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1
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Vervaeke A, Lamkanfi M. MAP Kinase Signaling at the Crossroads of Inflammasome Activation. Immunol Rev 2025; 329:e13436. [PMID: 39754394 DOI: 10.1111/imr.13436] [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: 11/30/2024] [Accepted: 12/14/2024] [Indexed: 01/06/2025]
Abstract
Inflammasomes are crucial mediators of both antimicrobial host defense and inflammatory pathology, requiring stringent regulation at multiple levels. This review explores the pivotal role of mitogen-activated protein kinase (MAPK) signaling in modulating inflammasome activation through various regulatory mechanisms. We detail recent advances in understanding MAPK-mediated regulation of NLRP3 inflammasome priming, licensing and activation, with emphasis on MAPK-induced activator protein-1 (AP-1) signaling in NLRP3 priming, ERK1 and JNK in NLRP3 licensing, and TAK1 in connecting death receptor signaling to NLRP3 inflammasome activation. Furthermore, we discuss novel insights into MAPK signaling in human NLRP1 inflammasome activation, focusing on the MAP3K member ZAKα as a key kinase linking ribosomal stress to inflammasome activation. Lastly, we review recent work elucidating how Bacillus anthracis lethal toxin (LeTx) manipulates host MAPK signaling to induce macrophage apoptosis as an immune evasion strategy, and the counteraction of this effect through genotype-specific Nlrp1b inflammasome activation in certain rodent strains.
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Affiliation(s)
- Alex Vervaeke
- Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium
| | - Mohamed Lamkanfi
- Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium
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2
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Pryce BR, Oles A, Talbert EE, Romeo MJ, Vaena S, Sharma S, Spadafora V, Tolliver L, Mahvi DA, Morgan KA, Lancaster WP, Beal E, Koren N, Watts B, Overstreet M, Berto S, Subramanian S, Calisir K, Crawford A, Neelon B, Ostrowski MC, Zimmers TA, Tidball JG, Wang DJ, Guttridge DC. Muscle inflammation is regulated by NF-κB from multiple cells to control distinct states of wasting in cancer cachexia. Cell Rep 2024; 43:114925. [PMID: 39475511 PMCID: PMC11774514 DOI: 10.1016/j.celrep.2024.114925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 07/01/2024] [Accepted: 10/14/2024] [Indexed: 12/01/2024] Open
Abstract
Although cancer cachexia is classically characterized as a systemic inflammatory disorder, emerging evidence indicates that weight loss also associates with local tissue inflammation. We queried the regulation of this inflammation and its causality to cachexia by exploring skeletal muscle, whose atrophy strongly associates with poor outcomes. Using multiple mouse models and patient samples, we show that cachectic muscle is marked by enhanced innate immunity. Nuclear factor κB (NF-κB) activity in multiple cells, including satellite cells, myofibers, and fibro-adipogenic progenitors, promotes macrophage expansion equally derived from infiltrating monocytes and resident cells. Moreover, NF-κB-activated cells and macrophages undergo crosstalk; NF-κB+ cells recruit macrophages to inhibit regeneration and promote atrophy but, interestingly, also protect myofibers, while macrophages stimulate NF-κB+ cells to sustain an inflammatory feedforward loop. Together, we propose that NF-κB functions in multiple cells in the muscle microenvironment to stimulate macrophages that both promote and protect against muscle wasting in cancer.
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Affiliation(s)
- Benjamin R Pryce
- Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Alexander Oles
- Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Erin E Talbert
- Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Health and Human Physiology, and the Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
| | - Martin J Romeo
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Silvia Vaena
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Sudarshana Sharma
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Victoria Spadafora
- Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Lauren Tolliver
- Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
| | - David A Mahvi
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
| | - Katherine A Morgan
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
| | - William P Lancaster
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
| | - Eryn Beal
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
| | - Natlie Koren
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
| | - Bailey Watts
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
| | - Morgan Overstreet
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
| | - Stefano Berto
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Suganya Subramanian
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Kubra Calisir
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Anna Crawford
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Brian Neelon
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Michael C Ostrowski
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Teresa A Zimmers
- Department of Cell, Developmental, and Cancer Biology, Knight Cancer Institute, Portland, Oregon Health Science University, Portland, OR 97239, USA
| | - James G Tidball
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - David J Wang
- Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Denis C Guttridge
- Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
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Ortiz Flores RM, Cáceres CS, Cortiñas TI, Gomez Mejiba SE, Sasso CV, Ramirez DC, Mattar Domínguez MA. Exotoxins secreted by Clostridium septicum induce macrophage death: Implications for bacterial immune evasion mechanisms at infection sites. Toxicon 2024; 249:108070. [PMID: 39127083 DOI: 10.1016/j.toxicon.2024.108070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 07/25/2024] [Accepted: 08/07/2024] [Indexed: 08/12/2024]
Abstract
The induction of macrophage death is considered a potential mechanism by which components secreted by Clostridium septicum are used to evade the innate immune response and cause tissue damage. This study aimed to determine the effects of partially purified fractions of extracellular proteins secreted by C. septicum on the death of mouse peritoneal macrophages. Elicited mouse peritoneal macrophages were incubated with partially purified fractions of proteins secreted by C. septicum into the culture medium. After incubation, the protein fraction with a molecular weight ≥100 kDa caused significant cell death in macrophages, altered cell morphology, increased the expression of markers of apoptosis and autophagy, and increased the expression (protein and mRNA) of IL-10 and TNFα. Our data suggest that the proteins secreted by C. septicum (MW, ≥100 kDa) induce cell death in macrophages by promoting autophagy-triggered apoptosis. This study may contribute to our understanding of the molecular mechanism of immune evasion by C. septicum at the infection site.
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Affiliation(s)
- R M Ortiz Flores
- Department of Human Physiology, School of Medicine, CAMPUS TEATINOS C/Boulevard Luis Pasteur, University of Malaga, 29010, Malaga, Malaga, Spain.
| | - C S Cáceres
- Laboratory of Microbiology, School of Chemistry Biochemistry and Pharmacy, National University of San Luis, 5700, San Luis, San Luis, Argentina.
| | - T I Cortiñas
- Laboratory of Microbiology, School of Chemistry Biochemistry and Pharmacy, National University of San Luis, 5700, San Luis, San Luis, Argentina.
| | - S E Gomez Mejiba
- Laboratory of Experimental Therapeutics and Nutrition, IMIBIO-SL, CCT-San Luis, CONICET-National University of San Luis, 5700, San Luis, San Luis, Argentina.
| | - C V Sasso
- Department of Medicine and Dermatology, School of Medicine, CAMPUS TEATINOS, C/Boulevard Luis Pasteur, University of Malaga, 29010, Malaga, Malaga, Spain.
| | - D C Ramirez
- Laboratory of Experimental and Translational Medicine, IMIBIO-SL, CCT-San Luis, CONICET-National University of San Luis, 5700, San Luis, San Luis, Argentina.
| | - M A Mattar Domínguez
- Laboratory of Microbiology, School of Chemistry Biochemistry and Pharmacy, National University of San Luis, 5700, San Luis, San Luis, Argentina.
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da Fonseca IIM, Nagamine MK, Gentile LB, Nishiya AT, da Fonseca JM, de Oliveira Massoco C, Ward JM, Liu S, Leppla SH, Dagli MLZ. Targeting canine mammary neoplastic epithelial cells with a reengineered anthrax toxin: first study. Vet Res Commun 2024; 48:2407-2428. [PMID: 38805149 DOI: 10.1007/s11259-024-10400-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 04/29/2024] [Indexed: 05/29/2024]
Abstract
Mammary tumors are the most frequent type of neoplasms in intact female dogs. New therapies that target neoplastic cells without affecting normal cells are highly sought. The Bacillus anthracis toxin has been reengineered to target tumor cells that express urokinase plasminogen activators and metalloproteinases. In previous studies carried out in our laboratory, the reengineered anthrax toxin had inhibitory effects on canine oral mucosal melanoma and canine osteosarcoma cells. In this study, five canine neoplastic epithelial cell lines (four adenocarcinomas and one adenoma) and one non-neoplastic canine mammary epithelial cell line were treated with different concentrations of reengineered anthrax toxin components. Cell viability was quantified using an MTT assay and half-maximal inhibitory concentration (IC50) values. Cell lines were considered sensitive when the IC50 was lower than 5000 ng/ml. One canine mammary adenocarcinoma cell line and one mammary adenoma cell line showed significantly decreased viability after treatment, whereas the non-neoplastic cell line was resistant. We conclude that the reengineered anthrax toxin may be considered a targeted therapy for canine mammary neoplasms while preserving normal canine mammary epithelial cells.
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Affiliation(s)
- Ivone Izabel Mackowiak da Fonseca
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, São Paulo, SP, 05508-270, Brazil
| | - Márcia Kazumi Nagamine
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, São Paulo, SP, 05508-270, Brazil
| | - Luciana Boffoni Gentile
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, São Paulo, SP, 05508-270, Brazil
| | - Adriana Tomoko Nishiya
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, São Paulo, SP, 05508-270, Brazil
| | - Jonathan Mackowiak da Fonseca
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, São Paulo, SP, 05508-270, Brazil
| | - Cristina de Oliveira Massoco
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, São Paulo, SP, 05508-270, Brazil
| | | | - Shihui Liu
- Aging Institute and Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Stephen Howard Leppla
- Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Maria Lucia Zaidan Dagli
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, São Paulo, SP, 05508-270, Brazil.
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Gao X, Teng T, Liu Y, Ai T, Zhao R, Fu Y, Zhang P, Han J, Zhang Y. Anthrax lethal toxin and tumor necrosis factor-α synergize on intestinal epithelia to induce mouse death. Protein Cell 2024; 15:135-148. [PMID: 37855658 PMCID: PMC10833652 DOI: 10.1093/procel/pwad050] [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: 08/16/2023] [Accepted: 09/26/2023] [Indexed: 10/20/2023] Open
Abstract
Bacillus anthracis lethal toxin (LT) is a determinant of lethal anthrax. Its function in myeloid cells is required for bacterial dissemination, and LT itself can directly trigger dysfunction of the cardiovascular system. The interplay between LT and the host responses is important in the pathogenesis, but our knowledge on this interplay remains limited. Tumor necrosis factor-α (TNF-α) is a pleiotropic pro-inflammatory cytokine induced by bacterial infections. Since LT accumulates and cytokines, predominantly TNF, amass during B. anthracis infection, co-treatment of TNF + LT in mice was used to mimic in vivo conditions for LT to function in inflamed hosts. Bone marrow transplantation and genetically engineered mice showed unexpectedly that the death of intestinal epithelial cells (IECs) rather than that of hematopoietic cells led to LT + TNF-induced lethality. Inhibition of p38α mitogen-activated protein kinase (MAPK) signaling by LT in IECs promoted TNF-induced apoptosis and necroptosis of IECs, leading to intestinal damage and mouse death. Consistently, p38α inhibition by LT enhanced TNF-mediated cell death in human colon epithelial HT-29 cells. As intestinal damage is one of the leading causes of lethality in anthrax patients, the IEC damage caused by LT + TNF would most likely be a mechanism underneath this clinical manifestation and could be a target for interventions.
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Affiliation(s)
- Xinhe Gao
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
| | - Teng Teng
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
| | - Yifei Liu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
| | - Tingting Ai
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
| | - Rui Zhao
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
| | - Yilong Fu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
| | - Peipei Zhang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
| | - Jiahuai Han
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
- Research Unit of Cellular Stress of CAMS, Xiang’an Hospital of Xiamen University, Cancer Research Center of Xiamen University, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
- Laboratory Animal Center, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
| | - Yingying Zhang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
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Avloniti M, Evangelidou M, Gomini M, Loupis T, Emmanouil M, Mitropoulou A, Tselios T, Lassmann H, Gruart A, Delgado-García JM, Probert L, Kyrargyri V. IKKβ deletion from CNS macrophages increases neuronal excitability and accelerates the onset of EAE, while from peripheral macrophages reduces disease severity. J Neuroinflammation 2024; 21:34. [PMID: 38279130 PMCID: PMC10821407 DOI: 10.1186/s12974-024-03023-9] [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: 09/18/2023] [Accepted: 01/15/2024] [Indexed: 01/28/2024] Open
Abstract
BACKGROUND Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease characterized by motor deficits and cognitive decline. Many immune aspects of the disease are understood through studies in the experimental autoimmune encephalomyelitis (EAE) model, including the contribution of the NF-κB transcription factor to neuroinflammation. However, the cell-specific roles of NF-κB to EAE and its cognitive comorbidities still needs further investigation. We have previously shown that the myeloid cell NF-κB plays a role in the healthy brain by exerting homeostatic regulation of neuronal excitability and synaptic plasticity and here we investigated its role in EAE. METHODS We used constitutive MφIKKβΚΟ mice, in which depletion of IKKβ, the main activating kinase of NF-κB, was global to CNS and peripheral macrophages, and ΜgΙΚΚβKO mice, in which depletion was inducible and specific to CNS macrophages by 28 days after tamoxifen administration. We subjected these mice to MOG35-55 induced EAE and cuprizone-induced demyelination. We measured pathology by immunohistochemistry, investigated molecular mechanisms by RNA sequencing analysis and studied neuronal functions by in vivo electrophysiology in awake animals. RESULTS Global depletion of IKKβ from myeloid cells in MφIKKβΚΟ mice accelerated the onset and significantly supressed chronic EAE. Knocking out IKKβ only from CNS resident macrophages accelerated the onset and exacerbated chronic EAE, accompanied by earlier demyelination and immune cell infiltration but had no effect in cuprizone-induced demyelination. Peripheral T cell effector functions were not affected by myeloid cell deletion of IKKβ, but CNS resident mechanisms, such as microglial activation and neuronal hyperexcitability were altered from early in EAE. Lastly, depletion of myeloid cell IKKβ resulted in enhanced late long-term potentiation in EAE. CONCLUSIONS IKKβ-mediated activation of NF-κΒ in myeloid cells has opposing roles in EAE depending on the cell type and the disease stage. In CNS macrophages it is protective while in peripheral macrophages it is disease-promoting and acts mainly during chronic disease. Although clinically protective, CNS myeloid cell IKKβ deletion dysregulates neuronal excitability and synaptic plasticity in EAE. These effects of IKKβ on brain cognitive abilities deserve special consideration when therapeutic interventions that inhibit NF-κB are used in MS.
