Age is an intrinsic driver of inflammatory responses to malaria

Age is a critical factor in immune responses to infection. In malaria, severe disease risk increases with age in non-immune individuals. Malaria severity is in part driven by inflammation, but mechanisms contributing to age-dependent disease risk are incompletely understood. We assessed inflammatory cytokines during malaria in non-immune children and adults, and innate cell responses in vitro to malaria parasites in naive children and adults. We show during malaria age is associated with increased inflammatory chemokines CCL2, CCL3, CXCL8, CXCL9, along with CRP, and IDO, which associate with symptoms. In naive individuals, classical monocyte and Vδ2⁺ γδ T cells from adults have higher inflammatory cytokine production, and transcriptional activation following stimulation with parasites. Classical monocyte responses in adults are dominated by CCL2, while in children increased IL10 and enrichment of IL10 signaling pathways is detected. Findings identify age-dependent cellular mechanisms that play crucial roles in driving inflammatory responses in malaria.