MAVS mediates a protective immune response in the brain to Rift Valley fever virus

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.

doi:10.1371/journal.ppat.1010231

Title: MAVS mediates a protective immune response in the brain to Rift Valley fever virus

Journal Article · Wed May 18 00:00:00 EDT 2022 · PLoS Pathogens

DOI:https://doi.org/10.1371/journal.ppat.1010231· OSTI ID:2217367

Hum, Nicholas R.; Bourguet, Feliza A.; Sebastian, Aimy; Lam, Doris; Phillips, Ashlee M.; Sanchez, Kristina R.; Rasley, Amy; Loots, Gabriela G.;

; Hartman, ed., Amy L.

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.

View Journal Article

Cite

Export

Save

Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: 17-LW-038; 22-ERD-038; AC52-07NA27344

OSTI ID:: 2217367

Alternate ID(s):: OSTI ID: 1868569; OSTI ID: 1874547

Report Number(s):: LLNL-JRNL-829758; 10.1371/journal.ppat.1010231

Journal Information:: PLoS Pathogens, Journal Name: PLoS Pathogens Vol. 18 Journal Issue: 5; ISSN 1553-7374

Publisher:: Public Library of Science (PLoS)Copyright Statement

Country of Publication:: United States

Language:: English

References (66)

The risk of Rift Valley fever virus introduction and establishment in the United States and European Union Rolin, Alicia I.; Berrang-Ford, Lea; Kulkarni, Manisha A. Emerging Microbes & Infections, Vol. 2, Issue 1 https://doi.org/10.1038/emi.2013.81	journal	January 2013
Innate Immune Sensing of Viruses and Its Consequences for the Central Nervous System Singh, Hina; Koury, Jeffrey; Kaul, Marcus Viruses, Vol. 13, Issue 2 https://doi.org/10.3390/v13020170	journal	January 2021
IPS-1 Is Essential for the Control of West Nile Virus Infection and Immunity Suthar, Mehul S.; Ma, Daphne Y.; Thomas, Sunil PLoS Pathogens, Vol. 6, Issue 2 https://doi.org/10.1371/journal.ppat.1000757	journal	February 2010
Sex- and Development-Dependent Responses of Rat Microglia to Pro- and Anti-inflammatory Stimulation Lively, Starlee; Wong, Raymond; Lam, Doris Frontiers in Cellular Neuroscience, Vol. 12 https://doi.org/10.3389/fncel.2018.00433	journal	November 2018
Perforin and granzymes: function, dysfunction and human pathology Voskoboinik, Ilia; Whisstock, James C.; Trapani, Joseph A. Nature Reviews Immunology, Vol. 15, Issue 6 https://doi.org/10.1038/nri3839	journal	May 2015
The pathogenesis of Rift Valley fever virus in the mouse model Smith, Darci R.; Steele, Keith E.; Shamblin, Joshua Virology, Vol. 407, Issue 2 https://doi.org/10.1016/j.virol.2010.08.016	journal	November 2010
IFIT1 is an antiviral protein that recognizes 5′-triphosphate RNA Pichlmair, Andreas; Lassnig, Caroline; Eberle, Carol-Ann Nature Immunology, Vol. 12, Issue 7 https://doi.org/10.1038/ni.2048	journal	June 2011
CD4 T Cells, CD8 T Cells, and Monocytes Coordinate To Prevent Rift Valley Fever Virus Encephalitis Harmon, Jessica R.; Spengler, Jessica R.; Coleman-McCray, Joann D. Journal of Virology, Vol. 92, Issue 24 https://doi.org/10.1128/JVI.01270-18	journal	December 2018
Nitric Oxide-Dependent Pathways as Critical Factors in the Consequences and Recovery after Brain Ischemic Hypoxia Wierońska, Joanna M.; Cieślik, Paulina; Kalinowski, Leszek Biomolecules, Vol. 11, Issue 8 https://doi.org/10.3390/biom11081097	journal	July 2021
STAR: ultrafast universal RNA-seq aligner Dobin, Alexander; Davis, Carrie A.; Schlesinger, Felix Bioinformatics, Vol. 29, Issue 1 https://doi.org/10.1093/bioinformatics/bts635	journal	October 2012
Toll-Like Receptor 3 Has a Protective Role against West Nile Virus Infection Daffis, Stephane; Samuel, Melanie A.; Suthar, Mehul S. Journal of Virology, Vol. 82, Issue 21 https://doi.org/10.1128/JVI.00935-08	journal	August 2008
