Mechanisms of Viral Pathogenesis in the Central Nervous System

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

The innate immune response to virus infection has a strong influence on virus infection in the brain and the clinical outcome of disease. Our studies have focused on animal models of virus-mediated neuropathogenesis to determine the host responses that are important for pathogenesis, understand differences between highly related viruses that differ in their ability to cause disease in humans and examine potential therapeutics. This year, we have continued our studies on vertical transmission (VTn) of Zika virus (ZIKV). In previous years, we developed and characterized a mouse model that showed clear VTn of ZIKV from dam to fetus (Winkler et al. Immunology 2018; Winkler et al. J. Immunol. 2017, Winkler et al. Sci. Rep. 2017) and examined the role innate immunity in VTn (Winkler et al. J. Immunology 2020). In 2021-2022, we utilized this model and knowledge to examine how ZIKV induces damage in the CNS. We found that ZIKV infection in the brain caused decreased cortical thickness and cerebellar volume, increased gliosis, and induces neuronal death in many brain areas, but did not inhibit neurogenesis (Winkler et al., Acta Neuropath Comm. 2022). One of the major focuses in 2021-2022 was determining the differences in pathogenesis between members of the California Serogroup (CSG) of Orthobunyaviruses. Several viruses in the CSG family cause encephalitis in humans, although the relative number of yearly cases differ dramatically. We found strong overlap in neutralizing antibody responses between these viruses, including NAbs higher against a cross-reactive virus than the inoculating virus (Evans et al. Sci. Rep. 2021). We also investigated why CSG viruses differ in their pathogenesis and showed clear differences in the innate immune responses required to control virus infection, ability to gain access to the CNS and ability to spread within the CNS and cause damage (Evans et al. PLoS Path 2022). We are currently studying virus and host factors that mediate these differences. Another primary focus was on potential therapeutics for these viruses. Currently, for most viral encephalitis cases, there is not treatment and only palliative care can be provided. We completed a screen of repurposed drugs and small molecules through a program at the National Center for Advancement of Translational Science (NCATS). We identified one particular compound, Rottlerin (RTL) that inhibited LACV infection and apoptosis of neurons in vitro, in a human organoid model and in a mouse of model of LACV encephalitis (Ojha et al. Nature Micro 2021). We further showed that RTL also inhibited ZIKV replication in vitro and defined parameters for investigating antivirals for CNS viruses (Ojha et al. Viruses 2021). Our current work is examining how RTL affects other RNA viruses and well as investigating other compounds for their ability to inhibit different encephalitic viruses.