Pathogenesis of chikungunya virus infection associated with fatal outcome

Chikungunya virus (CHIKV) is a mosquito-borne virus that causes acute, subacute, and chronic human diseases and can cause neurological complications and death. Here, we combined epidemiological, virological, histopathological, cytokine, molecular dynamics, metabolomics, proteomics, and genomic analyses to investigate viral and pathophysiologic factors that contribute to deaths caused by chikungunya (CHIK). Our results indicate that CHIK-deaths presented multiple organs infection, central nervous system damage, and exhibited significantly elevated serum levels of pro-inflammatory cytokines and chemokines compared to survivors. The histopathology, metabolite, and proteomic signatures of CHIK-deaths revealed hemodynamic disorders and dysregulated immune system response. CHIKV East-Central-South-African lineage caused fatal and survivor cases, and CHIKV crosses the blood–brain barrier without tight junction alterations. IFN-λ3 was highly expressed in fatal cases but did not present a direct antiviral effect on CHIKV replication in vitro. In summary, our results reveal insights to improve understanding of CHIK pathogenesis, especially the pathophysiology of fatal infections.