Modeling chikungunya virus neuroinvasion and neuropathogenesis in mice

PROJECT SUMMARY The alphavirus chikungunya virus (CHIKV) represents a re-emerging public health concern as mosquito vectors spread to new territories. While CHIKV typically induces an arthritogenic disease, up to 16% of cases result in neurological disease such as encephalitis and meningitis. Surviving patients are often left with long-term neurological deficits, including impaired motor control, emotional and behavioral disinhibition, and cognitive disorders. Despite numerous published clinical case and public health impact reports, very little is known about the neuropathogenesis of CHIKV infection. The limited accessibility and minimally regenerative nature of the central nervous system (CNS) create an insurmountable barrier to studying the course of neurological CHIKV infection in humans and require the use of animal models. Mice have been used extensively to study arthritogenic disease induced by CHIKV and neurological disease induced by other alphaviruses, including long-term neurological sequalae. However, almost all mouse studies examining neurological CHIKV infection have utilized neonatal or immunocompromised mice, which do not accurately reflect the neurodevelopmental or immunological status of susceptible human populations. Furthermore, both arthritogenic and neurological disease induced by alphaviruses have been shown to primarily be mediated by the immune response rather than by the virus itself, further necessitating the use of immunocompetent mice. Preliminary work by our group has found that while young adult C57BL/6J mice are susceptible to infection and replicate the CNS pathology reported in humans following intracranial infection, CNS infection cannot be consistently achieved following peripheral inoculation. In contrast, CC041 mice, a Collaborative Cross strain, consistently demonstrate infection of the brain and signs of neurological disease following subcutaneous inoculation, presenting a potential mouse model by which to evaluate neurological disease induced by CHIKV following peripheral infection. This proposal aims to characterize neurological CHIKV infection in CC041 mice following peripheral inoculation and determine whether CC041 mice develop the neurological disease and CNS pathology seen in humans. In Aim 1, we will determine the mechanism and dynamics by which CHIKV infects the brain in CC041 mice. In Aim 2, we will determine whether CC041 mice develop CNS pathology and long-term neurological sequelae similar to human patients following neurological CHIKV infection. Our studies will establish a new neurodevelopmentally- appropriate, immunocompetent mouse model of peripheral CHIKV infection, allowing for future in depth evaluation of the mechanisms driving neurological disease development and by which to test new potential vaccines, antivirals, and host-directed treatments for neurological infection with CHIKV and other alphaviruses.