Malaria Modifies Neonatal and Early-Life Toll-Like Receptor Cytokine Responses

Abstract

ABSTRACTProtection from infections in early life relies extensively on innate immunity, but it is unknown whether and how maternal infections modulate infants' innate immune responses, thereby altering susceptibility to infections.Plasmodium falciparumcauses pregnancy-associated malaria (PAM), and epidemiological studies have shown that PAM enhances infants' susceptibility to infection withP. falciparum. We investigated how PAM-mediated exposuresin uteroaffect innate immune responses and their relationship with infection in infancy. In a prospective study of mothers and their babies in Benin, we investigated changes in Toll-like receptor (TLR)-mediated cytokine responses related toP. falciparuminfections. Whole-blood samples from 134 infants at birth and at 3, 6, and 12 months of age were stimulated with agonists specific for TLR3, TLR4, TLR7/8, and TLR9. TLR-mediated interleukin 6 (IL-6) and IL-10 production was robust at birth and then stabilized, whereas tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) responses were weak at birth and then increased. In multivariate analyses, maternalP. falciparuminfections at delivery were associated with significantly higher TLR3-mediated IL-6 and IL-10 responses in the first 3 months of life (P< 0.05) and with significantly higher TLR3-, TLR7/8-, and TLR9-mediated TNF-α responses between 6 and 12 months of age (P< 0.05). Prospective analyses showed that higher TLR3- and TLR7/8-mediated IL-10 responses at birth were associated with a significantly higher risk ofP. falciparuminfection in infancy (P< 0.05). Neonatal and infant intracellular TLR-mediated cytokine responses are conditioned byin uteroexposure through PAM late in pregnancy. Enhanced TLR-mediated IL-10 responses at birth are associated with an increased risk ofP. falciparuminfection, suggesting a compromised ability to combat infection in early life.