threatens the health and growth of aquatic animals. In this study, we demonstrated that ammonia stress suppresses shrimp antiviral immunity by targeting the shrimp interferon-like system and that heat shock factor 1 (Hsf1) is a central regulator of this process. When shrimp are stressed by ammonia, they activate Hsf1 for stress relief and well-being. Hsf1 upregulates the expression of negative regulators that inhibit the production and function of interferon analogs in shrimp, thereby enhancing white spot syndrome viral infection. Therefore, this study, from a molecular perspective, explains the problem in the aquaculture industry that animals living in stressed environments are more susceptible to pathogens than those living in unstressed conditions. Moreover, this study provides new insights into the side effects of heat shock responses and highlights the complexity of achieving cellular homeostasis under stressful conditions.
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Affiliation(s)
- Xin-Xin Wang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, Shandong, China
| | - Hui Zhang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, Shandong, China
| | - Jie Gao
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, Shandong, China
| | - Xian-Wei Wang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, Shandong, China
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, China
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Shimizu Y, Bandaru S, Hara M, Young S, Sano T, Usami K, Kurano Y, Lee S, Kumagai-Takei N, Takashiba S, Sano S, Ito T. An RNA-immunoprecipitation via CRISPR/dCas13 reveals an interaction between the SARS-CoV-2 5'UTR RNA and the process of human lipid metabolism. Sci Rep 2023; 13:10413. [PMID: 37369697 DOI: 10.1038/s41598-023-36680-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
We herein elucidate the function of SARS-CoV-2derived 5'UTR in the human cells. 5'UTR bound host cellular RNAs were immunoprecipitated by gRNA-dCas13 (targeting luciferase RNA fused to SARS-CoV-2 5'UTR) in HEK293T and A549 cells. The 5'UTR bound RNA extractions were predominantly enriched for regulating lipid metabolism. Overexpression of SARS-CoV-2 5'UTR RNA altered the expression of factors involved in the process of the human Mevalonate pathway. In addition, we found that HMG-CoA reductase inhibitors were shown to suppress SARS-CoV-2 5'UTR-mediated translation activities. In conclusion, we deduce the array of host RNAs interacting with SARS-CoV-2 5'UTR that drives SARS-CoV-2 translation and influences host metabolic pathways.
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Affiliation(s)
- Yurika Shimizu
- Department of Hygiene, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan
- Department of Pathophysiology - Periodontal Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama, 700-8525, Japan
| | - Srinivas Bandaru
- Department of Hygiene, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan
- Koneru Lakshmaiah Educational Foundation, Green Fields, Vaddeswaram, Andhra Pradesh, 522302, India
| | - Mari Hara
- Department of Hygiene, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan
| | - Sonny Young
- Stanford University, Stanford, CA, 94305, USA
| | - Toshikazu Sano
- Department of Surgery, Division of Pediatric Cardiothoracic Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Kaya Usami
- Okayama University Medical School, Okayama, 700-8558, Japan
| | - Yuta Kurano
- Kawasaki Medical School, Kurashiki, Okayama, 701-0192, Japan
| | - Suni Lee
- Department of Hygiene, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan
| | - Naoko Kumagai-Takei
- Department of Hygiene, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan
| | - Shogo Takashiba
- Department of Pathophysiology - Periodontal Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama, 700-8525, Japan
| | - Shunji Sano
- Department of Surgery, Division of Pediatric Cardiothoracic Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Tatsuo Ito
- Department of Hygiene, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
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Al-Kuraishy HM, Al-Gareeb AI, Hetta HF, Alexiou A, Papadakis M, Batiha GES. Heparanase is the possible link between monkeypox and Covid-19: robust candidature in the mystic and present perspective. AMB Express 2023; 13:13. [PMID: 36705773 PMCID: PMC9880376 DOI: 10.1186/s13568-023-01517-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 01/18/2023] [Indexed: 01/28/2023] Open
Abstract
Heparanase (HPSE) is an endoglycosidase cleaves heparan sulfate (HS) and this contributes to the degradation and remodeling of the extracellular matrix. HS cleaved by HPSE induces activation of autophagy and formation of autophagosommes which facilitate binding of HPSE to the HS and subsequent release of growth factors. The interaction between HPSE and HS triggers releases of chemokines and cytokines which affect inflammatory response and cell signaling pathways with development of hyperinflammation, cytokine storm (CS) and coagulopathy. HPSE expression is induced by both SARS-CoV-2 and monkeypox virus (MPXV) leading to induction release of pro-inflammatory cytokines, endothelial dysfunction and thrombotic events. Co-infection of MPX with SARS-CoV-2 may occur as we facing many outbreaks of MPX cases during Covid-19 pandemic. Therefore, targeting of HPSE by specific inhibitors may reduce the risk of complications in both SARS-CoV-2 and MPXV infections. Taken together, HPSE could be a potential link between MPX with SARS-CoV-2 in Covid-19 era.
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Affiliation(s)
- Hayder M. Al-Kuraishy
- Department of Clinical Pharmacology and Therapeutic Medicine, College of Medicine, ALmustansiriyiah University, Baghdad, Iraq
| | - Ali I. Al-Gareeb
- Department of Clinical Pharmacology and Therapeutic Medicine, College of Medicine, ALmustansiriyiah University, Baghdad, Iraq
| | - Helal F. Hetta
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, 71515 Egypt
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW 2770 Australia
- AFNP Med, 1030 Vienna, Austria
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283 Wuppertal, Germany
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, AlBeheira, Damanhour, 22511 Egypt
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Al-Kuraishy HM, Al-Gareeb AI, Hetta HF, Alexiou A, Papadakis M, Batiha GES. Monkeypox epidemic at the door: should we remain idly by or prepare strongly? AMB Express 2023; 13:5. [PMID: 36637577 PMCID: PMC9837758 DOI: 10.1186/s13568-023-01507-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 01/01/2023] [Indexed: 01/14/2023] Open
Abstract
Monkeypox (MPX) is a common zoonotic disease caused by a double-strand DNA MPX virus (MPXV). MPX was considered a sporadic rare disease causing a mild disease with a low capacity to spread among humans. The clinical picture of human MPX highly resembles smallpox, though early lymphadenopathy in human MPX is the distinguishing sign not present in smallpox. The incubation period is 1-3 weeks, and fever, headache, joint pain, myalgia, and nausea for about 3 days. Skin lesions that appear 1-3 days following fever and lymphadenopathy usually appear simultaneously on the face and periphery. By cross-reactivity and protection, the smallpox vaccine produced 85% protection against infection with Orthopoxviruses, including MPX. Antiviral drugs like tecovirimate and brincidofovir could be effective agents against the development of MPX. MPX epidemics are less reported and described as other life-threatening epidemics, leading to an unclear picture of this disease's pathogenesis, epidemiology, and management. With the recent wide range of MPX outbreaks, immense research is mandatory to revise the importance of MPX pathogenesis and risk for epidemic development worldwide. Therefore, this critical study aimed to review MPX's pathogenesis, epidemiology, and management with possible repurposed drugs.
