Mechanisms of Viral Pathogenesis in the Central Nervous System

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

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. One of the primary focuses this year was on potential therapeutics for RNA viruses including bunyaviruses, flaviviruses and coronaviruses. The lack of useful therapeutics and accurate, differential diagnostics are major barriers for the treatment of viral encephalitis, including LACV encephalitis. We collaborated with the National Center for Advancing Translational Sciences (NCATS) and identified the small molecule Rottlerin (RTL) as an inhibitor of LACV and Zika virus (ZIKV)-induced neuronal death (Ojha et al. Nature Micro. 2021; Ojha et al. Viruses, 2021). Our current work focused on targeting cellular organelles to identify key aspects of virus replication that could be inhibiting by therapeutics. We found that ZIKV replication in neurons was inhibited the most significantly by inducing ER stress through sarcoplasmic/endoplasmic reticulum Ca2+-ATPases (SERCA). This work was published in Antiviral Research (Ojha, D., Basu, R. Peterson, K.E. 2022. Therapeutic targeting of organelles for inhibition of Zika virus replication in neurons. Antiviral Research, 209:105464. doi: 10.1016). Another key area of focus is how encephalitic viruses gain access to the central nervous system. We have previously shown that LACV gains access to the CNS via vascular leakage of brain capillary endothelial cells (BCECs) (Winkler et al. Acta Neuropath 2015). We found age-related differences in BCECs and their ability to respond to virus infection, including age-related virus-infection and damage to these cells in vitro (Basu et al. J. Neuroinflam. 2021). In a long-standing collaboration with Dr. Iain Fraser, our labs examined differences between BCECs from adult (resistant) and weanling (susceptible) mice by hi-seq analysis. Top differences were then examined by si-RNA treatment of BCECs and two genes that substantially impacted BCECs were selected for analysis in vivo. We found that EphrinA2 and Connexin 43 protected against virus entry in adult mice. These studies demonstrated regional and age-related differences in the blood-brain barrier that have a critical role in mediating neuroinvasion by LACV and could be used to target potential therapeutics to limit access to the CNS and were published in Nature Communications (Basu, R., Ganesan, S., Winkler, C.W., Anzick, S., Martens, C., Peterson, K.E., Fraser, I.D.C. 2023. Identification of age-specific gene regulators of La Crosse virus neuroinvasion and pathogenesis. Nat. Comm.,14:2836. doi: 10.1038/s41467-023-37833-x). Finally, our lab collaborated with three other laboratories within DIR to study virus infections and disease pathogenesis in the brain. We collaborated with Dr. Danial Chertows group to determine the localization of SARS-CoV-2 in different tissues in the body, including showing virus replication in neurons in the brain. (Stein et al. Nature 2023). We collaborated with Dr. Priolas laboratory to examine the role of innate immune marker Sterile alpha and heat/Armadillo motif 1 (SARM1), which we found to be active in LACV-induced neuronal death, to determine if it affected prion disease (Ward et al. PLoS One 2022). Finally, we collaborated with Dr. Haighs laboratory in helping develop herpes virus infection model in cerebral organoids to examine the effect of virus infection on prion protein conversion (Smith et al. PLoS One, 2022).