MAVS mediates a protective immune response in the brain to Rift Valley fever virus
Abstract
Rift Valley fever virus (RVFV) is a highly pathogenic mosquito-borne virus capable of causing hepatitis, encephalitis, blindness, hemorrhagic syndrome, and death in humans and livestock. Upon aerosol infection with RVFV, the brain is a major site of viral replication and tissue damage, yet pathogenesis in this organ has been understudied. Here, we investigated the immune response in the brain of RVFV infected mice. In response to infection, microglia initiated robust transcriptional upregulation of antiviral immune genes, as well as increased levels of activation markers and cytokine secretion that is dependent on mitochondrial antiviral-signaling protein (MAVS) and independent of toll-like receptors 3 and 7. In vivo , Mavs -/- mice displayed enhanced susceptibility to RVFV as determined by increased brain viral burden and higher mortality. Single-cell RNA sequence analysis identified defects in type I interferon and interferon responsive gene expression within microglia in Mavs -/- mice, as well as dysregulated lymphocyte infiltration. The results of this study provide a crucial step towards understanding the precise molecular mechanisms by which RVFV infection is controlled in the brain and will help inform the development of vaccines and antiviral therapies that are effective in preventing encephalitis.
- Publication Date:
- Research Org.:
- Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
- Sponsoring Org.:
- USDOE National Nuclear Security Administration (NNSA)
- OSTI Identifier:
- 2217367
- Alternate Identifier(s):
- OSTI ID: 1868569; OSTI ID: 1874547
- Report Number(s):
- LLNL-JRNL-829758
Journal ID: ISSN 1553-7374; 10.1371/journal.ppat.1010231
- Grant/Contract Number:
- 17-LW-038; 22-ERD-038; AC52-07NA27344
- Resource Type:
- Published Article
- Journal Name:
- PLoS Pathogens
- Additional Journal Information:
- Journal Name: PLoS Pathogens Journal Volume: 18 Journal Issue: 5; Journal ID: ISSN 1553-7374
- Publisher:
- Public Library of Science (PLoS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; microglial cells; Rift Valley fever virus; immune response; viral gene expression; mouse models; cytokines; lymphocytes; respiratory infections
Citation Formats
Hum, Nicholas R., Bourguet, Feliza A., Sebastian, Aimy, Lam, Doris, Phillips, Ashlee M., Sanchez, Kristina R., Rasley, Amy, Loots, Gabriela G., Weilhammer, Dina R., and Hartman, ed., Amy L. MAVS mediates a protective immune response in the brain to Rift Valley fever virus. United States: N. p., 2022.
Web. doi:10.1371/journal.ppat.1010231.
Hum, Nicholas R., Bourguet, Feliza A., Sebastian, Aimy, Lam, Doris, Phillips, Ashlee M., Sanchez, Kristina R., Rasley, Amy, Loots, Gabriela G., Weilhammer, Dina R., & Hartman, ed., Amy L. MAVS mediates a protective immune response in the brain to Rift Valley fever virus. United States. https://doi.org/10.1371/journal.ppat.1010231
Hum, Nicholas R., Bourguet, Feliza A., Sebastian, Aimy, Lam, Doris, Phillips, Ashlee M., Sanchez, Kristina R., Rasley, Amy, Loots, Gabriela G., Weilhammer, Dina R., and Hartman, ed., Amy L. Wed .
"MAVS mediates a protective immune response in the brain to Rift Valley fever virus". United States. https://doi.org/10.1371/journal.ppat.1010231.
@article{osti_2217367,
title = {MAVS mediates a protective immune response in the brain to Rift Valley fever virus},
author = {Hum, Nicholas R. and Bourguet, Feliza A. and Sebastian, Aimy and Lam, Doris and Phillips, Ashlee M. and Sanchez, Kristina R. and Rasley, Amy and Loots, Gabriela G. and Weilhammer, Dina R. and Hartman, ed., Amy L.},
abstractNote = {Rift Valley fever virus (RVFV) is a highly pathogenic mosquito-borne virus capable of causing hepatitis, encephalitis, blindness, hemorrhagic syndrome, and death in humans and livestock. Upon aerosol infection with RVFV, the brain is a major site of viral replication and tissue damage, yet pathogenesis in this organ has been understudied. Here, we investigated the immune response in the brain of RVFV infected mice. In response to infection, microglia initiated robust transcriptional upregulation of antiviral immune genes, as well as increased levels of activation markers and cytokine secretion that is dependent on mitochondrial antiviral-signaling protein (MAVS) and independent of toll-like receptors 3 and 7. In vivo , Mavs -/- mice displayed enhanced susceptibility to RVFV as determined by increased brain viral burden and higher mortality. Single-cell RNA sequence analysis identified defects in type I interferon and interferon responsive gene expression within microglia in Mavs -/- mice, as well as dysregulated lymphocyte infiltration. The results of this study provide a crucial step towards understanding the precise molecular mechanisms by which RVFV infection is controlled in the brain and will help inform the development of vaccines and antiviral therapies that are effective in preventing encephalitis.},
doi = {10.1371/journal.ppat.1010231},
journal = {PLoS Pathogens},
number = 5,
volume = 18,
place = {United States},
year = {Wed May 18 00:00:00 EDT 2022},
month = {Wed May 18 00:00:00 EDT 2022}
}
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