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Affiliation(s)
- Maria Avloniti
- Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece
| | - Maria Evangelidou
- Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece
| | - Maria Gomini
- Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece
| | - Theodore Loupis
- Greek Genome Centre, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece
- Haematology Research Laboratory, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece
| | - Mary Emmanouil
- Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece
| | | | | | - Hans Lassmann
- Department of Neuroimmunology, Centre for Brain Research, Medical University of Vienna, Vienna, Austria
| | - Agnès Gruart
- Division of Neurosciences, Pablo de Olavide University, 41013, Seville, Spain
| | | | - Lesley Probert
- Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece
| | - Vasiliki Kyrargyri
- Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece.
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Solomon SL, Bryson BD. Single-cell analysis reveals a weak macrophage subpopulation response to Mycobacterium tuberculosis infection. Cell Rep 2023; 42:113418. [PMID: 37963018 PMCID: PMC10842899 DOI: 10.1016/j.celrep.2023.113418] [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: 04/24/2023] [Revised: 08/28/2023] [Accepted: 10/25/2023] [Indexed: 11/16/2023] Open
Abstract
Mycobacterium tuberculosis (Mtb) infection remains one of society's greatest human health challenges. Macrophages integrate multiple signals derived from ontogeny, infection, and the environment. This integration proceeds heterogeneously during infection. Some macrophages are infected, while others are not; therefore, bulk approaches mask the subpopulation dynamics. We establish a modular, targeted, single-cell protein analysis framework to study the immune response to Mtb. We demonstrate that during Mtb infection, only a small fraction of resting macrophages produce tumor necrosis factor (TNF) protein. We demonstrate that Mtb infection results in muted phosphorylation of p38 and JNK, regulators of inflammation, and leverage our single-cell methods to distinguish between pathogen-mediated interference in host signaling and weak activation of host pathways. We demonstrate that the inflammatory signal magnitude is decoupled from the ability to control Mtb growth. These data underscore the importance of developing pathogen-specific models of signaling and highlight barriers to activation of pathways that control inflammation.
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Affiliation(s)
- Sydney L Solomon
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; The Ragon Institute of MGH, Harvard & MIT, Cambridge, MA 02139, USA
| | - Bryan D Bryson
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; The Ragon Institute of MGH, Harvard & MIT, Cambridge, MA 02139, USA.
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8
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Zhang QA, Ma S, Li P, Xie J. The dynamics of Mycobacterium tuberculosis phagosome and the fate of infection. Cell Signal 2023; 108:110715. [PMID: 37192679 DOI: 10.1016/j.cellsig.2023.110715] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 04/25/2023] [Accepted: 05/12/2023] [Indexed: 05/18/2023]
Abstract
Phagosomes are vesicles produced by phagocytosis of phagocytes, which are crucial in immunity against Mycobacterium tuberculosis (Mtb) infection. After the phagocyte ingests the pathogen, it activates the phagosomes to recruit a series of components and process proteins, to phagocytose, degrade and kill Mtb. Meanwhile, Mtb can resist acid and oxidative stress, block phagosome maturation, and manipulate host immune response. The interaction between Mtb and phagocytes leads to the outcome of infection. The dynamic of this process can affect the cell fate. This article mainly reviews the development and maturation of phagosomes, as well as the dynamics and modifications of Mtb effectors and phagosomes components, and new diagnostic and therapeutic markers involved in phagosomes.
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Affiliation(s)
- Qi-Ao Zhang
- State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Institute of Modern Biopharmaceuticals, Southwest University, Chongqing, China
| | - Shaying Ma
- Chongqing Emergency Medical Center, Chongqing the Fourth Hospital, Jiankang Road, Yuzhong, Chongqing 400014, China
| | - Peibo Li
- Chongqing Public Health Medical Center, Chongqing, China
| | - Jianping Xie
- State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Institute of Modern Biopharmaceuticals, Southwest University, Chongqing, China; Chongqing Public Health Medical Center, Chongqing, China.
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9
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Ciaston I, Dobosz E, Potempa J, Koziel J. The subversion of toll-like receptor signaling by bacterial and viral proteases during the development of infectious diseases. Mol Aspects Med 2022; 88:101143. [PMID: 36152458 PMCID: PMC9924004 DOI: 10.1016/j.mam.2022.101143] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/29/2022] [Accepted: 09/09/2022] [Indexed: 02/05/2023]
Abstract
Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) that respond to pathogen-associated molecular patterns (PAMPs). The recognition of specific microbial ligands by TLRs triggers an innate immune response and also promotes adaptive immunity, which is necessary for the efficient elimination of invading pathogens. Successful pathogens have therefore evolved strategies to subvert and/or manipulate TLR signaling. Both the impairment and uncontrolled activation of TLR signaling can harm the host, causing tissue destruction and allowing pathogens to proliferate, thus favoring disease progression. In this context, microbial proteases are key virulence factors that modify components of the TLR signaling pathway. In this review, we discuss the role of bacterial and viral proteases in the manipulation of TLR signaling, highlighting the importance of these enzymes during the development of infectious diseases.
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Affiliation(s)
- Izabela Ciaston
- Department of Microbiology Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Ewelina Dobosz
- Department of Microbiology Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Jan Potempa
- Department of Microbiology Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland; Department of Oral Health and Systemic Disease, University of Louisville School of Dentistry, University of Louisville, Louisville, KY, USA.
| | - Joanna Koziel
- Department of Microbiology Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
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10
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Anwar MU, Sergeeva OA, Abrami L, Mesquita FS, Lukonin I, Amen T, Chuat A, Capolupo L, Liberali P, D'Angelo G, van der Goot FG. ER-Golgi-localized proteins TMED2 and TMED10 control the formation of plasma membrane lipid nanodomains. Dev Cell 2022; 57:2334-2346.e8. [PMID: 36174556 DOI: 10.1016/j.devcel.2022.09.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 07/24/2022] [Accepted: 09/08/2022] [Indexed: 11/03/2022]
Abstract
To promote infections, pathogens exploit host cell machineries such as structural elements of the plasma membrane. Studying these interactions and identifying molecular players are ideal for gaining insights into the fundamental biology of the host cell. Here, we used the anthrax toxin to screen a library of 1,500 regulatory, cell-surface, and membrane trafficking genes for their involvement in the intoxication process. We found that endoplasmic reticulum (ER)-Golgi-localized proteins TMED2 and TMED10 are required for toxin oligomerization at the plasma membrane of human cells, an essential step dependent on localization to cholesterol-rich lipid nanodomains. Biochemical, morphological, and mechanistic analyses showed that TMED2 and TMED10 are essential components of a supercomplex that operates the exchange of both cholesterol and ceramides at ER-Golgi membrane contact sites. Overall, this study of anthrax intoxication led to the discovery that lipid compositional remodeling at ER-Golgi interfaces fully controls the formation of functional membrane nanodomains at the cell surface.
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Affiliation(s)
- Muhammad U Anwar
- Global Health Institute, School of Life Sciences, EPFL, 1015 Lausanne, Switzerland
| | - Oksana A Sergeeva
- Global Health Institute, School of Life Sciences, EPFL, 1015 Lausanne, Switzerland
| | - Laurence Abrami
- Global Health Institute, School of Life Sciences, EPFL, 1015 Lausanne, Switzerland
| | - Francisco S Mesquita
- Global Health Institute, School of Life Sciences, EPFL, 1015 Lausanne, Switzerland
| | - Ilya Lukonin
- Friedrich Miescher Institute for Biomedical Research (FMI), 4058 Basel, Switzerland; University of Basel, 4056 Basel, Switzerland
| | - Triana Amen
- Global Health Institute, School of Life Sciences, EPFL, 1015 Lausanne, Switzerland
| | - Audrey Chuat
- Global Health Institute, School of Life Sciences, EPFL, 1015 Lausanne, Switzerland
| | - Laura Capolupo
- Institute of Bioengineering, School of Life Sciences, EPFL, 1015 Lausanne, Switzerland
| | - Prisca Liberali
- Friedrich Miescher Institute for Biomedical Research (FMI), 4058 Basel, Switzerland; University of Basel, 4056 Basel, Switzerland
| | - Giovanni D'Angelo
- Institute of Bioengineering, School of Life Sciences, EPFL, 1015 Lausanne, Switzerland.
| | - F Gisou van der Goot
- Global Health Institute, School of Life Sciences, EPFL, 1015 Lausanne, Switzerland.
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11
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Woida PJ, Satchell KJF. Bacterial Toxin and Effector Regulation of Intestinal Immune Signaling. Front Cell Dev Biol 2022; 10:837691. [PMID: 35252199 PMCID: PMC8888934 DOI: 10.3389/fcell.2022.837691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/24/2022] [Indexed: 11/13/2022] Open
Abstract
The host immune response is highly effective to detect and clear infecting bacterial pathogens. Given the elaborate surveillance systems of the host, it is evident that in order to productively infect a host, the bacteria often coordinate virulence factors to fine-tune the host response during infection. These coordinated events can include either suppressing or activating the signaling pathways that control the immune response and thereby promote bacterial colonization and infection. This review will cover the surveillance and signaling systems for detection of bacteria in the intestine and a sample of the toxins and effectors that have been characterized that cirumvent these signaling pathways. These factors that promote infection and disease progression have also been redirected as tools or therapeutics. Thus, these toxins are enemies deployed to enhance infection, but can also be redeployed as allies to enable research and protect against infection.
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Affiliation(s)
| | - Karla J. F. Satchell
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
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12
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Van Hauwermeiren F, Van Opdenbosch N, Van Gorp H, de Vasconcelos N, van Loo G, Vandenabeele P, Kanneganti TD, Lamkanfi M. Bacillus anthracis induces NLRP3 inflammasome activation and caspase-8-mediated apoptosis of macrophages to promote lethal anthrax. Proc Natl Acad Sci U S A 2022; 119:e2116415119. [PMID: 34996874 PMCID: PMC8764678 DOI: 10.1073/pnas.2116415119] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/01/2021] [Indexed: 12/29/2022] Open
Abstract
Lethal toxin (LeTx)-mediated killing of myeloid cells is essential for Bacillus anthracis, the causative agent of anthrax, to establish systemic infection and induce lethal anthrax. The "LeTx-sensitive" NLRP1b inflammasome of BALB/c and 129S macrophages swiftly responds to LeTx intoxication with pyroptosis and secretion of interleukin (IL)-1β. However, human NLRP1 is nonresponsive to LeTx, prompting us to investigate B. anthracis host-pathogen interactions in C57BL/6J (B6) macrophages and mice that also lack a LeTx-sensitive Nlrp1b allele. Unexpectedly, we found that LeTx intoxication and live B. anthracis infection of B6 macrophages elicited robust secretion of IL-1β, which critically relied on the NLRP3 inflammasome. TNF signaling through both TNF receptor 1 (TNF-R1) and TNF-R2 were required for B. anthracis-induced NLRP3 inflammasome activation, which was further controlled by RIPK1 kinase activity and LeTx-mediated proteolytic inactivation of MAP kinase signaling. In addition to activating the NLRP3 inflammasome, LeTx-induced MAPKK inactivation and TNF production sensitized B. anthracis-infected macrophages to robust RIPK1- and caspase-8-dependent apoptosis. In agreement, purified LeTx triggered RIPK1 kinase activity- and caspase-8-dependent apoptosis only in macrophages primed with TNF or following engagement of TRIF-dependent Toll-like receptors. Consistently, genetic and pharmacological inhibition of RIPK1 inhibited NLRP3 inflammasome activation and apoptosis of LeTx-intoxicated and B. anthracis-infected macrophages. Caspase-8/RIPK3-deficient mice were significantly protected from B. anthracis-induced lethality, demonstrating the in vivo pathophysiological relevance of this cytotoxic mechanism. Collectively, these results establish TNF- and RIPK1 kinase activity-dependent NLRP3 inflammasome activation and macrophage apoptosis as key host-pathogen mechanisms in lethal anthrax.
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Affiliation(s)
- Filip Van Hauwermeiren
- Department of Internal Medicine and Paediatrics, Ghent University, Ghent B-9000, Belgium
- Center for Inflammation Research, VIB, Ghent B-9000, Belgium
| | - Nina Van Opdenbosch
- Department of Internal Medicine and Paediatrics, Ghent University, Ghent B-9000, Belgium
- Center for Inflammation Research, VIB, Ghent B-9000, Belgium
| | - Hanne Van Gorp
- Department of Internal Medicine and Paediatrics, Ghent University, Ghent B-9000, Belgium
- Center for Inflammation Research, VIB, Ghent B-9000, Belgium
| | - Nathalia de Vasconcelos
- Department of Internal Medicine and Paediatrics, Ghent University, Ghent B-9000, Belgium
- Center for Inflammation Research, VIB, Ghent B-9000, Belgium
| | - Geert van Loo
- Center for Inflammation Research, VIB, Ghent B-9000, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium
| | - Peter Vandenabeele
- Center for Inflammation Research, VIB, Ghent B-9000, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium
| | | | - Mohamed Lamkanfi
- Department of Internal Medicine and Paediatrics, Ghent University, Ghent B-9000, Belgium;
- Center for Inflammation Research, VIB, Ghent B-9000, Belgium
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13
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Sequence Variability of pXO1-Located Pathogenicity Genes of Bacillus anthracis Natural Strains of Different Geographic Origin. Pathogens 2021; 10:pathogens10121556. [PMID: 34959512 PMCID: PMC8703917 DOI: 10.3390/pathogens10121556] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/11/2021] [Accepted: 11/26/2021] [Indexed: 11/18/2022] Open
Abstract
The main pathogenic factor of Bacillus anthracis is a three-component toxin encoded by the pagA, lef, and cya genes, which are located on the pXO1 plasmid. The atxA gene, which encodes the primary regulator of pathogenicity factor expression, is located on the same plasmid. In this work, we evaluated the polymorphism of the pagA, lef, cya, and atxA genes for 85 B. anthracis strains from different evolutionary lineages and canSNP groups. We have found a strong correlation of 19 genotypes with the main evolutionary lineages, but the correlation with the canSNP group of the strain was not as strong. We have detected several genetic markers indicating the geographical origin of the strains, for example, their source from the steppe zone of the former USSR. We also found that strains of the B.Br.001/002 group caused an anthrax epidemic in Russia in 2016 and strains isolated during paleontological excavations in the Russian Arctic have the same genotype as the strains of the B.Br.CNEVA group circulating in Central Europe. This data could testify in favor of the genetic relationship of these two groups of strains and hypothesize the ways of distribution of their ancestral forms between Europe and the Arctic.
