Effect of Viral Strain and Host Age on Clinical Disease and Viral Replication in Immunocompetent Mouse Models of Chikungunya Encephalomyelitis

Abstract

The alphavirus chikungunya virus (CHIKV) represents a reemerging public health threat as mosquito vectors spread and viruses acquire advantageous mutations. Although primarily arthritogenic in nature, CHIKV can produce neurological disease with long-lasting sequelae that are difficult to study in humans. We therefore evaluated immunocompetent mouse strains/stocks for their susceptibility to intracranial infection with three different CHIKV strains, the East/Central/South African (ECSA) lineage strain SL15649 and Asian lineage strains AF15561 and SM2013. In CD-1 mice, neurovirulence was age- and CHIKV strain-specific, with SM2013 inducing less severe disease than SL15649 and AF15561. In 4–6-week-old C57BL/6J mice, SL15649 induced more severe disease and increased viral brain and spinal cord titers compared to Asian lineage strains, further indicating that neurological disease severity is CHIKV-strain-dependent. Proinflammatory cytokine gene expression and CD4+ T cell infiltration in the brain were also increased with SL15649 infection, suggesting that like other encephalitic alphaviruses and with CHIKV-induced arthritis, the immune response contributes to CHIKV-induced neurological disease. Finally, this study helps overcome a current barrier in the alphavirus field by identifying both 4–6-week-old CD-1 and C57BL/6J mice as immunocompetent, neurodevelopmentally appropriate mouse models that can be used to examine CHIKV neuropathogenesis and immunopathogenesis following direct brain infection.

Attenuation of neurovirulence of chikungunya virus by a single amino acid mutation in viral E2 envelope protein

“…Subsequent studies have confirmed the association of CHIKV infection with neurological complications [ 15 ], and it appears that new variants of CHIKV are becoming more neurovirulent [ 16 ]. An in vivo study has provided evidence that the severity of CHIKV-induced neurological disease is dependent on the specific CHIKV strain, with infection by the ECSA lineage strain leading to more severe neurological manifestations [ 17 ]. In a prior investigation during the La Réunion outbreak of 2005–2006, out of 33 individuals who were admitted to the ICU and confirmed to have acute Chikungunya virus infection, 14 of them were found to have been diagnosed with encephalopathy [ 18 ].…”