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Affiliation(s)
- Hayder M. Al-Kuraishy
- Department of Clinical Pharmacology and Therapeutic Medicine, College of Medicine, Al-Mustansiriyiah University, Baghdad, Iraq
| | - Ali I. Al-Gareeb
- Department of Clinical Pharmacology and Therapeutic Medicine, College of Medicine, Al-Mustansiriyiah University, Baghdad, Iraq
| | - Helal F. Hetta
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, 71515 Egypt
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW 2770 Australia
- AFNP Med, 1030 Vienna, Austria
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283 Wuppertal, Germany
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, AlBeheira, Damanhûr, 22511 Egypt
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9
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Sohn EJ. Functional Analysis of Monkeypox and Interrelationship between Monkeypox and COVID-19 by Bioinformatic Analysis. Genet Res (Camb) 2023; 2023:8511036. [PMID: 37006463 PMCID: PMC10063359 DOI: 10.1155/2023/8511036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 03/03/2023] [Accepted: 03/15/2023] [Indexed: 04/04/2023] Open
Abstract
The outbreak of monkeypox may be considered a novel and urgent threat after the coronavirus disease (COVID-19). No wide-ranging studies have been conducted on this disease since it was first reported. We systematically assessed the functional role of gene expression in cells infected with the monkeypox virus using transcriptome profiling and compared the functional relation with that of COVID-19. Based on the Gene Expression Omnibus database, we obtained 212 differentially expressed genes (DEGs) of GSE36854 and GSE21001 of monkeypox datasets. Enrichment analyses, including KEGG and gene ontology (GO) analyses, were performed to identify the common function of 212 DEGs of GSE36854 and GSE21001. CytoHubba and Molecular Complex Detection were performed to determine the core genes after a protein-protein interaction (PPI). Metascape/COVID-19 was used to compare DEGs of monkeypox and COVID-19. GO analysis of 212 DEGs of GSE36854 and GSE21001 for monkeypox infection showed cellular response to cytokine stimulus, cell activation, and cell differentiation regulation. KEGG analysis of 212 DEGs of GSE36854 and GSE21001 for monkeypox infection showed involvement of monkeypox in COVID-19, cytokine-cytokine receptor interaction, inflammatory bowel disease, atherosclerosis, TNF signaling, and T cell receptor signaling. By comparing our data with published transcriptome of severe acute respiratory syndrome coronavirus 2 infections in other cell lines, the common function of monkeypox and COVID-19 includes cytokine signaling in the immune system, TNF signaling, and MAPK cascade regulation. Thus, our data suggest that the molecular connections identified between COVID-19 and monkeypox elucidate the causes of monkeypox.
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Affiliation(s)
- Eun Jung Sohn
- College of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
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10
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Tumor Temperature: Friend or Foe of Virus-Based Cancer Immunotherapy. Biomedicines 2022; 10:biomedicines10082024. [PMID: 36009571 PMCID: PMC9405776 DOI: 10.3390/biomedicines10082024] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/16/2022] [Accepted: 08/16/2022] [Indexed: 11/17/2022] Open
Abstract
The temperature of a solid tumor is often dissimilar to baseline body temperature and, compared to healthy tissues, may be elevated, reduced, or a mix of both. The temperature of a tumor is dependent on metabolic activity and vascularization and can change due to tumor progression, treatment, or cancer type. Despite the need to function optimally within temperature-variable tumors, oncolytic viruses (OVs) are primarily tested at 37 °C in vitro. Furthermore, animal species utilized to test oncolytic viruses, such as mice, dogs, cats, and non-human primates, poorly recapitulate the temperature profile of humans. In this review, we discuss the importance of temperature as a variable for OV immunotherapy of solid tumors. Accumulating evidence supports that the temperature sensitivity of OVs lies on a spectrum, with some OVs likely hindered but others enhanced by elevated temperatures. We suggest that in vitro temperature sensitivity screening be performed for all OVs destined for the clinic to identify potential hinderances or benefits with regard to elevated temperature. Furthermore, we provide recommendations for the clinical use of temperature and OVs.
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11
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Reyes A, Navarro AJ, Diethelm-Varela B, Kalergis AM, González PA. Is there a role for HSF1 in viral infections? FEBS Open Bio 2022; 12:1112-1124. [PMID: 35485710 PMCID: PMC9157408 DOI: 10.1002/2211-5463.13419] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 03/29/2022] [Accepted: 04/27/2022] [Indexed: 11/29/2022] Open
Abstract
Cells undergo numerous processes to adapt to new challenging conditions and stressors. Heat stress is regulated by a family of heat shock factors (HSFs) that initiate a heat shock response by upregulating the expression of heat shock proteins (HSPs) intended to counteract cellular damage elicited by increased environmental temperature. Heat shock factor 1 (HSF1) is known as the master regulator of the heat shock response and upon its activation induces the transcription of genes that encode for molecular chaperones, such as HSP40, HSP70, and HSP90. Importantly, an accumulating body of studies relates HSF1 with viral infections; the induction of fever during viral infection may activate HSF1 and trigger a consequent heat shock response. Here, we review the role of HSF1 in different viral infections and its impact on the health outcome for the host. Studying the relationship between HSF1 and viruses could open new potential therapeutic strategies given the availability of drugs that regulate the activation of this transcription factor.
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Affiliation(s)
- Antonia Reyes
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile
| | - Areli J Navarro
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile
| | - Benjamín Diethelm-Varela
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile
| | - Alexis M Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile.,Departamento de Endocrinología, Escuela de Medicina, Facultad de Medicina Pontificia, Universidad Católica de Chile
| | - Pablo A González
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile
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12
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Smith RS, Takagishi SR, Amici DR, Metz K, Gayatri S, Alasady MJ, Wu Y, Brockway S, Taiberg SL, Khalatyan N, Taipale M, Santagata S, Whitesell L, Lindquist S, Savas JN, Mendillo ML. HSF2 cooperates with HSF1 to drive a transcriptional program critical for the malignant state. SCIENCE ADVANCES 2022; 8:eabj6526. [PMID: 35294249 PMCID: PMC8926329 DOI: 10.1126/sciadv.abj6526] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 01/25/2022] [Indexed: 05/14/2023]
Abstract
Heat shock factor 1 (HSF1) is well known for its role in the heat shock response (HSR), where it drives a transcriptional program comprising heat shock protein (HSP) genes, and in tumorigenesis, where it drives a program comprising HSPs and many noncanonical target genes that support malignancy. Here, we find that HSF2, an HSF1 paralog with no substantial role in the HSR, physically and functionally interacts with HSF1 across diverse types of cancer. HSF1 and HSF2 have notably similar chromatin occupancy and regulate a common set of genes that include both HSPs and noncanonical transcriptional targets with roles critical in supporting malignancy. Loss of either HSF1 or HSF2 results in a dysregulated response to nutrient stresses in vitro and reduced tumor progression in cancer cell line xenografts. Together, these findings establish HSF2 as a critical cofactor of HSF1 in driving a cancer cell transcriptional program to support the anabolic malignant state.