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14
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Papazian I, Tsoukala E, Boutou A, Karamita M, Kambas K, Iliopoulou L, Fischer R, Kontermann RE, Denis MC, Kollias G, Lassmann H, Probert L. Fundamentally different roles of neuronal TNF receptors in CNS pathology: TNFR1 and IKKβ promote microglial responses and tissue injury in demyelination while TNFR2 protects against excitotoxicity in mice. J Neuroinflammation 2021; 18:222. [PMID: 34565380 PMCID: PMC8466720 DOI: 10.1186/s12974-021-02200-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 04/20/2021] [Indexed: 11/22/2022] Open
Abstract
Background During inflammatory demyelination, TNF receptor 1 (TNFR1) mediates detrimental proinflammatory effects of soluble TNF (solTNF), whereas TNFR2 mediates beneficial effects of transmembrane TNF (tmTNF) through oligodendroglia, microglia, and possibly other cell types. This model supports the use of selective inhibitors of solTNF/TNFR1 as anti-inflammatory drugs for central nervous system (CNS) diseases. A potential obstacle is the neuroprotective effect of solTNF pretreatment described in cultured neurons, but the relevance in vivo is unknown. Methods To address this question, we generated mice with neuron-specific depletion of TNFR1, TNFR2, or inhibitor of NF-κB kinase subunit β (IKKβ), a main downstream mediator of TNFR signaling, and applied experimental models of inflammatory demyelination and acute and preconditioning glutamate excitotoxicity. We also investigated the molecular and cellular requirements of solTNF neuroprotection by generating astrocyte-neuron co-cultures with different combinations of wild-type (WT) and TNF and TNFR knockout cells and measuring N-methyl-d-aspartate (NMDA) excitotoxicity in vitro. Results Neither neuronal TNFR1 nor TNFR2 protected mice during inflammatory demyelination. In fact, both neuronal TNFR1 and neuronal IKKβ promoted microglial responses and tissue injury, and TNFR1 was further required for oligodendrocyte loss and axonal damage in cuprizone-induced demyelination. In contrast, neuronal TNFR2 increased preconditioning protection in a kainic acid (KA) excitotoxicity model in mice and limited hippocampal neuron death. The protective effects of neuronal TNFR2 observed in vivo were further investigated in vitro. As previously described, pretreatment of astrocyte-neuron co-cultures with solTNF (and therefore TNFR1) protected them against NMDA excitotoxicity. However, protection was dependent on astrocyte, not neuronal TNFR1, on astrocyte tmTNF-neuronal TNFR2 interactions, and was reproduced by a TNFR2 agonist. Conclusions These results demonstrate that neuronal TNF receptors perform fundamentally different roles in CNS pathology in vivo, with neuronal TNFR1 and IKKβ promoting microglial inflammation and neurotoxicity in demyelination, and neuronal TNFR2 mediating neuroprotection in excitotoxicity. They also reveal that previously described neuroprotective effects of solTNF against glutamate excitotoxicity in vitro are indirect and mediated via astrocyte tmTNF-neuron TNFR2 interactions. These results consolidate the concept that selective inhibition of solTNF/TNFR1 with maintenance of TNFR2 function would have combined anti-inflammatory and neuroprotective properties required for safe treatment of CNS diseases. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-021-02200-4.
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Affiliation(s)
- Irini Papazian
- Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 127 Vasilissis Sophias Ave, 11521, Athens, Greece
| | - Eleni Tsoukala
- Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 127 Vasilissis Sophias Ave, 11521, Athens, Greece
| | - Athena Boutou
- Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 127 Vasilissis Sophias Ave, 11521, Athens, Greece
| | - Maria Karamita
- Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 127 Vasilissis Sophias Ave, 11521, Athens, Greece
| | - Konstantinos Kambas
- Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 127 Vasilissis Sophias Ave, 11521, Athens, Greece
| | - Lida Iliopoulou
- Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 127 Vasilissis Sophias Ave, 11521, Athens, Greece
| | - Roman Fischer
- Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
| | - Roland E Kontermann
- Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
| | - Maria C Denis
- Institute of Immunology, Biomedical Sciences Research Centre (BSRC) "Alexander Fleming", Vari, 16672, Athens, Greece
| | - George Kollias
- Institute of Immunology, Biomedical Sciences Research Centre (BSRC) "Alexander Fleming", Vari, 16672, Athens, Greece
| | - Hans Lassmann
- Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A1090, Vienna, Austria
| | - Lesley Probert
- Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 127 Vasilissis Sophias Ave, 11521, Athens, Greece.
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15
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From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways. Comput Struct Biotechnol J 2021; 19:4641-4657. [PMID: 34504660 PMCID: PMC8405902 DOI: 10.1016/j.csbj.2021.07.038] [Citation(s) in RCA: 303] [Impact Index Per Article: 75.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/27/2021] [Accepted: 07/28/2021] [Indexed: 02/07/2023] Open
Abstract
Pyroptosis, apoptosis and necroptosis are the most genetically well-defined programmed cell death (PCD) pathways, and they are intricately involved in both homeostasis and disease. Although the identification of key initiators, effectors and executioners in each of these three PCD pathways has historically delineated them as distinct, growing evidence has highlighted extensive crosstalk among them. These observations have led to the establishment of the concept of PANoptosis, defined as an inflammatory PCD pathway regulated by the PANoptosome complex with key features of pyroptosis, apoptosis and/or necroptosis that cannot be accounted for by any of these PCD pathways alone. In this review, we provide a brief overview of the research history of pyroptosis, apoptosis and necroptosis. We then examine the intricate crosstalk among these PCD pathways to discuss the current evidence for PANoptosis. We also detail the molecular evidence for the assembly of the PANoptosome complex, a molecular scaffold for contemporaneous engagement of key molecules from pyroptosis, apoptosis, and/or necroptosis. PANoptosis is now known to be critically involved in many diseases, including infection, sterile inflammation and cancer, and future discovery of novel PANoptotic components will continue to broaden our understanding of the fundamental processes of cell death and inform the development of new therapeutics.
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16
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Banihashemi SR, Rahbarizadeh F, Zavaran Hosseini A, Ahmadvand D, Khoshtinat Nikkhoi S. Liposome-based nanocarriers loaded with anthrax lethal factor and armed with anti-CD19 VHH for effectively inhibiting MAPK pathway in B cells. Int Immunopharmacol 2021; 100:107927. [PMID: 34500284 DOI: 10.1016/j.intimp.2021.107927] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 01/26/2023]
Abstract
OBJECTIVE One of the vital signaling pathways in cancer development and metastasis is mitogen-activated protein kinases (MAPKs). Bacillus anthracis Lethal Toxin (LT) is a potent MAPK signaling inhibitor. This toxin is comprised of two distinct domains, Lethal Factor (LF), MAPK inhibitor, and Protective Antigen (PA). To enter various cell lines, LF must be associated with the protective antigen (PA), which facilitates LF delivery. In the current study, to block MAPK signaling, LF was loaded into anti-CD19 immunoliposomes nanoparticle to deliver the cargo to Raji B cells. METHODS The liposome nanoparticle was prepared using classical lipid film formation, then conjugated to anti-CD19 VHH. The binding efficiency was measured through flow cytometry. The targeted cytotoxicity of LF immunoliposome was confirmed by BrdU lymphoproliferation assay. This was followed by Real-Time PCR to assess the effect of formulation on pro-apoptotic genes. The inhibitory effect of LF on MAPK signaling was confirmed by western blot. RESULTS Liposome nano-formulation was optimized to reach the maximum LF encapsulation and targeted delivery. Next, phosphorylation of MAPK pathway mediators like MEK1/2, P38 and JNK were inhibited following the treatment of Raji cells with LF-immunoliposome. The treatment also upregulated caspase genes, clearly illustrating cell death induced by LF through pyroptosis and caspase-dependent apoptosis. CONCLUSIONS In conclusion, anti-CD19 VHH immunoliposome was loaded with LF, a potent MAPK inhibitor targeting B cells, which curbs proliferation and ushers B cells toward apoptosis. Thus, immunoliposome presents as a versatile nanoparticle for delivery of LF to block aberrant MAPK activation. To use LF as a therapy, it would be necessary to materialize LF without PA. In the current study, PA was substituted with anti-CD19 immunoliposome to make it targeted to CD19+ while keeping the normal cells intact.
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Affiliation(s)
- S Reza Banihashemi
- Department of Medical Immunology, Faculty of Medical Sciences, Tarbiat Modarres University, Tehran, Iran; Department of Immunology, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization, Karaj, Iran
| | - Fatemeh Rahbarizadeh
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modarres University, Tehran, Iran.
| | - Ahmad Zavaran Hosseini
- Department of Medical Immunology, Faculty of Medical Sciences, Tarbiat Modarres University, Tehran, Iran
| | - Davoud Ahmadvand
- School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran
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17
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Müller-Winkler J, Mitter R, Rappe JCF, Vanes L, Schweighoffer E, Mohammadi H, Wack A, Tybulewicz VLJ. Critical requirement for BCR, BAFF, and BAFFR in memory B cell survival. J Exp Med 2021; 218:211510. [PMID: 33119032 PMCID: PMC7604764 DOI: 10.1084/jem.20191393] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 07/22/2020] [Accepted: 09/14/2020] [Indexed: 01/23/2023] Open
Abstract
Memory B cells (MBCs) are long-lived cells that form a critical part of immunological memory, providing rapid antibody responses to recurring infections. However, very little is known about signals controlling MBC survival. Previous work has shown that antigen is not required for MBC survival, but a requirement for the B cell antigen receptor (BCR) has not been tested. Other studies have shown that, unlike naive B cells, MBCs do not express BAFFR and their survival is independent of BAFF, the ligand for BAFFR. Here, using inducible genetic ablation, we show that survival of MBCs is critically dependent on the BCR and on signaling through the associated CD79A protein. Unexpectedly, we found that MBCs express BAFFR and that their survival requires BAFF and BAFFR; hence, loss of BAFF or BAFFR impairs recall responses. Finally, we show that MBC survival requires IKK2, a kinase that transduces BAFFR signals. Thus, MBC survival is critically dependent on signaling from BCR and BAFFR.
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18
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Hammers D, Carothers K, Lee S. The Role of Bacterial Proteases in Microbe and Host-microbe Interactions. Curr Drug Targets 2021; 23:222-239. [PMID: 34370632 DOI: 10.2174/1389450122666210809094100] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 06/15/2021] [Accepted: 06/16/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Secreted proteases are an important class of factors used by bacterial to modulate their extracellular environment through the cleavage of peptides and proteins. These proteases can range from broad, general proteolytic activity to high degrees of substrate specificity. They are often involved in interactions between bacteria and other species, even across kingdoms, allowing bacteria to survive and compete within their niche. As a result, many bacterial proteases are of clinical importance. The immune system is a common target for these enzymes, and bacteria have evolved ways to use these proteases to alter immune responses for their benefit. In addition to the wide variety of human proteins that can be targeted by bacterial proteases, bacteria also use these secreted factors to disrupt competing microbes, ranging from outright antimicrobial activity to disrupting processes like biofilm formation. OBJECTIVE In this review, we address how bacterial proteases modulate host mechanisms of protection from infection and injury, including immune factors and cell barriers. We also discuss the contributions of bacterial proteases to microbe-microbe interactions, including antimicrobial and anti-biofilm dynamics. CONCLUSION Bacterial secreted proteases represent an incredibly diverse group of factors that bacteria use to shape and thrive in their microenvironment. Due to the range of activities and targets of these proteases, some have been noted for having potential as therapeutics. The vast array of bacterial proteases and their targets remains an expanding field of research, and this field has many important implications for human health.
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Affiliation(s)
- Daniel Hammers
- Department of Biological Sciences, University of Notre Dame, Galvin Hall, Notre Dame, IN 46556, United States
| | - Katelyn Carothers
- Department of Biological Sciences, University of Notre Dame, Galvin Hall, Notre Dame, IN 46556, United States
| | - Shaun Lee
- Department of Biological Sciences, University of Notre Dame, Galvin Hall, Notre Dame, IN 46556, United States
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19
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Larson-Casey JL, Gu L, Davis D, Cai GQ, Ding Q, He C, Carter AB. Post-translational regulation of PGC-1α modulates fibrotic repair. FASEB J 2021; 35:e21675. [PMID: 34038004 PMCID: PMC8252570 DOI: 10.1096/fj.202100339r] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/23/2021] [Accepted: 05/04/2021] [Indexed: 12/12/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease associated with mitochondrial oxidative stress. Mitochondrial reactive oxygen species (mtROS) are important for cell homeostasis by regulating mitochondrial dynamics. Here, we show that IPF BAL cells exhibited increased mitochondrial biogenesis that is, in part, due to increased nuclear expression of peroxisome proliferator-activated receptor-ɣ (PPARɣ) coactivator (PGC)-1α. Increased PPARGC1A mRNA expression directly correlated with reduced pulmonary function in IPF subjects. Oxidant-mediated activation of the p38 MAPK via Akt1 regulated PGC-1α activation to increase mitochondrial biogenesis in monocyte-derived macrophages. Demonstrating the importance of PGC-1α in fibrotic repair, mice harboring a conditional deletion of Ppargc1a in monocyte-derived macrophages or mice administered a chemical inhibitor of mitochondrial division had reduced biogenesis and increased apoptosis, and the mice were protected from pulmonary fibrosis. These observations suggest that Akt1-mediated regulation of PGC-1α maintains mitochondrial homeostasis in monocyte-derived macrophages to induce apoptosis resistance, which contributes to the pathogenesis of pulmonary fibrosis.
