Pathophysiology of chikungunya virus infection associated with fatal outcomes

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes acute, subacute, and chronic human arthritogenic diseases and, in rare instances, can lead to neurological complications and death. Here, we combined epidemiological, virological, histopathological, cytokine, molecular dynamics, metabolomic, proteomic, and genomic analyses to investigate viral and host factors that contribute to chikungunya-associated (CHIK) death. Our results indicate that CHIK deaths are associated with multi-organ infection, central nervous system damage, and elevated serum levels of pro-inflammatory cytokines and chemokines compared with survivors. The histopathologic, metabolite, and proteomic signatures of CHIK deaths reveal hemodynamic disorders and dysregulated immune responses. The CHIKV East-Central-South-African lineage infecting our study population causes both fatal and survival cases. Additionally, CHIKV infection impairs the integrity of the blood-brain barrier, as evidenced by an increase in permeability and altered tight junction protein expression. Overall, our findings improve the understanding of CHIK pathophysiology and the causes of fatal infections. [Display omitted] •Host and viral factors that are associated with chikungunya fatalities are defined•Chikungunya deaths involve the infection of multiple organs and severe inflammation•Chikungunya virus crosses the blood-brain barrier•Chikungunya deaths are associated with dysregulated hemostasis and immune response de Souza et al. show the complex factors behind fatal chikungunya cases, highlighting multi-organ infection, central nervous system damage, and severe inflammation. The findings suggest the chikungunya virus crosses the blood-brain barrier, contributing to central nervous system infection. This comprehensive study sheds light on chikungunya pathophysiology and fatal outcomes.