Comprehensive innate immune profiling of chikungunya virus infection in pediatric cases

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.