Factors Associated with Severe Human Rift Valley Fever in Sangailu, Garissa County, Kenya LaBeaud, A. Desirée; Pfeil, Sarah; Muiruri, Samuel PLOS Neglected Tropical Diseases, Vol. 9, Issue 3 https://doi.org/10.1371/journal.pntd.0003548	journal	March 2015
IL-27 enhances IL-15/IL-18-mediated activation of human natural killer cells Choi, Yeon Ho; Lim, Eun Jin; Kim, Se Wha Journal for ImmunoTherapy of Cancer, Vol. 7, Issue 1 https://doi.org/10.1186/s40425-019-0652-7	journal	July 2019
Rift Valley Fever Epidemic in Saudi Arabia: Epidemiological, Clinical, and Laboratory Characteristics Madani, T. A.; Al-Mazrou, Y. Y.; Al-Jeffri, M. H. Clinical Infectious Diseases, Vol. 37, Issue 8 https://doi.org/10.1086/378747	journal	October 2003
The brain parenchyma has a type I interferon response that can limit virus spread Drokhlyansky, Eugene; Göz Aytürk, Didem; Soh, Timothy K. Proceedings of the National Academy of Sciences, Vol. 114, Issue 1 https://doi.org/10.1073/pnas.1618157114	journal	December 2016
OASL1 inhibits translation of the type I interferon–regulating transcription factor IRF7 Lee, Myeong Sup; Kim, Byungil; Oh, Goo Taeg Nature Immunology, Vol. 14, Issue 4 https://doi.org/10.1038/ni.2535	journal	February 2013
Origin, fate and dynamics of macrophages at central nervous system interfaces Goldmann, Tobias; Wieghofer, Peter; Jordão, Marta Joana Costa Nature Immunology, Vol. 17, Issue 7 https://doi.org/10.1038/ni.3423	journal	May 2016
Borrelia burgdorferi induces inflammatory mediator production by murine microglia Rasley, Amy; Anguita, Juan; Marriott, Ian Journal of Neuroimmunology, Vol. 130, Issue 1-2 https://doi.org/10.1016/S0165-5728(02)00187-X	journal	September 2002
Neuroinflammation in Parkinson's disease: Its role in neuronal death and implications for therapeutic intervention Tansey, Malú G.; Goldberg, Matthew S. Neurobiology of Disease, Vol. 37, Issue 3 https://doi.org/10.1016/j.nbd.2009.11.004	journal	March 2010
featureCounts: an efficient general purpose program for assigning sequence reads to genomic features Liao, Y.; Smyth, G. K.; Shi, W. Bioinformatics, Vol. 30, Issue 7 https://doi.org/10.1093/bioinformatics/btt656	journal	November 2013
A Genome-Wide RNA Interference Screen Identifies a Role for Wnt/β-Catenin Signaling during Rift Valley Fever Virus Infection Harmon, Brooke; Bird, Sara W.; Schudel, Benjamin R. Journal of Virology, Vol. 90, Issue 16 https://doi.org/10.1128/JVI.00543-16	journal	August 2016
MAVS Expressed by Hematopoietic Cells Is Critical for Control of West Nile Virus Infection and Pathogenesis Zhao, Jincun; Vijay, Rahul; Zhao, Jingxian Journal of Virology, Vol. 90, Issue 16 https://doi.org/10.1128/JVI.00707-16	journal	August 2016
Association of Symptoms and Severity of Rift Valley Fever with Genetic Polymorphisms in Human Innate Immune Pathways Hise, Amy G.; Traylor, Zachary; Hall, Noémi B. PLOS Neglected Tropical Diseases, Vol. 9, Issue 3 https://doi.org/10.1371/journal.pntd.0003584	journal	March 2015
Innate Immunity in the CNS: Redefining the Relationship between the CNS and Its Environment Lampron, Antoine; ElAli, Ayman; Rivest, Serge Neuron, Vol. 78, Issue 2 https://doi.org/10.1016/j.neuron.2013.04.005	journal	April 2013
Cytokine response in mouse bone marrow derived macrophages after infection with pathogenic and non-pathogenic Rift Valley fever virus Holbrook, Michael R.; Hill, Terence E.; Freiberg, Alexander N. Journal of General Virology, Vol. 96, Issue 7 https://doi.org/10.1099/vir.0.000119	journal	July 2015
IL-27 stimulates human NK-cell effector functions and primes NK cells for IL-18 responsiveness: Immunomodulation Ziblat, Andrea; Domaica, Carolina I.; Spallanzani, Raúl G. European Journal of Immunology, Vol. 45, Issue 1 https://doi.org/10.1002/eji.201444699	journal	December 2014
