title: Malaria modifies neonatal and early-life toll-like receptor cytokine responses.
abstract: Protection 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 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 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, maternal P. falciparum infections 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 of P. falciparum infection in infancy (P < 0.05). Neonatal and infant intracellular TLR-mediated cytokine responses are conditioned by in utero exposure through PAM late in pregnancy. Enhanced TLR-mediated IL-10 responses at birth are associated with an increased risk of P. falciparum infection, suggesting a compromised ability to combat infection in early life.
authors.affiliation: Centre d'Etude et de Recherche sur le Paludisme Associé à la Grossesse et à l'Enfance (CERPAGE), Faculté des Sciences de la Santé, Université d'Abomey-Calavi, Cotonou, Benin.
authors.forename: Komi
authors.initials: K
authors.lastname: Gbédandé
authors.forename: Stefania
authors.initials: S
authors.lastname: Varani
authors.forename: Samad
authors.initials: S
authors.lastname: Ibitokou
authors.forename: Parfait
authors.initials: P
authors.lastname: Houngbegnon
authors.forename: Sophie
authors.initials: S
authors.lastname: Borgella
authors.forename: Odilon
authors.initials: O
authors.lastname: Nouatin
authors.forename: Sem
authors.initials: S
authors.lastname: Ezinmegnon
authors.forename: Adicatou-Laï
authors.initials: AL
authors.lastname: Adeothy
authors.forename: Gilles
authors.initials: G
authors.lastname: Cottrell
authors.forename: Achille
authors.initials: A
authors.lastname: Massougbodji
authors.forename: Kabirou
authors.initials: K
authors.lastname: Moutairou
authors.forename: Marita
authors.initials: M
authors.lastname: Troye-Blomberg
authors.forename: Philippe
authors.initials: P
authors.lastname: Deloron
authors.forename: Nadine
authors.initials: N
authors.lastname: Fievet
authors.forename: Adrian J F
authors.initials: AJ
authors.lastname: Luty
mesh_terms: D000328:Adult; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016778:Malaria, Falciparum / Q000276:immunology* / Q000378:metabolism; D008297:Male; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology*; D011297:Prenatal Exposure Delayed Effects / Q000276:immunology*; D051193:Toll-Like Receptors / Q000096:biosynthesis* / Q000276:immunology
chemical_list: D016207:Cytokines; D051193:Toll-Like Receptors