Comprehensive innate immune profiling of chikungunya virus infection in pediatric cases

Abstract Chikungunya virus (CHIKV) is a mosquito‐borne alphavirus that causes global epidemics of debilitating disease worldwide. To gain functional insight into the host cellular genes required for virus infection, we performed whole‐blood RNA‐seq, 37‐plex mass cytometry of peripheral blood mononuclear cells (PBMCs), and serum cytokine measurements of acute‐ and convalescent‐phase samples obtained from 42 children naturally infected with CHIKV. Semi‐supervised classification and clustering of single‐cell events into 57 sub‐communities of canonical leukocyte phenotypes revealed a monocyte‐driven response to acute infection, with the greatest expansions in “intermediate” CD14++CD16+ monocytes and an activated subpopulation of CD14+ monocytes. Increases in acute‐phase CHIKV envelope protein E2 expression were highest for monocytes and dendritic cells. Serum cytokine measurements confirmed significant acute‐phase upregulation of monocyte chemoattractants. Distinct transcriptomic signatures were associated with infection timepoint, as well as convalescent‐phase anti‐CHIKV antibody titer, acute‐phase viremia, and symptom severity. We present a multiscale network that summarizes all observed modulations across cellular and transcriptomic levels and their interactions with clinical outcomes, providing a uniquely global view of the biomolecular landscape of human CHIKV infection.