Comprehensive Integration of Single-Cell Data Stuart, Tim; Butler, Andrew; Hoffman, Paul Cell, Vol. 177, Issue 7 https://doi.org/10.1016/j.cell.2019.05.031	journal	June 2019
Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes Hammond, Timothy R.; Dufort, Connor; Dissing-Olesen, Lasse Immunity, Vol. 50, Issue 1 https://doi.org/10.1016/j.immuni.2018.11.004	journal	January 2019
Rift Valley Fever Virus Strain MP-12 Enters Mammalian Host Cells via Caveola-Mediated Endocytosis Harmon, B.; Schudel, B. R.; Maar, D. Journal of Virology, Vol. 86, Issue 23 https://doi.org/10.1128/JVI.02242-12	journal	September 2012
The natural killer cell response to West Nile virus in young and old individuals with or without a prior history of infection Yao, Yi; Strauss-Albee, Dara M.; Zhou, Julian Q. PLOS ONE, Vol. 12, Issue 2 https://doi.org/10.1371/journal.pone.0172625	journal	February 2017
Single Cell Transcriptome Analysis of Niemann–Pick Disease, Type C1 Cerebella Cougnoux, Antony; Yerger, Julia C.; Fellmeth, Mason International Journal of Molecular Sciences, Vol. 21, Issue 15 https://doi.org/10.3390/ijms21155368	journal	July 2020
Type I Interferon Receptor Signaling of Neurons and Astrocytes Regulates Microglia Activation during Viral Encephalitis Chhatbar, Chintan; Detje, Claudia N.; Grabski, Elena Cell Reports, Vol. 25, Issue 1 https://doi.org/10.1016/j.celrep.2018.09.003	journal	October 2018
Rift Valley Fever Virus Encephalitis Is Associated with an Ineffective Systemic Immune Response and Activated T Cell Infiltration into the CNS in an Immunocompetent Mouse Model Dodd, Kimberly A.; McElroy, Anita K.; Jones, Tara L. PLoS Neglected Tropical Diseases, Vol. 8, Issue 6 https://doi.org/10.1371/journal.pntd.0002874	journal	June 2014
edgeR: a Bioconductor package for differential expression analysis of digital gene expression data Robinson, M. D.; McCarthy, D. J.; Smyth, G. K. Bioinformatics, Vol. 26, Issue 1 https://doi.org/10.1093/bioinformatics/btp616	journal	November 2009
CD8 ⁺ T Cells Require Perforin To Clear West Nile Virus from Infected Neurons Shrestha, Bimmi; Samuel, Melanie A.; Diamond, Michael S. Journal of Virology, Vol. 80, Issue 1 https://doi.org/10.1128/JVI.80.1.119-129.2006	journal	January 2006
Risk Factors for Severe Rift Valley Fever Infection in Kenya, 2007 Njenga, M. Kariuki; Paweska, Janusz T.; Lederman, Edith R. The American Journal of Tropical Medicine and Hygiene, Vol. 83, Issue 2_Suppl https://doi.org/10.4269/ajtmh.2010.09-0293	journal	August 2010
CSF1R antagonism limits local restimulation of antiviral CD8+ T cells during viral encephalitis Funk, Kristen E.; Klein, Robyn S. Journal of Neuroinflammation, Vol. 16, Issue 1 https://doi.org/10.1186/s12974-019-1397-4	journal	January 2019
IRF8 Is a Critical Transcription Factor for Transforming Microglia into a Reactive Phenotype Masuda, Takahiro; Tsuda, Makoto; Yoshinaga, Ryohei Cell Reports, Vol. 1, Issue 4 https://doi.org/10.1016/j.celrep.2012.02.014	journal	April 2012
Microglia influence host defense, disease, and repair following murine coronavirus infection of the central nervous system Mangale, Vrushali; Syage, Amber R.; Ekiz, H. Atakan Glia, Vol. 68, Issue 11 https://doi.org/10.1002/glia.23844	journal	May 2020
Normalization of RNA-seq data using factor analysis of control genes or samples Risso, Davide; Ngai, John; Speed, Terence P. Nature Biotechnology, Vol. 32, Issue 9 https://doi.org/10.1038/nbt.2931	journal	August 2014
