Neurological chikungunya virus infection induces corpus callosum degeneration associated with resident immune cell activation and peripheral immune cell infiltration

Abstract

Chikungunya virus (CHIKV) is an Old World alphavirus that typically induces arthralgia and rash. However, CHIKV is also capable of infecting the central nervous system (CNS), resulting in encephalitis, myelitis, and peripheral neuropathy. Patients who survive acute infection typically have long lasting neurological effects. To date, an immunocompetent small animal model that recapitulates CHIKV CNS disease has not been established. To develop a mouse model of CNS CHIKV infection, we intracranially inoculated 4–6 week old C57BL/6J mice with 1 of 3 clinical CHIKV isolates: Asian lineage strains SM2013 and AF15561, and ECSA lineage strain SL15649. CHIKV CNS disease is most commonly reported in regions where ECSA lineage strains circulate; in agreement with observations in humans, SL15649 was associated with more severe neurological disease, while SM2013 induced minimal to no disease, and AF15561 induced an intermediate clinical phenotype. At 7dpi when mice demonstrated signs of CNS disease but infectious virus was cleared from the brain, significant corpus callosum degeneration was observed in mice infected with SL15649, and to a lesser extent AF15561. Recruited CD4+ T cells and B cells were significantly elevated in the corpus callosum of mice infected with SL15649 compared to mice infected with SM2013. SL1549 infected mice also had significant micro- and astrogliosis in this area. At 3dpi, prior to neurological signs, the corpus callosum in SL1549 infected mice did not show significant degeneration but did have an influx of peripheral immune cells and increased gliosis. These results suggest that the CNS manifestations of CHIKV are associated with corpus callosum degeneration driven by both peripheral and CNS resident immune cells. Supported by the following grants: K01 OD026529 (VKB) T32AI0075151 (ACK) AAI Careers in Immunology Fellowship (VKB, ACK) UNC SOM Junior Investigator Development Award (VKB) UNC Department of Pathology and Laboratory Medicine (VKB)