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Affiliation(s)
- Jennifer L Larson-Casey
- Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Linlin Gu
- Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Dana Davis
- Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Guo-Qiang Cai
- Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Qiang Ding
- Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Chao He
- Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - A Brent Carter
- Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.,Birmingham Veterans Administration Medical Center, Birmingham, AL, USA
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20
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Ghislat G, Cheema AS, Baudoin E, Verthuy C, Ballester PJ, Crozat K, Attaf N, Dong C, Milpied P, Malissen B, Auphan-Anezin N, Manh TPV, Dalod M, Lawrence T. NF-κB-dependent IRF1 activation programs cDC1 dendritic cells to drive antitumor immunity. Sci Immunol 2021; 6:6/61/eabg3570. [PMID: 34244313 DOI: 10.1126/sciimmunol.abg3570] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 06/02/2021] [Indexed: 11/02/2022]
Abstract
Conventional type 1 dendritic cells (cDC1s) are critical for antitumor immunity. They acquire antigens from dying tumor cells and cross-present them to CD8+ T cells, promoting the expansion of tumor-specific cytotoxic T cells. However, the signaling pathways that govern the antitumor functions of cDC1s in immunogenic tumors are poorly understood. Using single-cell transcriptomics to examine the molecular pathways regulating intratumoral cDC1 maturation, we found nuclear factor κB (NF-κB) and interferon (IFN) pathways to be highly enriched in a subset of functionally mature cDC1s. We identified an NF-κB-dependent and IFN-γ-regulated gene network in cDC1s, including cytokines and chemokines specialized in the recruitment and activation of cytotoxic T cells. By mapping the trajectory of intratumoral cDC1 maturation, we demonstrated the dynamic reprogramming of tumor-infiltrating cDC1s by NF-κB and IFN signaling pathways. This maturation process was perturbed by specific inactivation of either NF-κB or IFN regulatory factor 1 (IRF1) in cDC1s, resulting in impaired expression of IFN-γ-responsive genes and consequently a failure to efficiently recruit and activate antitumoral CD8+ T cells. Last, we demonstrate the relevance of these findings to patients with melanoma, showing that activation of the NF-κB/IRF1 axis in association with cDC1s is linked with improved clinical outcome. The NF-κB/IRF1 axis in cDC1s may therefore represent an important focal point for the development of new diagnostic and therapeutic approaches to improve cancer immunotherapy.
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Affiliation(s)
- Ghita Ghislat
- CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France
| | - Ammar S Cheema
- CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France
| | - Elodie Baudoin
- CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France
| | - Christophe Verthuy
- CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France
| | - Pedro J Ballester
- Cancer Research Center of Marseille CRCM, INSERM, Institut Paoli-Calmettes, Aix-Marseille University, CNRS, 13009 Marseille, France
| | - Karine Crozat
- CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France
| | - Noudjoud Attaf
- CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France
| | - Chuang Dong
- CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France
| | - Pierre Milpied
- CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France
| | - Bernard Malissen
- CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France
| | - Nathalie Auphan-Anezin
- CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France
| | - Thien P Vu Manh
- CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France
| | - Marc Dalod
- CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France
| | - Toby Lawrence
- CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France. .,Centre for Inflammation Biology and Cancer Immunology, Cancer Research UK King's Health Partners Centre, School of Immunology and Microbial Sciences, King's College London, London SE1 1UL, UK.,Henan Key Laboratory of Immunology and Targeted Therapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
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21
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Shin JN, Rao L, Sha Y, Abdel Fattah E, Hyser J, Eissa NT. p38 MAPK Activity Is Required to Prevent Hyperactivation of NLRP3 Inflammasome. THE JOURNAL OF IMMUNOLOGY 2021; 207:661-670. [PMID: 34193605 DOI: 10.4049/jimmunol.2000416] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 05/06/2021] [Indexed: 11/19/2022]
Abstract
Inflammation contributes to the pathogenesis and morbidity of wide spectrum of human diseases. The inflammatory response must be actively controlled to prevent bystander damage to tissues. Yet, the mechanisms controlling excessive inflammatory responses are poorly understood. NLRP3 inflammasome plays an important role in innate immune response to cellular infection or stress. Its activation must be tightly regulated because uncontrolled inflammasome activation is associated with a number of human diseases. p38 MAPK signaling plays an essential role in the regulation of inflammation. The role of p38 MAPK in inflammatory response associated with the expression of proinflammatory molecules is known. However, the anti-inflammatory functions of p38 MAPK are largely unknown. In this study, we show that pharmacologic inhibition or genetic deficiency of p38 MAPK leads to hyperactivation of NLRP3 inflammasome, resulting in enhanced Caspase 1 activation and IL-1β and IL-18 production. The deficiency of p38 MAPK activity induced an increase of cytosolic Ca2+ and excessive mitochondrial Ca2+ uptake, leading to exacerbation of mitochondrial damage, which was associated with hyperactivation of NLRP3 inflammasome. In addition, mice with deficiency of p38 MAPK in granulocytes had evidence of in vivo hyperactivation of NLRP3 inflammasome and were more susceptible to LPS-induced sepsis compared with wild-type mice. Our results suggest that p38 MAPK negatively regulates NLRP3 inflammasome through control of Ca2+ mobilization. Hyperactivity of inflammasome in p38-deficient mice causes lung inflammation and increased susceptibility to septic shock.
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Affiliation(s)
- Jin Na Shin
- Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Lang Rao
- Department of Medicine, Baylor College of Medicine, Houston, TX; .,Veterans Administration Long Beach Healthcare System, University of California, Irvine, Irvine, CA.,Southern California Institute for Research and Education, Long Beach, CA; and
| | - Youbao Sha
- Department of Medicine, Baylor College of Medicine, Houston, TX
| | | | - Joseph Hyser
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX
| | - N Tony Eissa
- Department of Medicine, Baylor College of Medicine, Houston, TX; .,Veterans Administration Long Beach Healthcare System, University of California, Irvine, Irvine, CA
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22
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Immunoediting role for major vault protein in apoptotic signaling induced by bacterial N-acyl homoserine lactones. Proc Natl Acad Sci U S A 2021; 118:2012529118. [PMID: 33723037 PMCID: PMC8000436 DOI: 10.1073/pnas.2012529118] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The major vault protein (MVP) mediates diverse cellular responses, including cancer cell resistance to chemotherapy and protection against inflammatory responses to Pseudomonas aeruginosa Here, we report the use of photoactive probes to identify MVP as a target of the N-(3-oxo-dodecanoyl) homoserine lactone (C12), a quorum sensing signal of certain proteobacteria including P. aeruginosa. A treatment of normal and cancer cells with C12 or other N-acyl homoserine lactones (AHLs) results in rapid translocation of MVP into lipid raft (LR) membrane fractions. Like AHLs, inflammatory stimuli also induce LR-localization of MVP, but the C12 stimulation reprograms (functionalizes) bioactivity of the plasma membrane by recruiting death receptors, their apoptotic adaptors, and caspase-8 into LR. These functionalized membranes control AHL-induced signaling processes, in that MVP adjusts the protein kinase p38 pathway to attenuate programmed cell death. Since MVP is the structural core of large particles termed vaults, our findings suggest a mechanism in which MVP vaults act as sentinels that fine-tune inflammation-activated processes such as apoptotic signaling mediated by immunosurveillance cytokines including tumor necrosis factor-related apoptosis inducing ligand (TRAIL).
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23
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Wang JL, Chen WG, Zhang JJ, Xu CJ. Nogo-A-Δ20/EphA4 interaction antagonizes apoptosis of neural stem cells by integrating p38 and JNK MAPK signaling. J Mol Histol 2021; 52:521-537. [PMID: 33555537 DOI: 10.1007/s10735-021-09960-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 01/25/2021] [Indexed: 11/26/2022]
Abstract
Nogo-A protein consists of two main extracellular domains: Nogo-66 (rat amino acid [aa] 1019-1083) and Nogo-A-Δ20 (extracellular, active 180 amino acid Nogo-A region), which serve as strong inhibitors of axon regeneration in the adult CNS (Central Nervous System). Although receptors S1PR2 and HSPGs have been identified as Nogo-A-Δ20 binding proteins, it remains at present elusive whether other receptors directly interacting with Nogo-A-Δ20 exist, and decrease cell death. On the other hand, the key roles of EphA4 in the regulation of glioblastoma, axon regeneration and NSCs (Neural Stem Cells) proliferation or differentiation are well understood, but little is known the relationship between EphA4 and Nogo-A-Δ20 in NSCs apoptosis. Thus, we aim to determine whether Nogo-A-Δ20 can bind to EphA4 and affect survival of NSCs. Here, we discover that EphA4, belonging to a member of erythropoietin-producing hepatocellular (Eph) receptors family, could be acting as a high affinity ligand for Nogo-A-Δ20. Trans-membrane protein of EphA4 is needed for Nogo-A-Δ20-triggered inhibition of NSCs apoptosis, which are mediated by balancing p38 inactivation and JNK MAPK pathway activation. Finally, we predict at the atomic level that essential residues Lys-205, Ile-190, Pro-194 in Nogo-A-Δ20 and EphA4 residues Gln-390, Asn-425, Pro-426 might play critical roles in Nogo-A-Δ20/EphA4 binding via molecular docking.
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Affiliation(s)
- Jun-Ling Wang
- Center for Reproductive Medicine, Affiliated Hospital 1 of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Wei-Guang Chen
- Department of Histology & Embryology, School of Basic Medical Science, Wenzhou Medical University, Cha Shan University Town, No.1 Central North Road, Wenzhou, 325035, Zhejiang, People's Republic of China
| | - Jia-Jia Zhang
- School of 1St Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China
| | - Chao-Jin Xu
- Department of Histology & Embryology, School of Basic Medical Science, Wenzhou Medical University, Cha Shan University Town, No.1 Central North Road, Wenzhou, 325035, Zhejiang, People's Republic of China.
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24
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Park HJ, Lee R, Yoo H, Hong K, Song H. Nonylphenol Induces Apoptosis through ROS/JNK Signaling in a Spermatogonia Cell Line. Int J Mol Sci 2020; 22:ijms22010307. [PMID: 33396729 PMCID: PMC7796095 DOI: 10.3390/ijms22010307] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/23/2020] [Accepted: 12/28/2020] [Indexed: 12/22/2022] Open
Abstract
Nonylphenol (NP) is an endocrine-disruptor chemical that negatively affects reproductive health. Testes exposure to NP results in testicular structure disruption and a reduction in testicular size and testosterone levels. However, the effects of NP on spermatogonia in testes have not been fully elucidated. In this study, the molecular mechanisms of NP in GC-1 spermatogonia (spg) cells were investigated. We found that cell viability significantly decreased and apoptosis increased in a dose-dependent manner when GC-1 spg cells were exposed to NP. Furthermore, the expression levels of the pro-apoptotic proteins increased, whereas anti-apoptosis markers decreased in NP-exposed GC-1 spg cells. We also found that NP increased reactive oxygen species (ROS) generation, suggesting that ROS-induced activation of the MAPK signaling pathway is the molecular mechanism of NP-induced apoptosis in GC-1 spg cells. Thus, NP could induce c-Jun phosphorylation; dose-dependent expression of JNK, MKK4, p53, and p38; and the subsequent inhibition of ERK1/2 and MEK1/2 phosphorylation. The genes involved in apoptosis and JNK signaling were also upregulated in GC-1 spg cells treated with NP compared to those in the controls. Our findings suggest that NP induces apoptosis through ROS/JNK signaling in GC-1 spg cells.
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Affiliation(s)
| | | | | | | | - Hyuk Song
- Correspondence: ; Tel.: +82-2-450-0562
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25
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Co-Administration of Aluminium Hydroxide Nanoparticles and Protective Antigen Domain 4 Encapsulated Non-Ionic Surfactant Vesicles Show Enhanced Immune Response and Superior Protection against Anthrax. Vaccines (Basel) 2020; 8:vaccines8040571. [PMID: 33019545 PMCID: PMC7711981 DOI: 10.3390/vaccines8040571] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 09/16/2020] [Accepted: 09/17/2020] [Indexed: 12/11/2022] Open
Abstract
Aluminium salts have been the adjuvant of choice in more than 100 licensed vaccines. Here, we have studied the synergistic effect of aluminium hydroxide nanoparticles (AH np) and non-ionic surfactant-based vesicles (NISV) in modulating the immune response against protective antigen domain 4 (D4) of Bacillus anthracis. NISV was prepared from Span 60 and cholesterol, while AH np was prepared from aluminium chloride and sodium hydroxide. AH np was co-administered with NISV encapsulating D4 (NISV-D4) to formulate AHnp/NISV-D4. The antigen-specific immune response of AHnp/NISV-D4 was compared with that of commercial alhydrogel (alhy) co-administered with NISV-D4 (alhydrogel/NISV-D4), NISV-D4, AHnp/D4, and alhydrogel/D4. Co-administration of NISV-D4 with AH np greatly improved the D4-specific antibody titer as compared to the control groups. Based on IgG isotyping and ex vivo cytokine analysis, AHnp/NISV-D4 generated a balanced Th1/Th2 response. Furthermore, AH np/NISV-D4 showed superior protection against anthrax spore challenge in comparison to other groups. Thus, we demonstrate the possibility of developing a novel combinatorial nanoformulation capable of augmenting both humoral and cellular response, paving the way for adjuvant research.