Toll-like Receptor 7 Mitigates Lethal West Nile Encephalitis via Interleukin 23-Dependent Immune Cell Infiltration and Homing Town, Terrence; Bai, Fengwei; Wang, Tian Immunity, Vol. 30, Issue 2 https://doi.org/10.1016/j.immuni.2008.11.012	journal	February 2009
T cell engagement of cross-presenting microglia protects the brain from a nasal virus infection Moseman, E. Ashley; Blanchard, Alexa C.; Nayak, Debasis Science Immunology, Vol. 5, Issue 48 https://doi.org/10.1126/sciimmunol.abb1817	journal	June 2020
Highly Sensitive and Broadly Reactive Quantitative Reverse Transcription-PCR Assay for High-Throughput Detection of Rift Valley Fever Virus Bird, Brian H.; Bawiec, Darcy A.; Ksiazek, Thomas G. Journal of Clinical Microbiology, Vol. 45, Issue 11 https://doi.org/10.1128/JCM.00936-07	journal	November 2007
Innate antiviral signalling in the central nervous system Carty, Michael; Reinert, Line; Paludan, Søren R. Trends in Immunology, Vol. 35, Issue 2 https://doi.org/10.1016/j.it.2013.10.012	journal	February 2014
Isolation and culture of adult neurons and neurospheres Brewer, Gregory J.; Torricelli, John R. Nature Protocols, Vol. 2, Issue 6 https://doi.org/10.1038/nprot.2007.207	journal	June 2007
RNA Helicase Signaling Is Critical for Type I Interferon Production and Protection against Rift Valley Fever Virus during Mucosal Challenge Ermler, Megan E.; Yerukhim, Ekaterina; Schriewer, Jill Journal of Virology, Vol. 87, Issue 9 https://doi.org/10.1128/JVI.01997-12	journal	May 2013
The Interferon-Stimulated Gene Ifi27l2a Restricts West Nile Virus Infection and Pathogenesis in a Cell-Type- and Region-Specific Manner Lucas, Tiffany M.; Richner, Justin M.; Diamond, Michael S. Journal of Virology, Vol. 90, Issue 5 https://doi.org/10.1128/JVI.02463-15	journal	March 2016
Ultrastructural study of Rift Valley fever virus in the mouse model Reed, Christopher; Steele, Keith E.; Honko, Anna Virology, Vol. 431, Issue 1-2 https://doi.org/10.1016/j.virol.2012.05.012	journal	September 2012
Encephalitis due to emerging viruses: CNS innate immunity and potential therapeutic targets Denizot, M.; Neal, J. W.; Gasque, P. Journal of Infection, Vol. 65, Issue 1 https://doi.org/10.1016/j.jinf.2012.03.019	journal	July 2012
Expression of functional NK-1 receptors in murine microglia Rasley, Amy; Bost, Kenneth L.; Olson, Julie K. Glia, Vol. 37, Issue 3 https://doi.org/10.1002/glia.10034	journal	February 2002
ToppGene Suite for gene list enrichment analysis and candidate gene prioritization Chen, J.; Bardes, E. E.; Aronow, B. J. Nucleic Acids Research, Vol. 37, Issue Web Server https://doi.org/10.1093/nar/gkp427	journal	May 2009
Rift Valley Fever Virus Clearance and Protection from Neurologic Disease Are Dependent on CD4 ⁺ T Cell and Virus-Specific Antibody Responses Dodd, Kimberly A.; McElroy, Anita K.; Jones, Megan E. B. Journal of Virology, Vol. 87, Issue 11 https://doi.org/10.1128/JVI.00337-13	journal	June 2013
IFN-γ Regulation of Class II Transactivator Promoter IV in Macrophages and Microglia: Involvement of the Suppressors of Cytokine Signaling-1 Protein O’Keefe, George M.; Nguyen, Vince T.; Ping Tang, Li The Journal of Immunology, Vol. 166, Issue 4 https://doi.org/10.4049/jimmunol.166.4.2260	journal	February 2001
A Single-Cell RNA Sequencing Study Reveals Cellular and Molecular Dynamics of the Hippocampal Neurogenic Niche Artegiani, Benedetta; Lyubimova, Anna; Muraro, Mauro Cell Reports, Vol. 21, Issue 11 https://doi.org/10.1016/j.celrep.2017.11.050	journal	December 2017
Update on T cells in the virally infected brain: friends and foes Ai, Shenjian; Klein, Robyn S. Current Opinion in Neurology, Vol. 33, Issue 3 https://doi.org/10.1097/WCO.0000000000000825	journal	January 2020