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Affiliation(s)
- Roger S. Smith
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Medical Scientist Training Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Seesha R. Takagishi
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Department of Biochemistry and Biophysics, UCSF, San Francisco, CA 94158, USA
- Tetrad Graduate Program, UCSF, San Francisco, CA 94143, USA
| | - David R. Amici
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Medical Scientist Training Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Kyle Metz
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Sitaram Gayatri
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Milad J. Alasady
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Yaqi Wu
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Master of Biotechnology Program, Northwestern University, Evanston, IL 60208, USA
| | - Sonia Brockway
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Stephanie L. Taiberg
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Natalia Khalatyan
- Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Mikko Taipale
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- Molecular Architecture of Life Program, Canadian Institute for Advanced Research (CIFAR), Toronto, ON, Canada
| | - Sandro Santagata
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
- Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA
- Ludwig Center at Harvard, Boston, MA 02115, USA
| | - Luke Whitesell
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Susan Lindquist
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
- Massachusetts Institute of Technology, Cambridge, MA 02142, USA
- Howard Hughes Medical Institute, Cambridge, MA 02139, USA
| | - Jeffrey N. Savas
- Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Marc L. Mendillo
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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13
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Network Theoretical Approach to Explore Factors Affecting Signal Propagation and Stability in Dementia’s Protein-Protein Interaction Network. Biomolecules 2022; 12:biom12030451. [PMID: 35327643 PMCID: PMC8946103 DOI: 10.3390/biom12030451] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 02/13/2022] [Accepted: 02/16/2022] [Indexed: 02/04/2023] Open
Abstract
Dementia—a syndrome affecting human cognition—is a major public health concern given to its rising prevalence worldwide. Though multiple research studies have analyzed disorders such as Alzheimer’s disease and Frontotemporal dementia using a systems biology approach, a similar approach to dementia syndrome as a whole is required. In this study, we try to find the high-impact core regulating processes and factors involved in dementia’s protein–protein interaction network. We also explore various aspects related to its stability and signal propagation. Using gene interaction databases such as STRING and GeneMANIA, a principal dementia network (PDN) consisting of 881 genes and 59,085 interactions was achieved. It was assortative in nature with hierarchical, scale-free topology enriched in various gene ontology (GO) categories and KEGG pathways, such as negative and positive regulation of apoptotic processes, macroautophagy, aging, response to drug, protein binding, etc. Using a clustering algorithm (Louvain method of modularity maximization) iteratively, we found a number of communities at different levels of hierarchy in PDN consisting of 95 “motif-localized hubs”, out of which, 7 were present at deepest level and hence were key regulators (KRs) of PDN (HSP90AA1, HSP90AB1, EGFR, FYN, JUN, CELF2 and CTNNA3). In order to explore aspects of network’s resilience, a knockout (of motif-localized hubs) experiment was carried out. It changed the network’s topology from a hierarchal scale-free topology to scale-free, where independent clusters exhibited greater control. Additionally, network experiments on interaction of druggable genome and motif-localized hubs were carried out where UBC, EGFR, APP, CTNNB1, NTRK1, FN1, HSP90AA1, MDM2, VCP, CTNNA1 and GRB2 were identified as hubs in the resultant network (RN). We finally concluded that stability and resilience of PDN highly relies on motif-localized hubs (especially those present at deeper levels), making them important therapeutic intervention candidates. HSP90AA1, involved in heat shock response (and its master regulator, i.e., HSF1), and EGFR are most important genes in pathology of dementia apart from KRs, given their presence as KRs as well as hubs in RN.
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14
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Amici DR, Jackson JM, Truica MI, Smith RS, Abdulkadir SA, Mendillo ML. FIREWORKS: a bottom-up approach to integrative coessentiality network analysis. Life Sci Alliance 2021; 4:e202000882. [PMID: 33328249 PMCID: PMC7756899 DOI: 10.26508/lsa.202000882] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 12/11/2022] Open
Abstract
Genetic coessentiality analysis, a computational approach which identifies genes sharing a common effect on cell fitness across large-scale screening datasets, has emerged as a powerful tool to identify functional relationships between human genes. However, widespread implementation of coessentiality to study individual genes and pathways is limited by systematic biases in existing coessentiality approaches and accessibility barriers for investigators without computational expertise. We created FIREWORKS, a method and interactive tool for the construction and statistical analysis of coessentiality networks centered around gene(s) provided by the user. FIREWORKS incorporates a novel bias reduction approach to reduce false discoveries, enables restriction of coessentiality analyses to custom subsets of cell lines, and integrates multiomic and drug-gene interaction datasets to investigate and target contextual gene essentiality. We demonstrate the broad utility of FIREWORKS through case vignettes investigating gene function and specialization, indirect therapeutic targeting of "undruggable" proteins, and context-specific rewiring of genetic networks.
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Affiliation(s)
- David R Amici
- Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA
- Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Medical Scientist Training Program, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jasen M Jackson
- Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA
- Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Mihai I Truica
- Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Medical Scientist Training Program, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Roger S Smith
- Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA
- Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Medical Scientist Training Program, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Sarki A Abdulkadir
- Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Marc L Mendillo
- Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA
- Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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15
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Baugh R, Khalique H, Seymour LW. Convergent Evolution by Cancer and Viruses in Evading the NKG2D Immune Response. Cancers (Basel) 2020; 12:E3827. [PMID: 33352921 PMCID: PMC7766243 DOI: 10.3390/cancers12123827] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/11/2020] [Accepted: 12/16/2020] [Indexed: 02/06/2023] Open
Abstract
The natural killer group 2 member D (NKG2D) receptor and its family of NKG2D ligands (NKG2DLs) are key components in the innate immune system, triggering NK, γδ and CD8+ T cell-mediated immune responses. While surface NKG2DL are rarely found on healthy cells, expression is significantly increased in response to various types of cellular stress, viral infection, and tumour cell transformation. In order to evade immune-mediated cytotoxicity, both pathogenic viruses and cancer cells have evolved various mechanisms of subverting immune defences and preventing NKG2DL expression. Comparisons of the mechanisms employed following virus infection or malignant transformation reveal a pattern of converging evolution at many of the key regulatory steps involved in NKG2DL expression and subsequent immune responses. Exploring ways to target these shared steps in virus- and cancer-mediated immune evasion may provide new mechanistic insights and therapeutic opportunities, for example, using oncolytic virotherapy to re-engage the innate immune system towards cancer cells.
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Affiliation(s)
| | | | - Leonard W. Seymour
- Anticancer Viruses and Cancer Vaccines Research Group, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK; (R.B.); (H.K.)