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26
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Yang X, Zeng Q, Barış M, Tezel G. Transgenic inhibition of astroglial NF-κB restrains the neuroinflammatory and neurodegenerative outcomes of experimental mouse glaucoma. J Neuroinflammation 2020; 17:252. [PMID: 32859212 PMCID: PMC7456390 DOI: 10.1186/s12974-020-01930-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 08/17/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Glia-driven neuroinflammation promotes neuron injury in glaucoma that is a chronic neurodegenerative disease of the optic nerve and a leading cause of irreversible blindness. Although therapeutic modulation of neuroinflammation is increasingly viewed as a logical strategy to avoid inflammatory neurotoxicity in glaucoma, current understanding of the molecular regulation of neuroinflammation is incomplete, and the molecular targets for immunomodulation remains unknown. Growing datasets pointed to nuclear factor-kappaB (NF-κB), a key transcriptional activator of inflammation, which was identified to be most affected in glaucomatous astroglia. Using a cell type-specific experimental approach, this study aimed to determine the value of astroglial NF-κB as a potential treatment target for immunomodulation in experimental mouse glaucoma. METHODS Neuroinflammatory and neurodegenerative outcomes of experimental glaucoma were comparatively analyzed in mice with or without cre/lox-based conditional deletion of astroglial IκKβ, which is the main activating kinase involved in IκB degradation through the canonical pathway of NF-κB activation. Glial responses and the inflammatory status of the retina and optic nerve were analyzed by cell morphology and cytokine profiling, and neuron structure and function were analyzed by counting retinal ganglion cell (RGC) axons and somas and recording pattern electroretinography (PERG) responses. RESULTS Analysis of glial inflammatory responses showed immunomodulatory outcomes of the conditional transgenic deletion of IκKβ in astroglia. Various pro-inflammatory cytokines known to be transcriptional targets for NF-κB exhibited decreased production in IκKβ-deleted astroglia, which included TNF-α that can induce RGC apoptosis and axon degeneration during glaucomatous neurodegeneration. Indeed, transgenic modulation of inflammatory responses by astroglial IκKβ deletion reduced neurodegeneration at different neuronal compartments, including both RGC axons and somas, and protected PERG responses. CONCLUSIONS The findings of this study support a key role for astroglial NF-κB in neuroinflammatory and neurodegenerative outcomes of experimental glaucoma and the potential of this transcriptional regulator pathway as a glial treatment target to provide neuroprotection through immunomodulation. By pointing to a potential treatment strategy targeting the astroglia, these experimental findings are promising for future clinical translation through transgenic applications to improve the treatment of this blinding disease.
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Affiliation(s)
- Xiangjun Yang
- Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University, Edward S. Harkness Eye Institute, 635 West 165th Street, New York, NY, 10032, USA
| | - Qun Zeng
- Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University, Edward S. Harkness Eye Institute, 635 West 165th Street, New York, NY, 10032, USA
| | - Mine Barış
- Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University, Edward S. Harkness Eye Institute, 635 West 165th Street, New York, NY, 10032, USA
| | - Gülgün Tezel
- Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University, Edward S. Harkness Eye Institute, 635 West 165th Street, New York, NY, 10032, USA.
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27
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He F, Antonucci L, Yamachika S, Zhang Z, Taniguchi K, Umemura A, Hatzivassiliou G, Roose-Girma M, Reina-Campos M, Duran A, Diaz-Meco MT, Moscat J, Sun B, Karin M. NRF2 activates growth factor genes and downstream AKT signaling to induce mouse and human hepatomegaly. J Hepatol 2020; 72:1182-1195. [PMID: 32105670 PMCID: PMC8054878 DOI: 10.1016/j.jhep.2020.01.023] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 01/02/2020] [Accepted: 01/16/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Hepatomegaly can be triggered by insulin and insulin-unrelated etiologies. Insulin acts via AKT, but how other challenges cause hepatomegaly is unknown. METHODS Since many hepatomegaly-inducing toxicants and stressors activate NRF2, we examined the effect of NRF2 activation on liver size and metabolism using a conditional allele encoding a constitutively active NRF2 variant to generate Nrf2Act-hep mice in which NRF2 is selectively activated in hepatocytes. We also used adenoviruses encoding variants of the autophagy adaptor p62/SQSTM1, which activates liver NRF2, as well as liver-specific ATG7-deficient mice (Atg7Δhep) and liver specimens from patients with hepatic sinusoidal obstruction syndrome (HSOS) and autoimmune hepatitis (AIH). RNA sequencing and cell signaling analyses were used to determine cellular consequences of NRF2 activation and diverse histological analyses were used to study effects of the different manipulations on liver and systemic pathophysiology. RESULTS Hepatocyte-specific NRF2 activation, due to p62 accumulation or inhibition of KEAP1 binding, led to hepatomegaly associated with enhanced glycogenosis, steatosis and G2/M cell cycle arrest, fostering hyperplasia without cell division. Surprisingly, all manipulations that led to NRF2 activation also activated AKT, whose inhibition blocked NRF2-induced hepatomegaly and glycogenosis, but not NRF2-dependent antioxidant gene induction. AKT activation was linked to NRF2-mediated transcriptional induction of PDGF and EGF receptor ligands that signaled through their cognate receptors in an autocrine manner. Insulin and insulin-like growth factors were not involved. The NRF2-AKT signaling axis was also activated in human HSOS- and AIH-related hepatomegaly. CONCLUSIONS NRF2, a transcription factor readily activated by xenobiotics, oxidative stress and autophagy disruptors, may be a common mediator of hepatomegaly; its effects on hepatic metabolism can be reversed by AKT/tyrosine kinase inhibitors. LAY SUMMARY Hepatomegaly can be triggered by numerous etiological factors, including infections, liver cancer, metabolic disturbances, toxicant exposure, as well as alcohol abuse or drug-induced hepatitis. This study identified the oxidative stress response transcription factor NRF2 as a common mediator of hepatomegaly. NRF2 activation results in elevated expression of several growth factors. These growth factors are made by hepatocytes and activate their receptors in an autocrine fashion to stimulate the accumulation of glycogen and lipids that lead to hepatocyte and liver enlargement. The protein kinase AKT plays a key role in this process and its inhibition leads to reversal of hepatomegaly.
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Affiliation(s)
- Feng He
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Laura Antonucci
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Shinichiro Yamachika
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Zechuan Zhang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu Province, China
| | - Koji Taniguchi
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Atsushi Umemura
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | | | | | - Miguel Reina-Campos
- Cancer Metabolism and Signaling Networks Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Angeles Duran
- Cancer Metabolism and Signaling Networks Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Maria T Diaz-Meco
- Cancer Metabolism and Signaling Networks Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Jorge Moscat
- Cancer Metabolism and Signaling Networks Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Beicheng Sun
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu Province, China.
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
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Savransky V, Ionin B, Reece J. Current Status and Trends in Prophylaxis and Management of Anthrax Disease. Pathogens 2020; 9:E370. [PMID: 32408493 PMCID: PMC7281134 DOI: 10.3390/pathogens9050370] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 04/29/2020] [Accepted: 05/07/2020] [Indexed: 12/30/2022] Open
Abstract
Bacillus anthracis has been identified as a potential military and bioterror agent as it is relatively simple to produce, with spores that are highly resilient to degradation in the environment and easily dispersed. These characteristics are important in describing how anthrax could be used as a weapon, but they are also important in understanding and determining appropriate prevention and treatment of anthrax disease. Today, anthrax disease is primarily enzootic and found mostly in the developing world, where it is still associated with considerable mortality and morbidity in humans and livestock. This review article describes the spectrum of disease caused by anthrax and the various prevention and treatment options. Specifically we discuss the following; (1) clinical manifestations of anthrax disease (cutaneous, gastrointestinal, inhalational and intravenous-associated); (2) immunology of the disease; (3) an overview of animal models used in research; (4) the current World Health Organization and U.S. Government guidelines for investigation, management, and prophylaxis; (5) unique regulatory approaches to licensure and approval of anthrax medical countermeasures; (6) the history of vaccination and pre-exposure prophylaxis; (7) post-exposure prophylaxis and disease management; (8) treatment of symptomatic disease through the use of antibiotics and hyperimmune or monoclonal antibody-based antitoxin therapies; and (9) the current landscape of next-generation product candidates under development.
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Affiliation(s)
- Vladimir Savransky
- Emergent BioSolutions Inc., 300 Professional Drive, Gaithersburg, MD 20879, USA; (B.I.); (J.R.)
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29
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Namineni S, O'Connor T, Faure-Dupuy S, Johansen P, Riedl T, Liu K, Xu H, Singh I, Shinde P, Li F, Pandyra A, Sharma P, Ringelhan M, Muschaweckh A, Borst K, Blank P, Lampl S, Neuhaus K, Durantel D, Farhat R, Weber A, Lenggenhager D, Kündig TM, Staeheli P, Protzer U, Wohlleber D, Holzmann B, Binder M, Breuhahn K, Assmus LM, Nattermann J, Abdullah Z, Rolland M, Dejardin E, Lang PA, Lang KS, Karin M, Lucifora J, Kalinke U, Knolle PA, Heikenwalder M. A dual role for hepatocyte-intrinsic canonical NF-κB signaling in virus control. J Hepatol 2020; 72:960-975. [PMID: 31954207 DOI: 10.1016/j.jhep.2019.12.019] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 12/02/2019] [Accepted: 12/11/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Hepatic innate immune control of viral infections has largely been attributed to Kupffer cells, the liver-resident macrophages. However, hepatocytes, the parenchymal cells of the liver, also possess potent immunological functions in addition to their known metabolic functions. Owing to their abundance in the liver and known immunological functions, we aimed to investigate the direct antiviral mechanisms employed by hepatocytes. METHODS Using lymphocytic choriomeningitis virus (LCMV) as a model of liver infection, we first assessed the role of myeloid cells by depletion prior to infection. We investigated the role of hepatocyte-intrinsic innate immune signaling by infecting mice lacking canonical NF-κB signaling (IkkβΔHep) specifically in hepatocytes. In addition, mice lacking hepatocyte-specific interferon-α/β signaling-(IfnarΔHep), or interferon-α/β signaling in myeloid cells-(IfnarΔMyel) were infected. RESULTS Here, we demonstrate that LCMV activates NF-κB signaling in hepatocytes. LCMV-triggered NF-κB activation in hepatocytes did not depend on Kupffer cells or TNFR1 signaling but rather on Toll-like receptor signaling. LCMV-infected IkkβΔHep livers displayed strongly elevated viral titers due to LCMV accumulation within hepatocytes, reduced interferon-stimulated gene (ISG) expression, delayed intrahepatic immune cell influx and delayed intrahepatic LCMV-specific CD8+ T cell responses. Notably, viral clearance and ISG expression were also reduced in LCMV-infected primary hepatocytes lacking IKKβ, demonstrating a hepatocyte-intrinsic effect. Similar to livers of IkkβΔHep mice, enhanced hepatocytic LCMV accumulation was observed in livers of IfnarΔHep mice, whereas IfnarΔMyel mice were able to control LCMV infection. Hepatocytic NF-κB signaling was also required for efficient ISG induction in HDV-infected dHepaRG cells and interferon-α/β-mediated inhibition of HBV replication in vitro. CONCLUSIONS Together, these data show that hepatocyte-intrinsic NF-κB is a vital amplifier of interferon-α/β signaling, which is pivotal for strong early ISG responses, immune cell infiltration and hepatic viral clearance. LAY SUMMARY Innate immune cells have been ascribed a primary role in controlling viral clearance upon hepatic infections. We identified a novel dual role for NF-κB signaling in infected hepatocytes which was crucial for maximizing interferon responses and initiating adaptive immunity, thereby efficiently controlling hepatic virus replication.
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Affiliation(s)
- Sukumar Namineni
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Virology, Technical University of Munich and Helmholtz Zentrum München, Schneckenburgerstrasse 8, 81675 Munich, Germany; Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, Ismaningerstraße 22, 81675 Munich, Germany
| | - Tracy O'Connor
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, Ismaningerstraße 22, 81675 Munich, Germany
| | - Suzanne Faure-Dupuy
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Pål Johansen
- Department of Dermatology, University Hospital Zurich and University of Zurich, Gloriastrasse 31, 8091 Zurich, Switzerland
| | - Tobias Riedl
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Kaijing Liu
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Haifeng Xu
- Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, Essen 45147, Germany
| | - Indrabahadur Singh
- Emmy Noether Research Group Epigenetic Machineries and Cancer, Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Prashant Shinde
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätstr.1, 40225 Düsseldorf, Germany
| | - Fanghui Li
- Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, Essen 45147, Germany
| | - Aleksandra Pandyra
- Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, Essen 45147, Germany
| | - Piyush Sharma
- Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, Essen 45147, Germany; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA, 38105
| | - Marc Ringelhan
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Virology, Technical University of Munich and Helmholtz Zentrum München, Schneckenburgerstrasse 8, 81675 Munich, Germany; Department of Internal Medicine II, University Hospital rechts der Isar, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
| | - Andreas Muschaweckh
- Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
| | - Katharina Borst
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hanover Medical School and the Helmholtz Centre for Infection Research, Brunswick, Germany
| | - Patrick Blank
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hanover Medical School and the Helmholtz Centre for Infection Research, Brunswick, Germany
| | - Sandra Lampl
- Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, Ismaningerstraße 22, 81675 Munich, Germany
| | - Katharina Neuhaus
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - David Durantel
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR 5286, Centre Léon Bérard, Lyon, France
| | - Rayan Farhat
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR 5286, Centre Léon Bérard, Lyon, France
| | - Achim Weber
- Department of Pathology and Molecular Pathology, University Hospital of Zurich, 8091 Zurich, Switzerland
| | - Daniela Lenggenhager
- Department of Pathology and Molecular Pathology, University Hospital of Zurich, 8091 Zurich, Switzerland
| | - Thomas M Kündig
- Department of Dermatology, University Hospital Zurich and University of Zurich, Gloriastrasse 31, 8091 Zurich, Switzerland
| | - Peter Staeheli
- Institute of Virology, University of Freiburg, Freiburg, Germany
| | - Ulrike Protzer
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Virology, Technical University of Munich and Helmholtz Zentrum München, Schneckenburgerstrasse 8, 81675 Munich, Germany
| | - Dirk Wohlleber
- Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, Ismaningerstraße 22, 81675 Munich, Germany
| | - Bernhard Holzmann
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Marco Binder
- Research Group "Dynamics of Early Viral Infection and the Innate Antiviral Response", Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Kai Breuhahn
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Jacob Nattermann
- Department of Internal Medicine, University of Bonn, Bonn, Germany
| | | | - Maude Rolland
- Laboratory of Molecular Immunology and Signal Transduction, GIGA-Institute, University of Liège, 4000 Liège, Belgium
| | - Emmanuel Dejardin
- Laboratory of Molecular Immunology and Signal Transduction, GIGA-Institute, University of Liège, 4000 Liège, Belgium
| | - Philipp A Lang
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätstr.1, 40225 Düsseldorf, Germany
| | - Karl S Lang
- Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, Essen 45147, Germany
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, California 92093, USA
| | - Julie Lucifora
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR 5286, Centre Léon Bérard, Lyon, France
| | - Ulrich Kalinke
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hanover Medical School and the Helmholtz Centre for Infection Research, Brunswick, Germany
| | - Percy A Knolle
- Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, Ismaningerstraße 22, 81675 Munich, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Virology, Technical University of Munich and Helmholtz Zentrum München, Schneckenburgerstrasse 8, 81675 Munich, Germany; Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, Ismaningerstraße 22, 81675 Munich, Germany.
