Toll-Like Receptor-Induced Immune Responses During Early Childhood and Their Associations With Clinical Outcomes Following Acute Illness Among Infants in Sub-Saharan Africa

Severely ill children in low- and middle-income countries (LMICs) experience high rates of mortality from a broad range of infectious diseases, with the risk of infection-related death compounded by co-existing undernutrition. How undernutrition and acute illness impact immune responses in young children in LMICs remains understudied, and it is unclear what aspects of immunity are compromised in this highly vulnerable population. To address this knowledge gap, we profiled longitudinal whole blood cytokine responses to Toll-like receptor (TLR) ligands among severely ill children (n=63; 2-23 months old) with varied nutritional backgrounds, enrolled in the CHAIN Network cohort from Kampala, Uganda, and Kilifi, Kenya, and compared these responses to similar-aged well children in local communities (n=41). Cytokine responses to ligands for TLR-4 and TLR-7/8, as well as Staphylococcus enterotoxin B (SEB), demonstrated transient impairment in T cell function among acutely ill children, whereas innate cytokine responses were exaggerated during both acute illness and following clinical recovery. Nutritional status was associated with the magnitude of cytokine responses in all stimulated conditions. Among children who died following hospital discharge or required hospital re-admission, exaggerated production of interleukin-7 (IL-7) to all stimulation conditions, as well as leukopenia with reduced lymphocyte and monocyte counts, were observed. Overall, our findings demonstrate exaggerated innate immune responses to pathogen-associated molecules among acutely ill young children that persist during recovery. Heightened innate immune responses to TLR ligands may contribute to chronic systemic inflammation and dysregulated responses to subsequent infectious challenges. Further delineating mechanisms of innate immune dysregulation in this population should be prioritized to identify novel interventions that promote immune homeostasis and improve outcomes.