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16
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Alakunle E, Moens U, Nchinda G, Okeke MI. Monkeypox Virus in Nigeria: Infection Biology, Epidemiology, and Evolution. Viruses 2020; 12:E1257. [PMID: 33167496 PMCID: PMC7694534 DOI: 10.3390/v12111257] [Citation(s) in RCA: 415] [Impact Index Per Article: 83.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/22/2020] [Accepted: 10/30/2020] [Indexed: 12/16/2022] Open
Abstract
Monkeypox is a zoonotic disease caused by monkeypox virus (MPXV), which is a member of orthopoxvirus genus. The reemergence of MPXV in 2017 (at Bayelsa state) after 39 years of no reported case in Nigeria, and the export of travelers' monkeypox (MPX) from Nigeria to other parts of the world, in 2018 and 2019, respectively, have raised concern that MPXV may have emerged to occupy the ecological and immunological niche vacated by smallpox virus. This review X-rays the current state of knowledge pertaining the infection biology, epidemiology, and evolution of MPXV in Nigeria and worldwide, especially with regard to the human, cellular, and viral factors that modulate the virus transmission dynamics, infection, and its maintenance in nature. This paper also elucidates the role of recombination, gene loss and gene gain in MPXV evolution, chronicles the role of signaling in MPXV infection, and reviews the current therapeutic options available for the treatment and prevention of MPX. Additionally, genome-wide phylogenetic analysis was undertaken, and we show that MPXV isolates from recent 2017 outbreak in Nigeria were monophyletic with the isolate exported to Israel from Nigeria but do not share the most recent common ancestor with isolates obtained from earlier outbreaks, in 1971 and 1978, respectively. Finally, the review highlighted gaps in knowledge particularly the non-identification of a definitive reservoir host animal for MPXV and proposed future research endeavors to address the unresolved questions.
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Affiliation(s)
- Emmanuel Alakunle
- Department of Natural and Environmental Sciences, Biomedical Science Concentration, School of Arts and Sciences, American University of Nigeria, 98 Lamido Zubairu Way, PMB 2250 Yola, Nigeria;
| | - Ugo Moens
- Molecular Inflammation Research Group, Institute of Medical Biology, University i Tromsø (UIT)—The Arctic University of Norway, N-9037 Tromsø, Norway;
| | - Godwin Nchinda
- Laboratory of Vaccinology and Immunology, The Chantal Biya International Reference Center for Research on the Prevention and Management HIV/AIDS (CIRCB), P.O Box 3077 Yaoundé-Messa, Cameroon;
- Department of Pharmaceutical Microbiology & Biotechnology, Faculty of Pharmaceutical Sciences, Nnamdi Azikiwe University, P.O Box 420110 Awka, Nigeria
| | - Malachy Ifeanyi Okeke
- Department of Natural and Environmental Sciences, Biomedical Science Concentration, School of Arts and Sciences, American University of Nigeria, 98 Lamido Zubairu Way, PMB 2250 Yola, Nigeria;
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17
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Cai W, Zhou W, Han Z, Lei J, Zhuang J, Zhu P, Wu X, Yuan W. Master regulator genes and their impact on major diseases. PeerJ 2020; 8:e9952. [PMID: 33083114 PMCID: PMC7546222 DOI: 10.7717/peerj.9952] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 08/25/2020] [Indexed: 01/10/2023] Open
Abstract
Master regulator genes (MRGs) have become a hot topic in recent decades. They not only affect the development of tissue and organ systems but also play a role in other signal pathways by regulating additional MRGs. Because a MRG can regulate the concurrent expression of several genes, its mutation often leads to major diseases. Moreover, the occurrence of many tumors and cardiovascular and nervous system diseases are closely related to MRG changes. With the development in omics technology, an increasing amount of investigations will be directed toward MRGs because their regulation involves all aspects of an organism’s development. This review focuses on the definition and classification of MRGs as well as their influence on disease regulation.
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Affiliation(s)
- Wanwan Cai
- The Center for Heart Development, State Key Laboratory of Development Biology of Freshwater Fish, Key Laboratory of MOE for Development Biology and Protein Chemistry, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
| | - Wanbang Zhou
- College of Physical Education, Hunan Normal University, Changsha, Hunan, China
| | - Zhe Han
- University of Maryland School of Medicine, Center for Precision Disease Modeling, Baltimore, MD, USA
| | - Junrong Lei
- College of Physical Education, Hunan Normal University, Changsha, Hunan, China
| | - Jian Zhuang
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Department of Cardiac Surgery, Guangzhou, Guangdong, China
| | - Ping Zhu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Department of Cardiac Surgery, Guangzhou, Guangdong, China
| | - Xiushan Wu
- The Center for Heart Development, State Key Laboratory of Development Biology of Freshwater Fish, Key Laboratory of MOE for Development Biology and Protein Chemistry, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
| | - Wuzhou Yuan
- The Center for Heart Development, State Key Laboratory of Development Biology of Freshwater Fish, Key Laboratory of MOE for Development Biology and Protein Chemistry, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
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18
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Sood A, Sui Y, McDonough E, Santamaría-Pang A, Al-Kofahi Y, Pang Z, Jahrling PB, Kuhn JH, Ginty F. Comparison of Multiplexed Immunofluorescence Imaging to Chromogenic Immunohistochemistry of Skin Biomarkers in Response to Monkeypox Virus Infection. Viruses 2020; 12:E787. [PMID: 32717786 PMCID: PMC7472296 DOI: 10.3390/v12080787] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 07/15/2020] [Accepted: 07/19/2020] [Indexed: 12/17/2022] Open
Abstract
Over the last 15 years, advances in immunofluorescence-imaging based cycling methods, antibody conjugation methods, and automated image processing have facilitated the development of a high-resolution, multiplexed tissue immunofluorescence (MxIF) method with single cell-level quantitation termed Cell DIVETM. Originally developed for fixed oncology samples, here it was evaluated in highly fixed (up to 30 days), archived monkeypox virus-induced inflammatory skin lesions from a retrospective study in 11 rhesus monkeys to determine whether MxIF was comparable to manual H-scoring of chromogenic stains. Six protein markers related to immune and cellular response (CD68, CD3, Hsp70, Hsp90, ERK1/2, ERK1/2 pT202_pY204) were manually quantified (H-scores) by a pathologist from chromogenic IHC double stains on serial sections and compared to MxIF automated single cell quantification of the same markers that were multiplexed on a single tissue section. Overall, there was directional consistency between the H-score and the MxIF results for all markers except phosphorylated ERK1/2 (ERK1/2 pT202_pY204), which showed a decrease in the lesion compared to the adjacent non-lesioned skin by MxIF vs an increase via H-score. Improvements to automated segmentation using machine learning and adding additional cell markers for cell viability are future options for improvement. This method could be useful in infectious disease research as it conserves tissue, provides marker colocalization data on thousands of cells, allowing further cell level data mining as well as a reduction in user bias.