Microglia retard dengue virus-induced acute viral encephalitis Tsai, Tsung-Ting; Chen, Chia-Ling; Lin, Yee-Shin Scientific Reports, Vol. 6, Issue 1 https://doi.org/10.1038/srep27670	journal	June 2016
Transcription factor IRF1 is responsible for IRF8-mediated IL-1β expression in reactive microglia Masuda, Takahiro; Iwamoto, Shosuke; Mikuriya, Satsuki Journal of Pharmacological Sciences, Vol. 128, Issue 4 https://doi.org/10.1016/j.jphs.2015.08.002	journal	August 2015
Aerosol Exposure to Rift Valley Fever Virus Causes Earlier and More Severe Neuropathology in the Murine Model, which Has Important Implications for Therapeutic Development Reed, Christopher; Lin, Kenny; Wilhelmsen, Catherine PLoS Neglected Tropical Diseases, Vol. 7, Issue 4 https://doi.org/10.1371/journal.pntd.0002156	journal	April 2013
The challenging management of Rift Valley Fever in humans: literature review of the clinical disease and algorithm proposal Javelle, Emilie; Lesueur, Alexandre; Pommier de Santi, Vincent Annals of Clinical Microbiology and Antimicrobials, Vol. 19, Issue 1 https://doi.org/10.1186/s12941-020-0346-5	journal	January 2020
Neutrophil and macrophage influx into the central nervous system are inflammatory components of lethal Rift Valley fever encephalitis in rats Albe, Joseph R.; Boyles, Devin A.; Walters, Aaron W. PLOS Pathogens, Vol. 15, Issue 6 https://doi.org/10.1371/journal.ppat.1007833	journal	June 2019
A molecular atlas of cell types and zonation in the brain vasculature Vanlandewijck, Michael; He, Liqun; Mäe, Maarja Andaloussi Nature, Vol. 554, Issue 7693 https://doi.org/10.1038/nature25739	journal	February 2018
A privileged brain Rustenhoven, Justin Science, Vol. 374, Issue 6567 https://doi.org/10.1126/science.abl7122	journal	October 2021
Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner Thion, Morgane Sonia; Low, Donovan; Silvin, Aymeric Cell, Vol. 172, Issue 3 https://doi.org/10.1016/j.cell.2017.11.042	journal	January 2018
Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity: HANAMSAGAR et al. Hanamsagar, Richa; Alter, Mark D.; Block, Carina S. Glia, Vol. 65, Issue 9 https://doi.org/10.1002/glia.23176	journal	June 2017
Microglia in Alzheimer’s Disease: A Target for Therapeutic Intervention Zhang, Guimei; Wang, Zicheng; Hu, Huiling Frontiers in Cellular Neuroscience, Vol. 15 https://doi.org/10.3389/fncel.2021.749587	journal	November 2021
Rift Valley fever virus ( Bunyaviridae: Phlebovirus ): an update on pathogenesis, molecular epidemiology, vectors, diagnostics and prevention Pepin, Michel; Bouloy, Michèle; Bird, Brian H. Veterinary Research, Vol. 41, Issue 6 https://doi.org/10.1051/vetres/2010033	journal	May 2010

Similar Records

Investigating the role of innate immunity in viral encephalitis caused by Rift Valley fever virus

Technical Report · Thu Oct 31 00:00:00 EDT 2019 · OSTI ID:2217367

Weilhammer, Dina R.

A genome-wide RNA interference screen identifies a role for Wnt/β-catenin signaling during Rift Valley Fever Virus infection

Journal Article · Wed Jul 27 00:00:00 EDT 2016 · Journal of Virology · OSTI ID:2217367

Harmon, Brooke; Bird, Sara W.; Schudel, Benjamin R.; +3 more

Peripheral dendritic cells are essential for both the innate and adaptive antiviral immune responses in the central nervous system

Journal Article · Sat Apr 25 00:00:00 EDT 2009 · Virology · OSTI ID:2217367

Steel, Christina D; Hahto, Suzanne M

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
microglial cells
Rift Valley fever virus
immune response
viral gene expression
mouse models
cytokines
lymphocytes
respiratory infections

Title: MAVS mediates a protective immune response in the brain to Rift Valley fever virus

Citation Formats

References (66)

Similar Records

Related Subjects