MAVS Expressed by Hematopoietic Cells Is Critical for Control of West Nile Virus Infection and Pathogenesis
Copyright © 2016, American Society for Microbiology. All Rights Reserved..
UNLABELLED: 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.
IMPORTANCE: 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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2016 |
|---|---|
| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:90 |
|---|---|
| Enthalten in: |
Journal of virology - 90(2016), 16 vom: 15. Aug., Seite 7098-7108 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zhao, Jincun [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Adaptor Proteins, Signal Transducing |
|---|
| Anmerkungen: |
Date Completed 15.05.2017 Date Revised 08.10.2019 published: Electronic-Print Citation Status MEDLINE |
|---|
| doi: |
10.1128/JVI.00707-16 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM260754684 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM260754684 | ||
| 003 | DE-627 | ||
| 005 | 20231224194101.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2016 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1128/JVI.00707-16 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0869.xml |
| 035 | |a (DE-627)NLM260754684 | ||
| 035 | |a (NLM)27226371 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Zhao, Jincun |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a MAVS Expressed by Hematopoietic Cells Is Critical for Control of West Nile Virus Infection and Pathogenesis |
| 264 | 1 | |c 2016 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 15.05.2017 | ||
| 500 | |a Date Revised 08.10.2019 | ||
| 500 | |a published: Electronic-Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2016, American Society for Microbiology. All Rights Reserved. | ||
| 520 | |a UNLABELLED: 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 | ||
| 520 | |a IMPORTANCE: 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 7 | |a Adaptor Proteins, Signal Transducing |2 NLM | |
| 650 | 7 | |a Cytokines |2 NLM | |
| 650 | 7 | |a IPS-1 protein, mouse |2 NLM | |
| 700 | 1 | |a Vijay, Rahul |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Jingxian |e verfasserin |4 aut | |
| 700 | 1 | |a Gale, Michael |c Jr |e verfasserin |4 aut | |
| 700 | 1 | |a Diamond, Michael S |e verfasserin |4 aut | |
| 700 | 1 | |a Perlman, Stanley |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of virology |d 1967 |g 90(2016), 16 vom: 15. Aug., Seite 7098-7108 |w (DE-627)NLM000006866 |x 1098-5514 |7 nnns |
| 773 | 1 | 8 | |g volume:90 |g year:2016 |g number:16 |g day:15 |g month:08 |g pages:7098-7108 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1128/JVI.00707-16 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 90 |j 2016 |e 16 |b 15 |c 08 |h 7098-7108 | ||