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Affiliation(s)
- Anup Sood
- GE Research, 1 Research Circle, Niskayuna, NY 12309, USA; (A.S.); (Y.S.); (E.M.); (A.S.-P.); (Y.A.-K.); (Z.P.)
| | - Yunxia Sui
- GE Research, 1 Research Circle, Niskayuna, NY 12309, USA; (A.S.); (Y.S.); (E.M.); (A.S.-P.); (Y.A.-K.); (Z.P.)
| | - Elizabeth McDonough
- GE Research, 1 Research Circle, Niskayuna, NY 12309, USA; (A.S.); (Y.S.); (E.M.); (A.S.-P.); (Y.A.-K.); (Z.P.)
| | - Alberto Santamaría-Pang
- GE Research, 1 Research Circle, Niskayuna, NY 12309, USA; (A.S.); (Y.S.); (E.M.); (A.S.-P.); (Y.A.-K.); (Z.P.)
| | - Yousef Al-Kofahi
- GE Research, 1 Research Circle, Niskayuna, NY 12309, USA; (A.S.); (Y.S.); (E.M.); (A.S.-P.); (Y.A.-K.); (Z.P.)
| | - Zhengyu Pang
- GE Research, 1 Research Circle, Niskayuna, NY 12309, USA; (A.S.); (Y.S.); (E.M.); (A.S.-P.); (Y.A.-K.); (Z.P.)
| | - Peter B. Jahrling
- Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, B-8200 Research Plaza, Frederick, MD 21702, USA;
| | - Jens H. Kuhn
- Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, B-8200 Research Plaza, Frederick, MD 21702, USA;
| | - Fiona Ginty
- GE Research, 1 Research Circle, Niskayuna, NY 12309, USA; (A.S.); (Y.S.); (E.M.); (A.S.-P.); (Y.A.-K.); (Z.P.)
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19
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Nekongo EE, Ponomarenko AI, Dewal MB, Butty VL, Browne EP, Shoulders MD. HSF1 Activation Can Restrict HIV Replication. ACS Infect Dis 2020; 6:1659-1666. [PMID: 32502335 DOI: 10.1021/acsinfecdis.0c00166] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Host protein folding stress responses can play important roles in RNA virus replication and evolution. Prior work suggested a complicated interplay between the cytosolic proteostasis stress response, controlled by the transcriptional master regulator heat shock factor 1 (HSF1), and human immunodeficiency virus-1 (HIV-1). We sought to uncouple HSF1 transcription factor activity from cytotoxic proteostasis stress and thereby better elucidate the proposed role(s) of HSF1 in the HIV-1 lifecycle. To achieve this objective, we used chemical genetic, stress-independent control of HSF1 activity to establish whether and how HSF1 influences HIV-1 replication. Stress-independent HSF1 induction decreased both the total quantity and infectivity of HIV-1 virions. Moreover, HIV-1 was unable to escape HSF1-mediated restriction over the course of several serial passages. These results clarify the interplay between the host's heat shock response and HIV-1 infection and motivate continued investigation of chaperones as potential antiviral therapeutic targets.
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Affiliation(s)
- Emmanuel E. Nekongo
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Anna I. Ponomarenko
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Mahender B. Dewal
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Vincent L. Butty
- BioMicro Center, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Edward P. Browne
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27516, United States
| | - Matthew D. Shoulders
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
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20
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Alasady MJ, Mendillo ML. The Multifaceted Role of HSF1 in Tumorigenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1243:69-85. [PMID: 32297212 DOI: 10.1007/978-3-030-40204-4_5] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Heat Shock Factor 1 (HSF1), the master transcriptional regulator of the heat shock response (HSR), was first cloned more than 30 years ago. Most early research interrogating the role that HSF1 plays in biology focused on its cytoprotective functions, as a factor that promotes the survival of organisms by protecting against the proteotoxicity associated with neurodegeneration and other pathological conditions. However, recent studies have revealed a deleterious role of HSF1, as a factor that is co-opted by cancer cells to promote their own survival to the detriment of the organism. In cancer, HSF1 operates in a multifaceted manner to promote oncogenic transformation, proliferation, metastatic dissemination, and anti-cancer drug resistance. Here we review our current understanding of HSF1 activation and function in malignant progression and discuss the potential for HSF1 inhibition as a novel anticancer strategy. Collectively, this ever-growing body of work points to a prominent role of HSF1 in nearly every aspect of carcinogenesis.
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Affiliation(s)
- Milad J Alasady
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.,Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Marc L Mendillo
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. .,Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. .,Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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21
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Ceccin ADF, Souza APD, Hilário GT, Muller DM, Romão PRT, Rodrigues Junior LC. HspBP1 and anti-HspBP1 levels in the serum of HIV-infected individuals are associated to the disease progression. J Appl Microbiol 2019; 127:576-585. [PMID: 30786116 DOI: 10.1111/jam.14230] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 01/16/2019] [Accepted: 02/06/2019] [Indexed: 12/24/2022]
Abstract
AIMS The objective of this research was to quantify the levels of circulating HspBP1 and anti-HspBP1 IgG in HIV-infected individuals and to correlate them with CD4 T cell counts and viral load, as well as to determine the kinetics of those proteins during acute phase. METHODS AND RESULTS Sixty serum samples from HIV-positive outpatients, thirty with high viral load and thirty with low viral load were analysed. The HspBP1 and anti-HspBP1 were quantified by ELISA. To investigate the kinetic of HspBP1 and anti-HspBp1 during the acute phase, these proteins and antibodies were quantified in samples of a commercial seroconverting HIV panel. All dosages were compared with the CD4 and CD8 T cell counts and HIV viral load. The results indicated that HIV positive outpatients presented significant increase in HspBP1 and anti-HspBP1 serum levels, compared with uninfected healthy. HspBP1 and anti-HspBP1 were negatively correlated with CD4 counts and CD4:CD8 ratio. In the acute phase, HspBP1 became significantly elevated 15 days after HIV infection. CONCLUSIONS These results indicate that the quantification of HspBP1 can be associated to others well-established parameters of the HIV progression. SIGNIFICANCE AND IMPACT OF THE STUDY The discovery that HspBp1 and anti-HspBp1 are associated with progression of HIV infection is new and corroborates to validate the quantification of these proteins as an additional strategy in the management of the HIV infection.
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Affiliation(s)
- A D F Ceccin
- Hemocenter of Santa Maria - Alameda Santiago de Chile Avenue, Santa Maria, RS, Brazil
| | - A P D Souza
- Laboratório de Imunologia Clínica e Experimental, Escola de Ciências. Pontifícia Universidade Católica do Rio Grande do Sul. Av. Ipiranga, Porto Alegre, RS, Brazil
| | - G T Hilário
- Laboratório de Imunologia, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA). Av. Sarmento Leite, 245, Porto Alegre, RS, Brazil
| | - D M Muller
- Laboratório de Imunologia, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA). Av. Sarmento Leite, 245, Porto Alegre, RS, Brazil
| | - P R T Romão
- Laboratório de Imunologia, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA). Av. Sarmento Leite, 245, Porto Alegre, RS, Brazil
| | - L C Rodrigues Junior
- Laboratório de Imunologia, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA). Av. Sarmento Leite, 245, Porto Alegre, RS, Brazil
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22
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Joutsen J, Sistonen L. Tailoring of Proteostasis Networks with Heat Shock Factors. Cold Spring Harb Perspect Biol 2019; 11:cshperspect.a034066. [PMID: 30420555 DOI: 10.1101/cshperspect.a034066] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Heat shock factors (HSFs) are the main transcriptional regulators of the heat shock response and indispensable for maintaining cellular proteostasis. HSFs mediate their protective functions through diverse genetic programs, which are composed of genes encoding molecular chaperones and other genes crucial for cell survival. The mechanisms that are used to tailor HSF-driven proteostasis networks are not yet completely understood, but they likely comprise from distinct combinations of both genetic and proteomic determinants. In this review, we highlight the versatile HSF-mediated cellular functions that extend from cellular stress responses to various physiological and pathological processes, and we underline the key advancements that have been achieved in the field of HSF research during the last decade.
