Journal article
MAVS Expressed by Hematopoietic Cells Is Critical for Control of West Nile Virus Infection and Pathogenesis
Journal of virology, Vol.90(16), pp.7098-7108
08/15/2016
DOI: 10.1128/JVI.00707-16
PMCID: PMC4984631
PMID: 27226371
Abstract
West Nile virus (WNV) is the most important cause of epidemic encephalitis in North America. Innate immune responses, which are critical for control of WNV infection, are initiated by signaling through pathogen recognition receptors, RIG-I and MDA5, and their downstream adaptor molecule, MAVS. Here, we show that a deficiency of MAVS in hematopoietic cells resulted in increased mortality and delayed WNV clearance from the brain. In Mavs(-/-) mice, a dysregulated immune response was detected, characterized by a massive influx of macrophages and virus-specific T cells into the infected brain. These T cells were polyfunctional and lysed peptide-pulsed target cells in vitro However, virus-specific T cells in the brains of infected Mavs(-/-) mice exhibited lower functional avidity than those in wild-type animals, and even virus-specific memory T cells generated by prior immunization could not protect Mavs(-/-) mice from WNV-induced lethal disease. Concomitant with ineffective virus clearance, macrophage numbers were increased in the Mavs(-/-) brain, and both macrophages and microglia exhibited an activated phenotype. Microarray analyses of leukocytes in the infected Mavs(-/-) brain showed a preferential expression of genes associated with activation and inflammation. Together, these results demonstrate a critical role for MAVS in hematopoietic cells in augmenting the kinetics of WNV clearance and thereby preventing a dysregulated and pathogenic immune response. West Nile virus (WNV) is the most important cause of mosquito-transmitted encephalitis in the United States. The innate immune response is known to be critical for protection in infected mice. Here, we show that expression of MAVS, a key adaptor molecule in the RIG-I-like receptor RNA-sensing pathway, in hematopoietic cells is critical for protection from lethal WNV infection. In the absence of MAVS, there is a massive infiltration of myeloid cells and virus-specific T cells into the brain and overexuberant production of proinflammatory cytokines. These results demonstrate the important role that MAVS expression in hematopoietic cells has in regulating the inflammatory response in the WNV-infected brain.
Details
- Title: Subtitle
- MAVS Expressed by Hematopoietic Cells Is Critical for Control of West Nile Virus Infection and Pathogenesis
- Creators
- Jincun Zhao - Department of Microbiology, University of Iowa, Iowa City, Iowa, USARahul Vijay - Department of Microbiology, University of Iowa, Iowa City, Iowa, USAJingxian Zhao - Department of Microbiology, University of Iowa, Iowa City, Iowa, USAMichael Gale JrMichael S Diamond - Departments of Medicine, Pathology and Immunology, and Molecular Microbiology, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri, USAStanley Perlman - Department of Microbiology, University of Iowa, Iowa City, Iowa, USA stanley-perlman@uiowa.edu zhaojincun@gird.cn
- Resource Type
- Journal article
- Publication Details
- Journal of virology, Vol.90(16), pp.7098-7108
- DOI
- 10.1128/JVI.00707-16
- PMID
- 27226371
- PMCID
- PMC4984631
- NLM abbreviation
- J Virol
- ISSN
- 0022-538X
- eISSN
- 1098-5514
- Publisher
- United States
- Grant note
- R01 AI104002 / NIAID NIH HHS R01 AI074973 / NIAID NIH HHS U54 AI057160 / NIAID NIH HHS U19 AI083019 / NIAID NIH HHS U19 AI100625 / NIAID NIH HHS
- Language
- English
- Date published
- 08/15/2016
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
- Record Identifier
- 9983777470802771
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