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Zhan G, Hu J, Xiao B, Wang X, Yang Z, Yang G, Lu L. Trillin prevents proliferation and induces apoptosis through inhibiting STAT3 nuclear translocation in hepatoma carcinoma cells. Med Oncol 2020; 37:44. [PMID: 32270306 DOI: 10.1007/s12032-020-01369-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Accepted: 03/25/2020] [Indexed: 01/10/2023]
Abstract
Trillin is a constituent of total Trillium Tschonoskii Maxim (TTM), which is extracted from TTM and displayed anti-tumor effect in many tumor cell lines. However, the anti-tumor mechanism of trillin is still unclear. This study demonstrated that trillin could dramatically inhibit hepatoma carcinoma cell proliferation, induce apoptosis and decrease migration and invasion through suppressing phosphorylated STAT3 translocated to nucleus. Trillin could down-regulate Bcl-2 and Survivin, up-regulate cleaved PRAP, leading to dramatically apoptosis; trillin could also down-regulate MMP1, MMP2, MucI and VEGF, which displayed an inhibition effect on hepatocellular tumor cells invasion and development. The results of this study indicated the potential utility of trillin as a STAT3 inhibitor for the treatment of cancers.
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Affiliation(s)
- Guangjie Zhan
- Medical School of Hubei MinZu University, Enshi, 445000, Hubei, People's Republic of China
| | - Jun Hu
- Demonstration Center for Experimental Basic Medicine Education of Wuhan University, Wuhan, 430071, Hubei, People's Republic of China
| | - Benjian Xiao
- Medical School of Hubei MinZu University, Enshi, 445000, Hubei, People's Republic of China
| | - Xianli Wang
- Science and Technology College of Hubei MinZu University, Enshi, 445000, Hubei, People's Republic of China
| | - Zixian Yang
- Demonstration Center for Experimental Basic Medicine Education of Wuhan University, Wuhan, 430071, Hubei, People's Republic of China
| | - Guohua Yang
- Demonstration Center for Experimental Basic Medicine Education of Wuhan University, Wuhan, 430071, Hubei, People's Republic of China.
| | - Lili Lu
- New Medicine Innovation and Development Institute, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, College of Medicine, Wuhan University of Science and Technology, Wuhan, 430065, Hubei, People's Republic of China.
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31
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Muendlein HI, Jetton D, Connolly WM, Eidell KP, Magri Z, Smirnova I, Poltorak A. cFLIP L protects macrophages from LPS-induced pyroptosis via inhibition of complex II formation. Science 2020; 367:1379-1384. [PMID: 32193329 DOI: 10.1126/science.aay3878] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 10/16/2019] [Accepted: 02/20/2020] [Indexed: 12/16/2022]
Abstract
Cell death and inflammation are interdependent host responses to infection. During pyroptotic cell death, interleukin-1β (IL-1β) release occurs through caspase-1 and caspase-11-mediated gasdermin D pore formation. In vivo, responses to lipopolysaccharide (LPS) result in IL-1β secretion. In vitro, however, murine macrophages require a second "danger signal" for the inflammasome-driven maturation of IL-1β. Recent reports have shown caspase-8-mediated pyroptosis in LPS-activated macrophages but have provided conflicting evidence regarding the release of IL-1β under these conditions. Here, to further characterize the mechanism of LPS-induced secretion in vitro, we reveal an important role for cellular FLICE-like inhibitory protein (cFLIP) in the regulation of the inflammatory response. Specifically, we show that deficiency of the long isoform cFLIPL promotes complex II formation, driving pyroptosis, and the secretion of IL-1β in response to LPS alone.
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Affiliation(s)
- Hayley I Muendlein
- Graduate Program in Genetics, Tufts Graduate School of Biomedical Sciences, Boston, MA 02111, USA
| | - David Jetton
- Graduate Program in Immunology, Tufts Graduate School of Biomedical Sciences, Boston, MA 02111, USA
| | - Wilson M Connolly
- Department of Immunology, Tufts University School of Medicine, Boston, MA 02111, USA
| | - Keith P Eidell
- Graduate Program in Immunology, Tufts Graduate School of Biomedical Sciences, Boston, MA 02111, USA
| | - Zoie Magri
- Graduate Program in Immunology, Tufts Graduate School of Biomedical Sciences, Boston, MA 02111, USA
| | - Irina Smirnova
- Department of Immunology, Tufts University School of Medicine, Boston, MA 02111, USA
| | - Alexander Poltorak
- Department of Immunology, Tufts University School of Medicine, Boston, MA 02111, USA. .,Laboratory of Genetics of Innate Immunity, Petrozavodsk State University, Petrozavodsk, Republic of Karelia 185910, Russia
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32
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Azimi T, Zamirnasta M, Sani MA, Soltan Dallal MM, Nasser A. Molecular Mechanisms of Salmonella Effector Proteins: A Comprehensive Review. Infect Drug Resist 2020; 13:11-26. [PMID: 32021316 PMCID: PMC6954085 DOI: 10.2147/idr.s230604] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 12/20/2019] [Indexed: 12/27/2022] Open
Abstract
Salmonella can be categorized into many serotypes, which are specific to known hosts or broadhosts. It makes no difference which one of the serotypes would penetrate the gastrointestinal tract because they all face similar obstacles such as mucus and microbiome. However, following their penetration, some species remain in the gastrointestinal tract; yet, others spread to another organ like gallbladder. Salmonella is required to alter the immune response to sustain its intracellular life. Changing the host response requires particular effector proteins and vehicles to translocate them. To this end, a categorized gene called Salmonella pathogenicity island (SPI) was developed; genes like Salmonella pathogenicity island encode aggressive or modulating proteins. Initially, Salmonella needs to be attached and stabilized via adhesin factor, without which no further steps can be taken. In this review, an attempt has been made to elaborate on each factor attached to the host cell or to modulating and aggressive proteins that evade immune systems. This review includes four sections: (A) attachment factors or T3SS- independent entrance, (B) effector proteins or T3SS-dependent entrance, (c) regulation of invasive genes, and (D) regulation of immune responses.
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Affiliation(s)
- Taher Azimi
- Pediatric Infections Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Students Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Zamirnasta
- Clinical Microbiology Research Center, Ilam University of Medical Science, Ilam, Iran
| | - Mahmood Alizadeh Sani
- Food Safety and Hygiene Division, Environmental health Department, School of Public Health, Tehran University of medical sciences, Tehran, Iran
- Students Research Committee, Department of Food Sciences and Technology, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Ahmad Nasser
- Clinical Microbiology Research Center, Ilam University of Medical Science, Ilam, Iran
- Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Department of Medical Microbiology, School of Medicine, Ilam University of Medical Science, Ilam, Iran
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Gupta N, Khatoon N, Mishra A, Verma VK, Prajapati VK. Structural vaccinology approach to investigate the virulent and secretory proteins of Bacillus anthracis for devising anthrax next-generation vaccine. J Biomol Struct Dyn 2019; 38:4895-4905. [DOI: 10.1080/07391102.2019.1688197] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- Nidhi Gupta
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Bandarsindri, Kishangarh, Ajmer, Rajasthan, India
| | - Nazia Khatoon
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Bandarsindri, Kishangarh, Ajmer, Rajasthan, India
| | - Amit Mishra
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, India
| | - Vijay Kumar Verma
- Department of Microbiology, School of Life Sciences, Central University of Rajasthan, Bandarsindri, Kishangarh, Ajmer, Rajasthan, India
| | - Vijay Kumar Prajapati
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Bandarsindri, Kishangarh, Ajmer, Rajasthan, India
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34
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Vrentas CE, Boggiatto PM, Olsen SC, Leppla SH, Moayeri M. Characterization of the NLRP1 inflammasome response in bovine species. Innate Immun 2019; 26:301-311. [PMID: 31711335 PMCID: PMC7251794 DOI: 10.1177/1753425919886649] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Inflammasomes act as sensors of infection or damage to initiate immune responses.
While extensively studied in rodents, understanding of livestock inflammasomes
is limited. The NLRP1 inflammasome sensor in rodents is activated by
Toxoplasma gondii, Bacillus anthracis
lethal toxin (LT), and potentially other zoonotic pathogens. LT activates NLRP1
by N-terminal proteolysis, inducing macrophage pyroptosis and a pro-inflammatory
cytokine response. In contrast, NLRP1 in macrophages from humans and certain
rodent strains is resistant to LT cleavage, and pyroptosis is not induced.
Evolution of NLRP1 sequences towards those leading to pyroptosis is of interest
in understanding innate immune responses in different hosts. We characterized
NLRP1 in cattle (Bos taurus) and American bison (Bison
bison). Bovine NLRP1 is not cleaved by LT, and cattle and bison
macrophages do not undergo toxin-induced pyroptosis. Additionally, we found a
predicted Nlrp1 splicing isoform in cattle macrophages lacking
the N-terminal domain. Resistance to LT in bovine and human NLRP1 correlates
with evolutionary sequence similarity to rodents. Consistent with LT-resistant
rodents, bovine macrophages undergo a slower non-pyroptotic death in the
presence of LPS and LT. Overall, our findings support the model that NLRP1
activation by LT requires N-terminal cleavage, and provide novel information on
mechanisms underlying immune response diversity.
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Affiliation(s)
- Catherine E Vrentas
- Infectious Bacterial Diseases Unit, National Animal Disease
Center, Agricultural Research Service, US Department of Agriculture, Ames,
USA
- Catherine E Vrentas, Infectious Bacterial
Diseases Unit, National Animal Disease Center, Agricultural Research Service, US
Department of Agriculture, Ames, IA 50010, USA.
| | - Paola M Boggiatto
- Infectious Bacterial Diseases Unit, National Animal Disease
Center, Agricultural Research Service, US Department of Agriculture, Ames,
USA
| | - Steven C Olsen
- Infectious Bacterial Diseases Unit, National Animal Disease
Center, Agricultural Research Service, US Department of Agriculture, Ames,
USA
| | - Stephen H Leppla
- Laboratory of Parasitic Diseases, National Institute of Allergy
and Infectious Diseases, National Institutes of Health, Bethesda, USA
| | - Mahtab Moayeri
- Laboratory of Parasitic Diseases, National Institute of Allergy
and Infectious Diseases, National Institutes of Health, Bethesda, USA
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35
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Cai J, Chen D, Chen D, Huang X, Li C, Liu H, Li M, Li G, Zhang Y. Complete Genome Sequence of Brevibacillus laterosporus Bl-zj, an Algicidal Bacterium Isolated from Soil. Microbiol Resour Announc 2019; 8:e00408-19. [PMID: 31346010 PMCID: PMC6658680 DOI: 10.1128/mra.00408-19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 06/27/2019] [Indexed: 11/20/2022] Open
Abstract
Brevibacillus laterosporus can be used as a biocontrol agent for varieties of plants, as it is a pathogen of invertebrates and can also inhibit many bacteria and fungi. Here, we describe the complete genome sequence of B. laterosporus strain Bl-zj, an algicidal bacterium on cyanobacteria isolated from the soil in China.
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Affiliation(s)
- Jian Cai
- Fisheries College of Guangdong Ocean University, Zhanjiang, China
| | - Dianyu Chen
- Fisheries College of Guangdong Ocean University, Zhanjiang, China
| | - Dong Chen
- Fisheries College of Guangdong Ocean University, Zhanjiang, China
- Engineering Technology Research Center for Algae Breeding and Application of Guangdong Province, Zhanjiang, China
| | - Xianghu Huang
- Fisheries College of Guangdong Ocean University, Zhanjiang, China
- Shenzhen Institute of Guangdong Ocean University, Shenzhen, China
- Engineering Technology Research Center for Algae Breeding and Application of Guangdong Province, Zhanjiang, China
| | - Changling Li
- Fisheries College of Guangdong Ocean University, Zhanjiang, China
- Shenzhen Institute of Guangdong Ocean University, Shenzhen, China
- Engineering Technology Research Center for Algae Breeding and Application of Guangdong Province, Zhanjiang, China
| | - Huiling Liu
- Fisheries College of Guangdong Ocean University, Zhanjiang, China
- Shenzhen Institute of Guangdong Ocean University, Shenzhen, China
- Engineering Technology Research Center for Algae Breeding and Application of Guangdong Province, Zhanjiang, China
| | - Mengjie Li
- Fisheries College of Guangdong Ocean University, Zhanjiang, China
| | - Guanbao Li
- Fisheries College of Guangdong Ocean University, Zhanjiang, China
| | - Yulei Zhang
- Fisheries College of Guangdong Ocean University, Zhanjiang, China
- Shenzhen Institute of Guangdong Ocean University, Shenzhen, China
- Engineering Technology Research Center for Algae Breeding and Application of Guangdong Province, Zhanjiang, China
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36
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Ehling-Schulz M, Lereclus D, Koehler TM. The Bacillus cereus Group: Bacillus Species with Pathogenic Potential. Microbiol Spectr 2019; 7:10.1128/microbiolspec.gpp3-0032-2018. [PMID: 31111815 PMCID: PMC6530592 DOI: 10.1128/microbiolspec.gpp3-0032-2018] [Citation(s) in RCA: 299] [Impact Index Per Article: 49.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Indexed: 12/17/2022] Open
Abstract
The Bacillus cereus group includes several Bacillus species with closely related phylogeny. The most well-studied members of the group, B. anthracis, B. cereus, and B. thuringiensis, are known for their pathogenic potential. Here, we present the historical rationale for speciation and discuss shared and unique features of these bacteria. Aspects of cell morphology and physiology, and genome sequence similarity and gene synteny support close evolutionary relationships for these three species. For many strains, distinct differences in virulence factor synthesis provide facile means for species assignment. B. anthracis is the causative agent of anthrax. Some B. cereus strains are commonly recognized as food poisoning agents, but strains can also cause localized wound and eye infections as well as systemic disease. Certain B. thuringiensis strains are entomopathogens and have been commercialized for use as biopesticides, while some strains have been reported to cause infection in immunocompromised individuals. In this article we compare and contrast B. anthracis, B. cereus, and B. thuringiensis, including ecology, cell structure and development, virulence attributes, gene regulation and genetic exchange systems, and experimental models of disease.