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Affiliation(s)
- Jenny Joutsen
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, 20520 Turku, Finland.,Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland
| | - Lea Sistonen
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, 20520 Turku, Finland.,Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland
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23
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Cheng W, Jia H, Wang X, He X, Jin Q, Cao J, Jing Z. Ectromelia virus upregulates the expression of heat shock protein�70 to promote viral replication. Int J Mol Med 2018; 42:1044-1053. [DOI: 10.3892/ijmm.2018.3655] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 04/26/2018] [Indexed: 11/05/2022] Open
Affiliation(s)
- Wenyu Cheng
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu�730046, P.R.�China
| | - Huaijie Jia
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, P.R. China
| | - Xiaoxia Wang
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, P.R. China
| | - Xiaobing He
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, P.R. China
| | - Qiwang Jin
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, P.R. China
| | - Jingxin Cao
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB�R3E 3R2, Canada
| | - Zhizhong Jing
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, P.R. China
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24
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Pan X, Lin J, Zeng X, Li W, Wu W, Lu WZ, Liu J, Liu S. Heat shock factor 1 suppresses the HIV-induced inflammatory response by inhibiting nuclear factor-κB. Cell Immunol 2018. [PMID: 29525181 DOI: 10.1016/j.cellimm.2018.01.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The persistent inflammation aggravated by a disordered immune response is considered to be the major cause of CD4+ T cell depletion in lymphoid tissue, which impels the progression of AIDS. Here, we report that heat shock factor 1 (HSF1) works as an innate repressor of HIV-induced inflammation. The activation of HSF1 was found to accompany inflammation during HIV infection. Further research uncovered that HSF1 activation inhibited HIV-induced inflammation. In addition, HSF1 overexpression suppressed the inflammatory response induced by HIV, while HSF1 deficiency exacerbated that inflammation. Mechanistically, HSF1 was found to compete with nuclear factor-κB (NF-κB) in the nucleus. Generally, our report highlights that HSF1 is an important host factor in regulating HIV-induced inflammation and may work as a potential target for curing AIDS.
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Affiliation(s)
- Xiaoyan Pan
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Science, Wuhan 430071, China; Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jian Lin
- Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Xiaoyun Zeng
- Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Wenjuan Li
- Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Wenjiao Wu
- Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
| | - Wan Zhen Lu
- Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jing Liu
- Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
| | - Shuwen Liu
- Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou 510515, China.
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25
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Cheng WY, Jia HJ, He XB, Chen GH, Feng Y, Wang CY, Wang XX, Jing ZZ. Comparison of Host Gene Expression Profiles in Spleen Tissues of Genetically Susceptible and Resistant Mice during ECTV Infection. BIOMED RESEARCH INTERNATIONAL 2017; 2017:6456180. [PMID: 29430463 PMCID: PMC5752998 DOI: 10.1155/2017/6456180] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 10/19/2017] [Accepted: 11/22/2017] [Indexed: 12/31/2022]
Abstract
Ectromelia virus (ECTV), the causative agent of mousepox, has emerged as a valuable model for investigating the host-Orthopoxvirus relationship as it relates to pathogenesis and the immune response. ECTV is a mouse-specific virus and causes high mortality in susceptible mice strains, including BALB/c and C3H, whereas C57BL/6 and 129 strains are resistant to the disease. To understand the host genetic factors in different mouse strains during the ECTV infection, we carried out a microarray analysis of spleen tissues derived from BALB/c and C57BL/6 mice, respectively, at 3 and 10 days after ECTV infection. Differential Expression of Genes (DEGs) analyses revealed distinct differences in the gene profiles of susceptible and resistant mice. The susceptible BALB/c mice generated more DEGs than the resistant C57BL/6 mice. Additionally, gene ontology and KEGG pathway analysis showed the DEGs of susceptible mice were involved in innate immunity, apoptosis, metabolism, and cancer-related pathways, while the DEGs of resistant mice were largely involved in MAPK signaling and leukocyte transendothelial migration. Furthermore, the BALB/c mice showed a strong induction of interferon-induced genes, which, however, were weaker in the C57BL/6 mice. Collectively, the differential transcriptome profiles of susceptible and resistant mouse strains with ECTV infection will be crucial for further uncovering the molecular mechanisms of the host-Orthopoxvirus interaction.
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Affiliation(s)
- Wen-Yu Cheng
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, China
| | - Huai-Jie Jia
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, China
| | - Xiao-Bing He
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, China
| | - Guo-Hua Chen
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, China
| | - Yuan Feng
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, China
| | - Chun-Yan Wang
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, China
| | - Xiao-Xia Wang
- School of Public Health, Lanzhou University, Lanzhou 730000, China
| | - Zhi-Zhong Jing
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, China
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26
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Wang Y, Jin F, Wang R, Li F, Wu Y, Kitazato K, Wang Y. HSP90: a promising broad-spectrum antiviral drug target. Arch Virol 2017; 162:3269-3282. [PMID: 28780632 DOI: 10.1007/s00705-017-3511-1] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2017] [Accepted: 06/27/2017] [Indexed: 12/13/2022]
Abstract
The emergence of antiviral drug-resistant mutants is the most important issue in current antiviral therapy. As obligate parasites, viruses require host factors for efficient replication. An ideal therapeutic target to prevent drug-resistance development is represented by host factors that are crucial for the viral life cycle. Recent studies have indicated that heat shock protein 90 (HSP90) is a crucial host factor that is required by many viruses for multiple phases of their life cycle including viral entry, nuclear import, transcription, and replication. In this review, we summarize the most recent advances regarding HSP90 function, mechanisms of action, and molecular pathways that are associated with viral infection, and provide a comprehensive understanding of the role of HSP90 in the immune response and exosome-mediated viral transmission. In addition, several HSP90 inhibitors have entered clinical trials for specific cancers that are associated with viral infection, which further implies a crucial role for HSP90 in the malignant transformation of virus-infected cells; as such, HSP90 inhibitors exhibit excellent therapeutic potential. Finally, we describe the challenge of developing HSP90 inhibitors as anti-viral drugs.
