Comparative Analysis of Bunyavirus Neuropathogenesis

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PROJECT SUMMARY/ABSTRACT Bunyaviruses are a large, diverse group of vector-borne viruses with the capacity to cause neurological disease with morbidity and mortality. A major limitation in our basic scientific understanding of bunyavirus neuropathogenesis stems from the fact that key target cells in the brain are not fully defined, therefore the effect of infection on target cells is unknown, and viral determinants that contribute to neurological disease have not been delineated. A broader, understanding of how bunyaviruses interact with the central nervous system (CNS), including molecular mechanisms of host-viral interactions, is fundamental for future goal of mitigating effects of disease and long-term sequelae in survivors. Here, we propose a comparative analysis of the basic neuropathogenesis of 3 important emerging bunyaviruses: Rift Valley fever (RVFV), Oropouche (OROV), and La Crosse (LACV). Infection by each of these viruses have the potential to cause significant neurological disease in humans. However, substantial gaps remain in our understanding of bunyavirus neuropathogenesis, including molecular mechanisms that contribute to disease. A limitation is the lack of rigor of prior research is that published studies on these viruses as they are difficult to directly compare due to use of different in vitro cell systems and disparate mouse models, including variations in age and infection route. We will address this gap by directly comparing CNS cell tropism, innate responses, and cell death pathways induced by RVFV, OROV, and LACV using novel in vitro and ex vivo model systems. Given the potential for diverse bunyaviruses to cause neurological sequelae in a subset of human cases, and the fact that all 3 are lethal in neurological mouse models, we hypothesize that diverse bunyaviruses have common target cells in the CNS and that neuronal infection is mediated by Lrp1, a newly identified host entry factor for RVFV. A key feature of bunyaviral virology is the expression of the viral non-structural protein produced from the small genome segment (NSs). NSs is the main antagonist of host cell antiviral responses. Each virus expresses a different NSs protein, and thus we further hypothesize that the degree of neurovirulence of each virus is directly related to NSs protein function, with RVFV NSs being the most potent inhibitor of innate responses. Our highly collaborative and synergistic team is led by Dr. Amy Hartman (PI), an expert in the pathogenesis of RVFV, Dr. Anita McElroy (Co-I), a molecular virologist and immunologist with expertise in emerging viral diseases, Dr. Gaya Amarasinghe (Co-I), a biochemist with expertise in host-pathogen interactions. Two additional Co-I’s are Dr. Leonard D’Aiuto and Dr. Zachary Wills, who are experts in viral infection of human neurons and rodent neurobiology, respectively. This R01 proposal represents a multidisciplinary approach to advance our understanding of bunyavirus interactions with the brain.