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

Protection from infections in early life relies extensively on innate immunity, but it is unknown whether and how maternal in-fections modulate infants ’ innate immune responses, thereby altering susceptibility to infections. Plasmodium falciparum causes pregnancy-associated malaria (PAM), and epidemiological studies have shown that PAM enhances infants ’ susceptibility to infection with P. falciparum. We investigated how PAM-mediated exposures in utero affect 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 to P. falciparum infections. Whole-blood samples from 134 in-fants 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-) and gamma interferon (IFN-) responses were weak at birth and then increased. In multivariate analyses, maternal P. falciparum infections at delivery were associated with significantly higher TLR3-mediated IL-6 and IL-10 responses in the first