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Affiliation(s)
- Yiliang Wang
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, Guangdong, People's Republic of China.,College of Pharmacy, Jinan University, Guangzhou, 510632, People's Republic of China
| | - Fujun Jin
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, Guangdong, People's Republic of China
| | - Rongze Wang
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, Guangdong, People's Republic of China.,College of Pharmacy, Jinan University, Guangzhou, 510632, People's Republic of China
| | - Feng Li
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, Guangdong, People's Republic of China.,College of Pharmacy, Jinan University, Guangzhou, 510632, People's Republic of China
| | - Yanting Wu
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, Guangdong, People's Republic of China
| | - Kaio Kitazato
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, Guangdong, People's Republic of China. .,Division of Molecular Pharmacology of Infectious Agents, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, 852-8521, Japan.
| | - Yifei Wang
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, Guangdong, People's Republic of China.
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Targeting heat shock factor 1 as an antiviral strategy against dengue virus replication in vitro and in vivo. Antiviral Res 2017; 145:44-53. [PMID: 28733114 DOI: 10.1016/j.antiviral.2017.07.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 07/12/2017] [Accepted: 07/13/2017] [Indexed: 11/22/2022]
Abstract
Fever onset is correlated with viremia in dengue virus (DENV) patients. Heat shock factor 1 (HSF1), a heat stress response host transcription factor, plays a crucial role in regulating multiple cellular functions, as well as the onset of infectious diseases. This study evaluated the role of HSF1 in DENV replication as a means of regulating DENV infection in vitro and in vivo. DENV infection activated HSF1 in both Ca2+ and protein kinase A-dependent manners. Inhibiting HSF1 effectively reduced DENV replication, not only in THP-1 cells but also in primary human monocytes. Activated HSF1 contributed to DENV replication by upregulating autophagy-related protein (Atg) 7, as autophagy is crucial for virus replication. Heat stress also activated HSF1, which in turn facilitated DENV replication. Activated HSF1, the increased Atg7, and autophagic induction were founded in the DENV-infected brains and pharmacologically inhibiting HSF1 reduced autophagy, viral protein expression, neuropathy, and mortality. These results provide new insight into HSF1 as a novel host factor for DENV infection through its role in facilitating autophagy-regulated viral replication in the brains.
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28
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Realegeno S, Puschnik AS, Kumar A, Goldsmith C, Burgado J, Sambhara S, Olson VA, Carroll D, Damon I, Hirata T, Kinoshita T, Carette JE, Satheshkumar PS. Monkeypox Virus Host Factor Screen Using Haploid Cells Identifies Essential Role of GARP Complex in Extracellular Virus Formation. J Virol 2017; 91:e00011-17. [PMID: 28331092 PMCID: PMC5432867 DOI: 10.1128/jvi.00011-17] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 03/14/2017] [Indexed: 12/17/2022] Open
Abstract
Monkeypox virus (MPXV) is a human pathogen that is a member of the Orthopoxvirus genus, which includes Vaccinia virus and Variola virus (the causative agent of smallpox). Human monkeypox is considered an emerging zoonotic infectious disease. To identify host factors required for MPXV infection, we performed a genome-wide insertional mutagenesis screen in human haploid cells. The screen revealed several candidate genes, including those involved in Golgi trafficking, glycosaminoglycan biosynthesis, and glycosylphosphatidylinositol (GPI)-anchor biosynthesis. We validated the role of a set of vacuolar protein sorting (VPS) genes during infection, VPS51 to VPS54 (VPS51-54), which comprise the Golgi-associated retrograde protein (GARP) complex. The GARP complex is a tethering complex involved in retrograde transport of endosomes to the trans-Golgi apparatus. Our data demonstrate that VPS52 and VPS54 were dispensable for mature virion (MV) production but were required for extracellular virus (EV) formation. For comparison, a known antiviral compound, ST-246, was used in our experiments, demonstrating that EV titers in VPS52 and VPS54 knockout (KO) cells were comparable to levels exhibited by ST-246-treated wild-type cells. Confocal microscopy was used to examine actin tail formation, one of the viral egress mechanisms for cell-to-cell dissemination, and revealed an absence of actin tails in VPS52KO- or VPS54KO-infected cells. Further evaluation of these cells by electron microscopy demonstrated a decrease in levels of wrapped viruses (WVs) compared to those seen with the wild-type control. Collectively, our data demonstrate the role of GARP complex genes in double-membrane wrapping of MVs necessary for EV formation, implicating the host endosomal trafficking pathway in orthopoxvirus infection.IMPORTANCE Human monkeypox is an emerging zoonotic infectious disease caused by Monkeypox virus (MPXV). Of the two MPXV clades, the Congo Basin strain is associated with severe disease, increased mortality, and increased human-to-human transmission relative to the West African strain. Monkeypox is endemic in regions of western and central Africa but was introduced into the United States in 2003 from the importation of infected animals. The threat of MPXV and other orthopoxviruses is increasing due to the absence of routine smallpox vaccination leading to a higher proportion of naive populations. In this study, we have identified and validated candidate genes that are required for MPXV infection, specifically, those associated with the Golgi-associated retrograde protein (GARP) complex. Identifying host targets required for infection that prevents extracellular virus formation such as the GARP complex or the retrograde pathway can provide a potential target for antiviral therapy.
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Affiliation(s)
- Susan Realegeno
- Poxvirus and Rabies Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Andreas S Puschnik
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA
| | - Amrita Kumar
- Immunology and Pathogenesis Branch, Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Cynthia Goldsmith
- Infectious Disease Pathology Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Jillybeth Burgado
- Poxvirus and Rabies Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Suryaprakash Sambhara
- Immunology and Pathogenesis Branch, Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Victoria A Olson
- Poxvirus and Rabies Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Darin Carroll
- Poxvirus and Rabies Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Inger Damon
- Poxvirus and Rabies Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Tetsuya Hirata
- Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Taroh Kinoshita
- Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Jan E Carette
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA
| | - Panayampalli Subbian Satheshkumar
- Poxvirus and Rabies Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
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Wang TY, Chen YM, Chen TY. Molecular cloning of orange-spotted grouper (Epinephelus coioides) heat shock transcription factor 1 isoforms and characterization of their expressions in response to nodavirus. FISH & SHELLFISH IMMUNOLOGY 2016; 59:123-136. [PMID: 27773730 DOI: 10.1016/j.fsi.2016.10.032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 10/14/2016] [Accepted: 10/18/2016] [Indexed: 06/06/2023]
Abstract
Heat shock transcription factor 1 (HSF1) regulates heat shock proteins (HSPs), which assist in protein folding and inhibit protein denaturation following stress. HSF1 was firstly cloned from orange-spotted grouper and exists as two isoforms, one with (osgHSF1a) and one without (osgHSF1b) exon 11. Heat exposure increased the expression of osgHSF1b while cold exposure increased that of osgHSF1a. Both isoforms were mainly expressed in the brains, eyes, and fins. Expression of osgHSF1b was higher than osgHSF1a during development. Poly I:C and LPS could also induce osgHSF1 isoforms expression differentially. Exposure to nervous necrosis virus (NNV) increased the level of both osgHSF1 isoforms at 12 h. GF-1 cells with overexpression of osgHSF1 isoforms enhanced viral loads within 24 h, whereas both pharmacological inhibition and RNA interference of HSF1 reduced virus infection. This study shows that osgHSF1 can support the early stage of virus infection and provides a new insight into the molecular regulation of osgHSF1 between the influence of temperatures and immunity.