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Affiliation(s)
- Monika Ehling-Schulz
- Institute of Microbiology, Department of Pathology, University of Veterinary Medicine, 1210 Vienna, Austria
| | - Didier Lereclus
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France
| | - Theresa M Koehler
- Department of Microbiology and Molecular Genetics, McGovern Medical School, University of Texas Health Science Center - Houston, Houston, TX 77030
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37
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Kumar S, Lata KS, Sharma P, Bhairappanavar SB, Soni S, Das J. Inferring pathogen-host interactions between Leptospira interrogans and Homo sapiens using network theory. Sci Rep 2019; 9:1434. [PMID: 30723266 PMCID: PMC6363727 DOI: 10.1038/s41598-018-38329-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 12/20/2018] [Indexed: 12/19/2022] Open
Abstract
Leptospirosis is the most emerging zoonotic disease of epidemic potential caused by pathogenic species of Leptospira. The bacterium invades the host system and causes the disease by interacting with the host proteins. Analyzing these pathogen-host protein interactions (PHPIs) may provide deeper insight into the disease pathogenesis. For this analysis, inter-species as well as intra-species protein interactions networks of Leptospira interrogans and human were constructed and investigated. The topological analyses of these networks showed lesser connectivity in inter-species network than intra-species, indicating the perturbed nature of the inter-species network. Hence, it can be one of the reasons behind the disease development. A total of 35 out of 586 PHPIs were identified as key interactions based on their sub-cellular localization. Two outer membrane proteins (GpsA and MetXA) and two periplasmic proteins (Flab and GlyA) participating in PHPIs were found conserved in all pathogenic, intermediate and saprophytic spp. of Leptospira. Furthermore, the bacterial membrane proteins involved in PHPIs were found playing major roles in disruption of the immune systems and metabolic processes within host and thereby causing infectious disease. Thus, the present results signify that the membrane proteins participating in such interactions hold potential to serve as effective immunotherapeutic candidates for vaccine development.
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Affiliation(s)
- Swapnil Kumar
- Gujarat Biotechnology Research Centre, Department of Science & Technology, Government of Gujarat, Gandhinagar, 382011, India
| | - Kumari Snehkant Lata
- Gujarat Biotechnology Research Centre, Department of Science & Technology, Government of Gujarat, Gandhinagar, 382011, India
| | - Priyanka Sharma
- Gujarat Biotechnology Research Centre, Department of Science & Technology, Government of Gujarat, Gandhinagar, 382011, India
| | - Shivarudrappa B Bhairappanavar
- Gujarat Biotechnology Research Centre, Department of Science & Technology, Government of Gujarat, Gandhinagar, 382011, India
| | - Subhash Soni
- Gujarat Biotechnology Research Centre, Department of Science & Technology, Government of Gujarat, Gandhinagar, 382011, India
| | - Jayashankar Das
- Gujarat Biotechnology Research Centre, Department of Science & Technology, Government of Gujarat, Gandhinagar, 382011, India.
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Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection. Proc Natl Acad Sci U S A 2018; 115:E10888-E10897. [PMID: 30381458 DOI: 10.1073/pnas.1809548115] [Citation(s) in RCA: 651] [Impact Index Per Article: 93.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Cell death and inflammation are intimately linked during Yersinia infection. Pathogenic Yersinia inhibits the MAP kinase TGFβ-activated kinase 1 (TAK1) via the effector YopJ, thereby silencing cytokine expression while activating caspase-8-mediated cell death. Here, using Yersinia pseudotuberculosis in corroboration with costimulation of lipopolysaccharide and (5Z)-7-Oxozeaenol, a small-molecule inhibitor of TAK1, we show that caspase-8 activation during TAK1 inhibition results in cleavage of both gasdermin D (GSDMD) and gasdermin E (GSDME) in murine macrophages, resulting in pyroptosis. Loss of GsdmD delays membrane rupture, reverting the cell-death morphology to apoptosis. We found that the Yersinia-driven IL-1 response arises from asynchrony of macrophage death during bulk infections in which two cellular populations are required to provide signal 1 and signal 2 for IL-1α/β release. Furthermore, we found that human macrophages are resistant to YopJ-mediated pyroptosis, with dampened IL-1β production. Our results uncover a form of caspase-8-mediated pyroptosis and suggest a hypothesis for the increased sensitivity of humans to Yersinia infection compared with the rodent reservoir.
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Prolonged IKKβ Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells. Cell Rep 2018; 21:578-586. [PMID: 29045828 DOI: 10.1016/j.celrep.2017.09.082] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 09/05/2017] [Accepted: 09/25/2017] [Indexed: 01/28/2023] Open
Abstract
Regulatory T cells (Tregs) prevent autoimmunity but limit antitumor immunity. The canonical NF-κB signaling pathway both activates immunity and promotes thymic Treg development. Here, we report that mature Tregs continue to require NF-κB signaling through IκB-kinase β (IKKβ) after thymic egress. Mice lacking IKKβ in mature Tregs developed scurfy-like immunopathology due to death of peripheral FoxP3+ Tregs. Also, pharmacological IKKβ inhibition reduced Treg numbers in the circulation by ∼50% and downregulated FoxP3 and CD25 expression and STAT5 phosphorylation. In contrast, activated cytotoxic T lymphocytes (CTLs) were resistant to IKKβ inhibition because other pathways, in particular nuclear factor of activated T cells (NFATc1) signaling, sustained their survival and expansion. In a melanoma mouse model, IKKβ inhibition after CTL cross-priming improved the antitumor response and delayed tumor growth. In conclusion, prolonged IKKβ inhibition decimates circulating Tregs and improves CTL responses when commenced after tumor vaccination, indicating that IKKβ represents a druggable checkpoint.
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40
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Ha SD, Cho W, Kim SO. HDAC8 Prevents Anthrax Lethal Toxin-induced Cell Cycle Arrest through Silencing PTEN in Human Monocytic THP-1 Cells. Toxins (Basel) 2017; 9:E162. [PMID: 28509866 PMCID: PMC5450710 DOI: 10.3390/toxins9050162] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 05/09/2017] [Accepted: 05/10/2017] [Indexed: 02/08/2023] Open
Abstract
Anthrax lethal toxin (LeTx) is a cytotoxic virulence factor that causes cell cycle arrest and cell death in various cell types. However, susceptibility to the cytotoxic effects varies depending on cell types. In proliferating monocytes, LeTx has only transient cytotoxic effects due to activation of the phosphoinositide 3-kinase (PI3K)-AKT-mediated adaptive responses. To date, the mechanism of LeTx in activating PI3K-AKT signaling axis is unknown. This study shows that the histone deacetylase 8 (HDAC8) is involved in activating PI3K-AKT signaling axis through down-regulating the phosphatase and tensin homolog 1 (PTEN) in human monocytic THP-1 cells. The HDAC8-specific activator TM-2-51 and inhibitor PCI-34051 enhanced and prevented, respectively, AKT activation and cell cycle progression in LeTx-treated cells. Furthermore, HDAC8 induced tri-methylation of histone H3 lysine 27 (H3K27me3), which is known to suppress PTEN expression, through at least in part down-regulating the H3K27me3 eraser Jumonji Domain Containing (JMJD) 3. Importantly, the JMJD3-specific inhibitor GSK-J4 induced AKT activation and protected cell cycle arrest in LeTx-treated cells, regardless the presence of HDAC8 activity. Collectively, this study for the first time demonstrated that HDAC8 activity determines susceptibility to cell cycle arrest induced by LeTx, through regulating the PI3K-PTEN-AKT signaling axis.
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Affiliation(s)
- Soon-Duck Ha
- Department of Microbiology and Immunology, The University of Western Ontario, London, ON N6G 2V4, Canada.
| | - Woohyun Cho
- Department of Microbiology and Immunology, The University of Western Ontario, London, ON N6G 2V4, Canada.
| | - Sung Ouk Kim
- Department of Microbiology and Immunology, The University of Western Ontario, London, ON N6G 2V4, Canada.
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41
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Dexheimer GM, De Oliveira Becker Delving LK, De Oliveira HS, Biolchi V, Goettert MI, Pozzobon A. Calyptranthes grandifolia O.Berg (Myrtaceae) ethanolic extract inhibits TNF-α gene expression and cytokine release in vitro. Mol Med Rep 2017; 15:2873-2880. [DOI: 10.3892/mmr.2017.6319] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 01/20/2017] [Indexed: 11/06/2022] Open
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42
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Schumacher MA, Hedl M, Abraham C, Bernard JK, Lozano PR, Hsieh JJ, Almohazey D, Bucar EB, Punit S, Dempsey PJ, Frey MR. ErbB4 signaling stimulates pro-inflammatory macrophage apoptosis and limits colonic inflammation. Cell Death Dis 2017; 8:e2622. [PMID: 28230865 PMCID: PMC5386486 DOI: 10.1038/cddis.2017.42] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 01/14/2017] [Accepted: 01/17/2017] [Indexed: 02/07/2023]
Abstract
Efficient clearance of pro-inflammatory macrophages from tissues after resolution of a challenge is critical to prevent prolonged inflammation. Defects in clearance can contribute to conditions such as inflammatory bowel disease, and thus may be therapeutically targetable. However, the signaling pathways that induce termination of pro-inflammatory macrophages are incompletely defined. We tested whether the ErbB4 receptor tyrosine kinase, previously not known to have role in macrophage biology, is involved in this process. In vitro, pro-inflammatory activation of cultured murine and human macrophages induced ErbB4 expression; in contrast, other ErbB family members were not induced in pro-inflammatory cells, and other innate immune lineages (dendritic cells, neutrophils) did not express detectable ErbB4 levels. Treatment of activated pro-inflammatory macrophages with the ErbB4 ligand neuregulin-4 (NRG4) induced apoptosis. ErbB4 localized to the mitochondria in these cells. Apoptosis was accompanied by loss of mitochondrial membrane potential, and was dependent upon the proteases that generate the cleaved ErbB4 intracellular domain fragment, suggesting a requirement for this fragment and mitochondrial pathway apoptosis. In vivo, ErbB4 was highly expressed on pro-inflammatory macrophages but not neutrophils during experimental DSS colitis in C57Bl/6 mice. Active inflammation in this model suppressed NRG4 expression, which may allow for macrophage persistence and ongoing inflammation. Consistent with this notion, NRG4 levels rebounded during the recovery phase, and administration of exogenous NRG4 during colitis reduced colonic macrophage numbers and ameliorated inflammation. These data define a novel role for ErbB4 in macrophage apoptosis, and outline a mechanism of feedback inhibition that may promote resolution of colitis.
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Affiliation(s)
- Michael A Schumacher
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.,Departments of Pediatrics and of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
| | - Matija Hedl
- Department of Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | - Clara Abraham
- Department of Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | - Jessica K Bernard
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.,Departments of Pediatrics and of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA.,University of Southern California Herman Ostrow School of Dentistry, Los Angeles, CA 90089, USA
| | - Patricia R Lozano
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Jonathan J Hsieh
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.,Departments of Pediatrics and of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
| | - Dana Almohazey
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.,Departments of Pediatrics and of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA.,University of Southern California Herman Ostrow School of Dentistry, Los Angeles, CA 90089, USA
| | - Edie B Bucar
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.,Departments of Pediatrics and of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
| | - Shivesh Punit
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Peter J Dempsey
- Department of Pediatrics, University of Colorado Medical School, Aurora, CO 80045, USA
| | - Mark R Frey
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.,Departments of Pediatrics and of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
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43
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Goldberg AB, Cho E, Miller CJ, Lou HJ, Turk BE. Identification of a Substrate-selective Exosite within the Metalloproteinase Anthrax Lethal Factor. J Biol Chem 2016; 292:814-825. [PMID: 27909054 DOI: 10.1074/jbc.m116.761734] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 11/23/2016] [Indexed: 01/02/2023] Open
Abstract
The metalloproteinase anthrax lethal factor (LF) is secreted by Bacillus anthracis to promote disease virulence through disruption of host signaling pathways. LF is a highly specific protease, exclusively cleaving mitogen-activated protein kinase kinases (MKKs) and rodent NLRP1B (NACHT leucine-rich repeat and pyrin domain-containing protein 1B). How LF achieves such restricted substrate specificity is not understood. Previous studies have suggested the existence of an exosite interaction between LF and MKKs that promotes cleavage efficiency and specificity. Through a combination of in silico prediction and site-directed mutagenesis, we have mapped an exosite to a non-catalytic region of LF. Mutations within this site selectively impair proteolysis of full-length MKKs yet have no impact on cleavage of short peptide substrates. Although this region appears important for cleaving all LF protein substrates, we found that mutation of specific residues within the exosite differentially affects MKK and NLRP1B cleavage in vitro and in cultured cells. One residue in particular, Trp-271, is essential for cleavage of MKK3, MKK4, and MKK6 but dispensable for targeting of MEK1, MEK2, and NLRP1B. Analysis of chimeric substrates suggests that this residue interacts with the MKK catalytic domain. We found that LF-W271A blocked ERK phosphorylation and growth in a melanoma cell line, suggesting that it may provide a highly selective inhibitor of MEK1/2 for use as a cancer therapeutic. These findings provide insight into how a bacterial toxin functions to specifically impair host signaling pathways and suggest a general strategy for mapping protease exosite interactions.
