Rift Valley Fever Virus (RVFV) is a Category A biodefense pathogen due to 1) its potential for intentional spread by aerosols and 2) the lack of a licensed vaccine or antiviral therapeutic. Although the brain is a major target of viral replication and tissue damage following aerosol infection, little is known about innate immune responses to RVFV in the brain.
We investigated the responses of resident, innate immune cells of the brain (microglia and astrocytes) during RVFV infection to identify how these cells are capable of controlling RVFV replication. Microglia mount a robust response to RVFV that is dependent upon mitochondrial antiviral-signaling protein (MAVS) and independent of toll-like receptors 3 and 7. Mice genetically modified to have nonfunctional MAVS (MAVS "knock out" or KO mice) have significantly higher viral loads in the brain following intranasal infection. Surprisingly, however, many markers of immune activity were similarly upregulated in the brains of MAVS KO and wild type (WT or "normal") mice. This outcome contrasts the in vitro response, in which microglia and astrocytes derived from MAVS KO mice were unresponsive to RVFV infection. RNA-sequencing analysis of infected brain tissue revealed that key antiviral genes are not activated in the MAVS KO animals. These results are an important step towards understanding the molecular pathways responsible for controlling RVFV infection in the brain, and they lay the groundwork for the development of targeted therapies for the prevention of RVFV encephalitis. Knowledge of the mechanisms of pathogenesis will be instrumental for the development of therapeutics that will effectively limit RVFV replication in the brain.
This project is directly relevant to Lawrence Livermore National Laboratory's focus on meeting R&D challenges in chemical and biological countermeasures by developing innovative systems and capabilities to effectively respond to intentional use of pathogens as well as natural outbreaks of pandemic diseases.
Sanchez, K.R., et al. 2017. "Assessment of UV Inactivation of Rift Valley Fever Virus-Infected Astrocytes." LLNL Summer Student Poster Symposium, Livermore, CA, August 2017. LLNL-POST-735487.
——— . 2018. "Understanding the Innate Immune Response of Astrocytes to Rift Valley Fever Virus." LLNL Summer Student Poster Symposium, Livermore, CA, August 2018. LLNL-POST-755827.
Weilhammer, D, et al. 2018. "Microglia Mount a Robust Response to Rift Valley Fever Virus Infection That is Dependent on MAVS and Independent of TLR7." Annual Meeting of the American Association of Immunologists, Austin, TX, May 2018. LLNL-POST-750867.
——— . 2018. "Microglia Mount a Robust Immune Response to RVFV Infection That Is Dependent on MAVS and Independent of TLR7." LLNL-ABS-744345.
——— . 2019. "Innate Immune Responses in the Brain to Rift Valley Fever Virus." Georgetown University Frontiers in Biotechnology Fall 2019 Seminar Series, Livermore, CA, October 2019. LLNL-PRES-792245.
——— . 2019. "Innate Immune Responses in the Brain to Rift Valley Fever Virus." Annual Meeting of the American Association of Immunologists, San Diego, CA, May 2019. LLNL-POST-777668.
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