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

Abstract

g 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. TLRmediated 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 3 months of life (P < 0.05) and with significantly higher TLR3-, TLR7/8-, and TLR9-mediated TNF-␣ 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 TLRmediated 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.

Changes in Antigen-Specific Cytokine and Chemokine Responses to Plasmodium falciparum Antigens in a Highland Area of Kenya after a Prolonged Absence of Malaria Exposure

“…Based on previous studies and the present study, it appears that in populations of low transmission, the absence of clinical malaria incidence is a crude indicator that malaria transmission is below the required level, and that malaria incidence at some level between 2 cases/1,000 persons/month (the maximum for this period of study) and 15 cases/1,000 persons/month (the minimum at the times of collection in the past study) reflects the necessary transmission level to sustain IFN-␥ and IL-10 responses. Our findings of a lack of correlation of cytokine responses with age contrast with the findings of other studies (54,55), and studies by our group in this highland area in a period of higher transmission (3,4), but also likely reflect the extremely low transmission setting of the current study, a setting in which responses are infrequently boosted because there is little or no malaria exposure. The study was limited by its sampling period: samples from the earlier time period would have provided valuable information about whether antigen-specific cytokine levels were higher at the start of interrupted transmission, and what the rate of decrease was if so.…”

Immune responses in neonates

“…Placental infection with Plasmodium falciparum (causative agent of malaria) or parasite-derived antigens in utero activate cord blood antigen presenting cells (APC) and modulates cord blood cytokine responses to TLR ligation [10]. P. falciparum infections at delivery are associated with higher TLR3-mediated IL-6 and IL-10 responses in the child in the first 3 months of life and significantly higher TLR3-, TLR7/8-, and TLR9-mediated TNF-α responses between 6 to 12 months of age [10].…”

“…Placental infection with Plasmodium falciparum (causative agent of malaria) or parasite-derived antigens in utero activate cord blood antigen presenting cells (APC) and modulates cord blood cytokine responses to TLR ligation [10]. P. falciparum infections at delivery are associated with higher TLR3-mediated IL-6 and IL-10 responses in the child in the first 3 months of life and significantly higher TLR3-, TLR7/8-, and TLR9-mediated TNF-α responses between 6 to 12 months of age [10]. Parasite antigen-specific immune responses of neonates born to helminth-infected mothers display a highly skewed Th2-type cytokine pattern, with a prominent role for the regulatory cytokine interleukin IL-10 that inhibits both APC HLA expression and Th1-type T-cell responses [11].…”

Chemokine levels and parasite- and allergen-specific antibody responses in children and adults with severe or uncomplicatedPlasmodium falciparummalaria

“…In parallel, these children had chemokine plasma levels at magnitudes observed to an equal extent in adults with uncomplicated malaria, notably TARC/CCL17, PARC/CCL18, and eotaxin-2/CCL24, which may signify a gradual evolution of regulated immune responses during early postnatal life. Resolution of P. falciparum infection will require immune responses which are of both proinfl ammatory and regulatory type; an early Th1-type gamma interferon (IFN-γ) cytokine response may support resistance [13]; and while high regulatory IL-10 levels were reported in children with severe malaria [18,36,37], IL-10 also exerts anti-infl ammatory effects, thus, limiting pathogenic and excessive Th1 cytokine responses. In the present work, the neutrophil granulocyte-activating and proinfl ammatory chemokine NAP-1/CXCL8/IL-8 was at highest levels in children with severe malaria, while CXCL8/IL-8 was low in adults with uncomplicated disease.…”