The purpose of this K01 SERCA application is to provide the protected research time and mentorship necessary for Dr. Victoria Baxter, DVM, PhD, DACLAM to make the transition to independent investigator. Dr. Baxter is a veterinarian with a strong background in comparative medicine, viral immunology, and animal models of infectious disease, making her uniquely qualified for a career in translational research. Under the guidance of her mentor Dr. Mark Heise and an experienced interdisciplinary advisory committee, the training and aims outlined in this proposal will allow Dr. Baxter to expand her knowledge in viral and host genetics in order to establish a solid foundation for her own independent research program focused on understanding the pathogenesis of emerging and re-emerging viral diseases. The University of North Carolina at Chapel Hill will provide the interactive and collaborative environment necessary to support her transition to independence. Encephalitic arboviruses represent a re-emerging cause of human disease and disability, as patients who survive the initial acute disease are often left with lifelong neurological deficits. While chikungunya virus (CHIKV), an alphavirus that has recently spread to the Americas and Caribbean, typically causes a systemic disease characterized by rash and arthritis, individuals frequently develop neurological complications. Very little has been done to examine CHIKV encephalomyelitis, as no reliable small animal model currently exists. Most of the knowledge regarding the pathogenesis of alphavirus infection of the central nervous system (CNS) comes from the well-characterized mouse model of alphavirus encephalomyelitis using Sindbis virus. Outcome of CNS infection by Sindbis virus is dependent on both viral and mouse strain genetics, and CNS damage is primarily mediated by the immune response. This suggests three independent but interrelated factors drive CHIKV encephalomyelitis: viral genetics, host genetics, and the host immune system. The central hypothesis of the proposed studies is that CHIKV encephalomyelitis develops due to a combination of viral and host genetic factors, resulting in CNS damage that is primarily mediated by the host immune response rather than directly by CHIKV. This hypothesis will be tested with the following specific aims:
Specific Aim #1 : Determine if CHIKV genetic variation confers neurovirulence in a mouse model of CHIKV encephalomyelitis.
Specific Aim #2 : Elucidate the contribution of the adaptive immune system to CHIKV encephalomyelitis.
Specific Aim #3 : Determine if host genetic variation impacts susceptibility to CHIKV encephalomyelitis. These studies will generate valuable data that will provide a foundation for a future R01 application aimed at further elucidating mechanisms of CHIKV neuropathogenesis, and SERCA funding will provide Dr. Baxter with the skills necessary to establish similar models for examining other emerging viral diseases in the future.
Encephalitic arboviruses, including alphaviruses and flaviviruses, present a re-emerging public health concern, as surviving patients are often left with lifelong neurological deficits, and treatment is currently limited to supportive care. Examining the neuropathogenesis of chikungunya virus, a naturally arthritogenic alphavirus that frequently induces neurological disease, is severely limited by the lack of a robust small animal model. This proposal aims to establish and characterize a mouse model of chikungunya virus infection of the central nervous system that can then be used to elucidate the mechanisms of chikungunya virus neuropathogenesis and identify viral and host pathways that may be targeted by potential therapeutics.