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Affiliation(s)
- Ting-Yu Wang
- Laboratory of Molecular Genetics, Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan; Translational Center for Marine Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan
| | - Young-Mao Chen
- Laboratory of Molecular Genetics, Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan; Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan; Translational Center for Marine Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan; Agriculture Biotechnology Research Center, National Cheng Kung University, Tainan 70101, Taiwan
| | - Tzong-Yueh Chen
- Laboratory of Molecular Genetics, Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan; Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan; Translational Center for Marine Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan; Agriculture Biotechnology Research Center, National Cheng Kung University, Tainan 70101, Taiwan; University Center for Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan.
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31
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Liem J, Liu J. Stress Beyond Translation: Poxviruses and More. Viruses 2016; 8:v8060169. [PMID: 27314378 PMCID: PMC4926189 DOI: 10.3390/v8060169] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 05/24/2016] [Accepted: 06/08/2016] [Indexed: 02/06/2023] Open
Abstract
Poxviruses are large double-stranded DNA viruses that form viral factories in the cytoplasm of host cells. These viruses encode their own transcription machinery, but rely on host translation for protein synthesis. Thus, poxviruses have to cope with and, in most cases, reprogram host translation regulation. Granule structures, called antiviral granules (AVGs), have been observed surrounding poxvirus viral factories. AVG formation is associated with abortive poxvirus infection, and AVGs contain proteins that are typically found in stress granules (SGs). With certain mutant poxviruses lack of immunoregulatory factor(s), we can specifically examine the mechanisms that drive the formation of these structures. In fact, cytoplasmic macromolecular complexes form during many viral infections and contain sensing molecules that can help reprogram transcription. More importantly, the similarity between AVGs and cytoplasmic structures formed during RNA and DNA sensing events prompts us to reconsider the cause and consequence of these AVGs. In this review, we first summarize recent findings regarding how poxvirus manipulates host translation. Next, we compare and contrast SGs and AVGs. Finally, we review recent findings regarding RNA- and especially DNA-sensing bodies observed during viral infection.
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Affiliation(s)
- Jason Liem
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
| | - Jia Liu
- Department of Microbiology and Immunology, Center for Microbial Pathogenesis and Host Inflammatory Responses, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
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Abstract
Deciphering the many interactions that occur between a virus and host cell over the course of infection is paramount to understanding mechanisms of pathogenesis and to the future development of antiviral therapies. Over the past decade, researchers have started to understand these complicated relationships through the development of methodologies, including advances in RNA interference, proteomics, and the development of genetic tools such as haploid cell lines, allowing high-throughput screening to identify critical contact points between virus and host. These advances have produced a wealth of data regarding host factors hijacked by viruses to promote infection, as well as antiviral factors responsible for subverting viral infection. This review highlights findings from virus-host screens and discusses our thoughts on the direction of screening strategies moving forward.
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Affiliation(s)
- Holly Ramage
- Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; ,
| | - Sara Cherry
- Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; ,
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Filone CM, Dower K, Cowley GS, Hensley LE, Connor JH. Probing the virus host interaction in high containment: an approach using pooled short hairpin RNA. Assay Drug Dev Technol 2015; 13:34-43. [PMID: 25646658 DOI: 10.1089/adt.2014.613] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
The study of viruses in high containment offers unique challenges for technology-intense approaches. These approaches include high-throughput screening for small-molecule antivirals and genetic perturbation-based screens for host factors required for viral replication. Here, we describe the use of whole-genome scale pooled short hairpin RNA (shRNA) libraries to screen for host factors necessary for viral infection at BSL2, and the transition of this technique into the BSL4 environment. Pooled screening provides a unique way to circumvent many of the technological challenges associated with other high-throughput screening approaches in high containment. Our pooled screening approach identified host factors involved in the replication of orthopoxviruses (Vaccinia and Monkeypox) and filoviruses (Ebola and Marburg) under conditions that enable straightforward screen-to-follow-up approaches.
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Affiliation(s)
- Claire Marie Filone
- 1 National Emerging Infectious Diseases Laboratory, Boston University School of Medicine , Boston, Massachusetts
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Leão TL, da Fonseca FG. Subversion of cellular stress responses by poxviruses. World J Clin Infect Dis 2014; 4:27-40. [DOI: 10.5495/wjcid.v4.i4.27] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Revised: 07/26/2014] [Accepted: 09/10/2014] [Indexed: 02/06/2023] Open
Abstract
Cellular stress responses are powerful mechanisms that prevent and cope with the accumulation of macromolecular damage in the cells and also boost host defenses against pathogens. Cells can initiate either protective or destructive stress responses depending, to a large extent, on the nature and duration of the stressing stimulus as well as the cell type. The productive replication of a virus within a given cell places inordinate stress on the metabolism machinery of the host and, to assure the continuity of its replication, many viruses have developed ways to modulate the cell stress responses. Poxviruses are among the viruses that have evolved a large number of strategies to manipulate host stress responses in order to control cell fate and enhance their replicative success. Remarkably, nearly every step of the stress responses that is mounted during infection can be targeted by virally encoded functions. The fine-tuned interactions between poxviruses and the host stress responses has aided virologists to understand specific aspects of viral replication; has helped cell biologists to evaluate the role of stress signaling in the uninfected cell; and has tipped immunologists on how these signals contribute to alert the cells against pathogen invasion and boost subsequent immune responses. This review discusses the diverse strategies that poxviruses use to subvert host cell stress responses.
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Activation of stress response pathways promotes formation of antiviral granules and restricts virus replication. Mol Cell Biol 2014; 34:2003-16. [PMID: 24662051 DOI: 10.1128/mcb.01630-13] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The formation of protein-RNA granules is a part of both natural cellular function (P-bodies and nuclear HNRNPs) and the response to cellular stress (stress granules and ND10 bodies). To better understand the role of stress-induced granules in viral infection, we have studied the ability of cells to restrict poxvirus replication through the formation of antiviral granules (AVGs). Of cells infected with a wild-type poxvirus, a small number spontaneously formed AVGs. In these AVG-positive cells, viral gene expression was inhibited. The addition of compounds that altered RNA helicase activity, induced oxidative stress, or stimulated translation initiation factor phosphorylation significantly increased the number of AVG-positive cells. When AVGs formed, both viral translation and titers were decreased even when host translation persisted. Treatment with the antiviral compound isatin β-thiosemicarbazone (IBT), a compound that was used to treat smallpox infections, induced AVGs, suggesting a role for these structures in the pharmacological inhibition of poxvirus replication. These findings provide evidence that AVGs are an innate host response that can be exogenously stimulated to combat virus infection. Since small molecules are able to stimulate AVG formation, it is a potential target for new antiviral development.
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