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Affiliation(s)
- Allison B Goldberg
- From the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520
| | - Eunice Cho
- From the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520
| | - Chad J Miller
- From the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520
| | - Hua Jane Lou
- From the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520
| | - Benjamin E Turk
- From the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520
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44
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Head BM, Rubinstein E, Meyers AFA. Alternative pre-approved and novel therapies for the treatment of anthrax. BMC Infect Dis 2016; 16:621. [PMID: 27809794 PMCID: PMC5094018 DOI: 10.1186/s12879-016-1951-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 10/22/2016] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Bacillus anthracis, the causative agent of anthrax, is a spore forming and toxin producing rod-shaped bacterium that is classified as a category A bioterror agent. This pathogenic microbe can be transmitted to both animals and humans. Clinical presentation depends on the route of entry (direct contact, ingestion, injection or aerosolization) with symptoms ranging from isolated skin infections to more severe manifestations such as cardiac or pulmonary shock, meningitis, and death. To date, anthrax is treatable if antibiotics are administered promptly and continued for 60 days. However, if treatment is delayed or administered improperly, the patient's chances of survival are decreased drastically. In addition, antibiotics are ineffective against the harmful anthrax toxins and spores. Therefore, alternative therapeutics are essential. In this review article, we explore and discuss advances that have been made in anthrax therapy with a primary focus on alternative pre-approved and novel antibiotics as well as anti-toxin therapies. METHODS A literature search was conducted using the University of Manitoba search engine. Using this search engine allowed access to a greater variety of journals/articles that would have otherwise been restricted for general use. In order to be considered for discussion for this review, all articles must have been published later than 2009. RESULTS The alternative pre-approved antibiotics demonstrated high efficacy against B. anthracis both in vitro and in vivo. In addition, the safety profile and clinical pharmacology of these drugs were already known. Compounds that targeted underexploited bacterial processes (DNA replication, RNA synthesis, and cell division) were also very effective in combatting B. anthracis. In addition, these novel compounds prevented bacterial resistance. Targeting B. anthracis virulence, more specifically the anthrax toxins, increased the length of which treatment could be administered. CONCLUSIONS Several novel and pre-existing antibiotics, as well as toxin inhibitors, have shown increasing promise. A combination treatment that targets both bacterial growth and toxin production would be ideal and probably necessary for effectively combatting this armed bacterium.
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Affiliation(s)
- Breanne M. Head
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9 Canada
| | - Ethan Rubinstein
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9 Canada
| | - Adrienne F. A. Meyers
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9 Canada
- National Laboratory for HIV Immunology, JC Wilt Infectious Disease Research Centre, Public Health Agency of Canada, Winnipeg, Canada
- Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya
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45
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Booth JL, Duggan ES, Patel VI, Langer M, Wu W, Braun A, Coggeshall KM, Metcalf JP. Bacillus anthracis spore movement does not require a carrier cell and is not affected by lethal toxin in human lung models. Microbes Infect 2016; 18:615-626. [PMID: 27320392 PMCID: PMC5534360 DOI: 10.1016/j.micinf.2016.06.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Revised: 05/04/2016] [Accepted: 06/08/2016] [Indexed: 01/29/2023]
Abstract
The lung is the entry site for Bacillus anthracis in inhalation anthrax, the most deadly form of the disease. Spores escape from the alveolus to regional lymph nodes, germinate and enter the circulatory system to cause disease. The roles of carrier cells and the effects of B. anthracis toxins in this process are unclear. We used a human lung organ culture model to measure spore uptake by antigen presenting cells (APC) and alveolar epithelial cells (AEC), spore partitioning between these cells, and the effects of B. anthracis lethal toxin and protective antigen. We repeated the study in a human A549 alveolar epithelial cell model. Most spores remained unassociated with cells, but the majority of cell-associated spores were in AEC, not in APC. Spore movement was not dependent on internalization, although the location of internalized spores changed in both cell types. Spores also internalized in a non-uniform pattern. Toxins affected neither transit of the spores nor the partitioning of spores into AEC and APC. Our results support a model of spore escape from the alveolus that involves spore clustering with transient passage through intact AEC. However, subsequent transport of spores by APC from the lung to the lymph nodes may occur.
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Affiliation(s)
- J Leland Booth
- Pulmonary and Critical Care Division of the Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Elizabeth S Duggan
- Pulmonary and Critical Care Division of the Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Vineet I Patel
- Pulmonary and Critical Care Division of the Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Marybeth Langer
- Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
| | - Wenxin Wu
- Pulmonary and Critical Care Division of the Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Armin Braun
- Fraunhofer Institute for Toxicology and Experimental Medicine, D-30625, Hannover, Germany.
| | - K Mark Coggeshall
- Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
| | - Jordan P Metcalf
- Pulmonary and Critical Care Division of the Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
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46
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Zhang J, Jing X, Niu W, Zhang M, Ge L, Miao C, Tang X. Peroxiredoxin 1 has an anti-apoptotic role via apoptosis signal-regulating kinase 1 and p38 activation in mouse models with oral precancerous lesions. Oncol Lett 2016; 12:413-420. [PMID: 27347160 DOI: 10.3892/ol.2016.4659] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 04/08/2016] [Indexed: 12/16/2022] Open
Abstract
Peroxiredoxin 1 (Prx1) is important in the protection of cells from oxidative damage and the regulation of cell proliferation and apoptosis. Prx1 is overexpressed in oral precancerous lesions of oral leukoplakia (OLK) and oral cancer; however, the association between Prx1 expression and OLK pathogenesis remains unknown. The present study investigated the role of Prx1 and its molecular mechanisms in oxidative stress-induced apoptosis during the pathogenesis of OLK. Wild-type and Prx1 knockout mice were treated with 50 µg/ml 4-nitroquinoline-1-oxide (4NQO) or 4NQO + H2O2 for 16 weeks to establish mouse models with tongue precancerous lesions. Apoptotic cells were detected using terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. The expression of Prx1, apoptosis signal-regulating kinase 1 (ASK1), phosphor-ASK1, p38 and phosphor-p38 was analyzed using immunohistochemical staining, and their mRNA expression levels were evaluated by reverse transcription quantitative polymerase chain reaction. The present results demonstrated that 4NQO or 4NQO + H2O2 induced the development of tongue precancerous lesions in Prx1 knockout and wild-type mice. Prx1 was overexpressed in tongue precancerous lesions compared with normal tongue mucosa. There was a significant decrease in the degree of moderate or severe epithelial dysplasia, and mild epithelial dysplasia was clearly elevated, in Prx1 knockout mice treated with 4NQO + H2O2 compared with wild-type mice treated with 4NQO + H2O2. Prx1 suppressed apoptosis and upregulated phosphor-ASK1 and phosphor-p38 expression in tongue precancerous lesions. The present results suggest that Prx1 suppresses oxidative stress-induced apoptosis via the ASK1/p38 signalling pathway in mouse tongue precancerous lesions. In conclusion, Prx1 and H2O2 have a coordination role in promoting the progression of tongue precancerous mucosa lesions. The present findings provide novel insight into Prx1 function and the mechanisms of Prx1 in OLK pathogenesis.
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Affiliation(s)
- Jianfei Zhang
- Beijing Institute of Dental Research, Beijing Stomatological Hospital and School of Stomatology, Beijing Key Laboratory, Capital Medical University, Beijing 100050, P.R. China
| | - Xinying Jing
- Beijing Institute of Dental Research, Beijing Stomatological Hospital and School of Stomatology, Beijing Key Laboratory, Capital Medical University, Beijing 100050, P.R. China
| | - Wenwen Niu
- Beijing Institute of Dental Research, Beijing Stomatological Hospital and School of Stomatology, Beijing Key Laboratory, Capital Medical University, Beijing 100050, P.R. China
| | - Min Zhang
- Beijing Institute of Dental Research, Beijing Stomatological Hospital and School of Stomatology, Beijing Key Laboratory, Capital Medical University, Beijing 100050, P.R. China
| | - Lihua Ge
- Beijing Institute of Dental Research, Beijing Stomatological Hospital and School of Stomatology, Beijing Key Laboratory, Capital Medical University, Beijing 100050, P.R. China
| | - Congcong Miao
- Beijing Institute of Dental Research, Beijing Stomatological Hospital and School of Stomatology, Beijing Key Laboratory, Capital Medical University, Beijing 100050, P.R. China
| | - Xiaofei Tang
- Beijing Institute of Dental Research, Beijing Stomatological Hospital and School of Stomatology, Beijing Key Laboratory, Capital Medical University, Beijing 100050, P.R. China
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47
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Cardona-Correa A, Rios-Velazquez C. Profiling lethal factor interacting proteins from human stomach using T7 phage display screening. Mol Med Rep 2016; 13:3797-804. [PMID: 27035230 PMCID: PMC4838128 DOI: 10.3892/mmr.2016.5031] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 02/22/2016] [Indexed: 12/17/2022] Open
Abstract
The anthrax lethal factor (LF) is a zinc dependent metalloproteinase that cleaves the majority of mitogen-activated protein kinase kinases and a member of NOD-like receptor proteins, inducing cell apoptosis. Despite efforts to fully understand the Bacillus anthracis toxin components, the gastrointestinal (GI) anthrax mechanisms have not been fully elucidated. Previous studies demonstrated gastric ulceration, and a substantial bacterial growth rate in Peyer's patches. However, the complete molecular pathways of the disease that results in tissue damage by LF proteolytic activity remains unclear. In the present study, to identify the profile of the proteins potentially involved in GI anthrax, protein-protein interactions were investigated using human stomach T7 phage display (T7PD) cDNA libraries. T7PD is a high throughput technique that allows the expression of cloned DNA sequences as peptides on the phage surface, enabling the selection and identification of protein ligands. A wild type and mutant LF (E687A) were used to differentiate interaction sites. A total of 124 clones were identified from 194 interacting-phages, at both the DNA and protein level, by in silico analysis. Databases revealed that the selected candidates were proteins from different families including lipase, peptidase-A1 and cation transport families, among others. Furthermore, individual T7PD candidates were tested against LF in order to detect their specificity to the target molecule, resulting in 10 LF-interacting peptides. With a minimum concentration of LF for interaction at 1 μg/ml, the T7PD isolated pepsin A3 pre-protein (PAP) demonstrated affinity to both types of LF. In addition, PAP was isolated in various lengths for the same protein, exhibiting common regions following PRALINE alignment. These findings will help elucidate and improve the understanding of the molecular pathogenesis of GI anthrax, and aid in the development of potential therapeutic agents.
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Affiliation(s)
- Albin Cardona-Correa
- Department of Biology, College of Arts and Sciences, University of Puerto Rico‑Mayagüez, Mayagüez 00681‑9000, PR, USA
| | - Carlos Rios-Velazquez
- Department of Biology, College of Arts and Sciences, University of Puerto Rico‑Mayagüez, Mayagüez 00681‑9000, PR, USA
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48
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Animal Models for the Pathogenesis, Treatment, and Prevention of Infection by Bacillus anthracis. Microbiol Spectr 2016; 3:TBS-0001-2012. [PMID: 26104551 DOI: 10.1128/microbiolspec.tbs-0001-2012] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
This article reviews the characteristics of the major animal models utilized for studies on Bacillus anthracis and highlights their contributions to understanding the pathogenesis and host responses to anthrax and its treatment and prevention. Advantages and drawbacks associated with each model, to include the major models (murine, guinea pig, rabbit, nonhuman primate, and rat), and other less frequently utilized models, are discussed. Although the three principal forms of anthrax are addressed, the main focus of this review is on models for inhalational anthrax. The selection of an animal model for study is often not straightforward and is dependent on the specific aims of the research or test. No single animal species provides complete equivalence to humans; however, each species, when used appropriately, can contribute to a more complete understanding of anthrax and its etiologic agent.
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49
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Friebe S, van der Goot FG, Bürgi J. The Ins and Outs of Anthrax Toxin. Toxins (Basel) 2016; 8:toxins8030069. [PMID: 26978402 PMCID: PMC4810214 DOI: 10.3390/toxins8030069] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 02/28/2016] [Accepted: 03/01/2016] [Indexed: 12/21/2022] Open
Abstract
Anthrax is a severe, although rather rare, infectious disease that is caused by the Gram-positive, spore-forming bacterium Bacillus anthracis. The infectious form is the spore and the major virulence factors of the bacterium are its poly-γ-D-glutamic acid capsule and the tripartite anthrax toxin. The discovery of the anthrax toxin receptors in the early 2000s has allowed in-depth studies on the mechanisms of anthrax toxin cellular entry and translocation from the endocytic compartment to the cytoplasm. The toxin generally hijacks the endocytic pathway of CMG2 and TEM8, the two anthrax toxin receptors, in order to reach the endosomes. From there, the pore-forming subunit of the toxin inserts into endosomal membranes and enables translocation of the two catalytic subunits. Insertion of the pore-forming unit preferentially occurs in intraluminal vesicles rather than the limiting membrane of the endosome, leading to the translocation of the enzymatic subunits in the lumen of these vesicles. This has important consequences that will be discussed. Ultimately, the toxins reach the cytosol where they act on their respective targets. Target modification has severe consequences on cell behavior, in particular on cells of the immune system, allowing the spread of the bacterium, in severe cases leading to host death. Here we will review the literature on anthrax disease with a focus on the structure of the toxin, how it enters cells and its immunological effects.
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Affiliation(s)
- Sarah Friebe
- Faculty of Life Sciences, Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland.
| | - F Gisou van der Goot
- Faculty of Life Sciences, Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland.
| | - Jérôme Bürgi
- Faculty of Life Sciences, Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland.
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50
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do Vale A, Cabanes D, Sousa S. Bacterial Toxins as Pathogen Weapons Against Phagocytes. Front Microbiol 2016; 7:42. [PMID: 26870008 PMCID: PMC4734073 DOI: 10.3389/fmicb.2016.00042] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 01/11/2016] [Indexed: 12/31/2022] Open
Abstract
Bacterial toxins are virulence factors that manipulate host cell functions and take over the control of vital processes of living organisms to favor microbial infection. Some toxins directly target innate immune cells, thereby annihilating a major branch of the host immune response. In this review we will focus on bacterial toxins that act from the extracellular milieu and hinder the function of macrophages and neutrophils. In particular, we will concentrate on toxins from Gram-positive and Gram-negative bacteria that manipulate cell signaling or induce cell death by either imposing direct damage to the host cells cytoplasmic membrane or enzymatically modifying key eukaryotic targets. Outcomes regarding pathogen dissemination, host damage and disease progression will be discussed.
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Affiliation(s)
- Ana do Vale
- Host Interaction and Response, Instituto de Investigação e Inovação em Saúde, Universidade do PortoPorto, Portugal; Group of Fish Immunology and Vaccinology, Instituto de Biologia Molecular e Celular, Universidade do PortoPorto, Portugal
| | - Didier Cabanes
- Host Interaction and Response, Instituto de Investigação e Inovação em Saúde, Universidade do PortoPorto, Portugal; Group of Molecular Microbiology, Instituto de Biologia Molecular e Celular, Universidade do PortoPorto, Portugal
| | - Sandra Sousa
- Host Interaction and Response, Instituto de Investigação e Inovação em Saúde, Universidade do PortoPorto, Portugal; Group of Molecular Microbiology, Instituto de Biologia Molecular e Celular, Universidade do PortoPorto, Portugal
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