Fetal and Maternal Innate Immunity Receptors Have Opposing Effects on the Severity of Experimental Malaria in Pregnancy: Beneficial Roles for Fetus-Derived Toll-Like Receptor 4 and Type I Interferon Receptor 1

Abstract

Malaria in pregnancy (MiP) is a distinctive clinical form of Plasmodium infection and is a cause of placental insufficiency leading to poor pregnancy outcomes. Maternal innate immunity responses play a decisive role in the development of placental inflammation, but the action of fetus-derived factors in MiP outcomes has been overlooked. We investigated the role of the Tlr4 and Ifnar1 genes, taking advantage of heterogenic mating strategies to dissect the effects mediated by maternally and fetally derived Toll-like receptor 4 (TLR4) or type I interferon receptor 1 (IFNAR1). Using a mouse infection system displaying severe MiP outcomes, we found that the expressions of TLR4 and IFNAR1 in the maternal compartment take part in deleterious MiP outcomes, but their fetal counterparts patently counteract these effects. We uncovered that fetal TLR4 contributes to the in vitro uptake of infected erythrocytes by trophoblasts and to the innate immune response in the placenta, offering robust protection of fetus viability, but had no sensible impact on the placental parasite burden. In contrast, we observed that the expression of IFNAR1 in the fetal compartment was associated with a reduced placental parasite burden but had little beneficial effect on fetus outcomes. Furthermore, the downregulation of Ifnar1 expression in infected placentas and in trophoblasts exposed to infected erythrocytes indicated that the interferon-IFNAR1 pathway is involved in the trophoblast response to infection. This work unravels that maternal and fetal counterparts of innate immune pathways drive opposing responses in murine placental malaria and implicates the activation of innate receptors in fetal trophoblast cells in the control of placental infection and in the protection of the fetus.

Insight Into TLR4-Mediated Immunomodulation in Normal Pregnancy and Related Disorders

“…Similarly, a decrease in maternal type 1 IFN receptor 1 (IFNAR1) during the course of infection promotes the parasite burden by limiting the activation and accumulation of Helper T cells. Increased fetal IFNAR1, however, helps in eliciting an anti-parasite response, but fetal IFNAR1 is not sufficient enough to reduce the placental parasite burden and its harmful effect on the fetus (6). In placental malaria, the TLR4 downstream partner MyD88 has no significant role in pregnancy outcome irrespective of maternal or fetal genetic background FIGURE 5 | Various Drugs that target TLR4 pathway in pregnancy disorders: drugs and anti-inflammatory agents that target TLR4 pathway and its downstream molecules during infection induced preterm birth.…”

“…A fine interplay between both phases ensures a healthy pregnancy. There are numerous reports that have suggested that any dysregulation in the immune status at the materno-fetal interface due to infections are the main cause of preterm delivery, preeclampsia, gestational diabetes, miscarriage, placental malaria, and other pregnancy-related disorders (4)(5)(6)(7). There are multiple routes through which the infections can gain access to the placenta, maternal endometrium, and amniotic fluid; ascending through the genital tract and colonizing uterine cavity is the most preferred of all (8).…”

Regulation of inflammation during gestation and birth outcomes: Inflammatory cytokine balance predicts birth weight and length

“…Although acute gestational insults like infection are risk factors for preterm birth and intrauterine growth restriction (Fried et al, ; Park et al, ; Qiu et al, ; Rodrigues‐Duarte, Pandya, Neres, & Penha‐Gonçalves, ), recent research has demonstrated that endogenous immune processes, such as chronic inflammation, can influence birth outcomes and increase the risk for adverse birth outcomes (Kuzawa, Fried, Borja, & McDade, ; McDade et al, ). The majority of studies on inflammation and pregnancy have used C‐reactive protein (CRP), an acute phase protein that serves as a global marker of inflammation, to characterize fetal exposure to maternal inflammation (Del Giudice & Gangestad, ; Kuzawa et al, , ; McDade, ; McDade et al, ; Madonna et al, ).…”

Intravital imaging of host‐parasite interactions in organs of the thoracic and abdominopelvic cavities

“…Further, infected erythrocytes interacting with trophoblasts showed to be able to cross the trophoblast layer and migrate between adjacent maternal blood spaces (de Moraes et al, ). These observations were confirmed by experiments showing that innate immune receptors expressed on trophoblasts (e.g.TLR4) contribute to in vitro engulfment of infected erythrocytes and to foetal protection during malaria infection (Rodrigues‐Duarte, Pandya, Neres, & Penha‐Gonçalves, ). These findings underpinned the hypothesis that innate immune recognition of Plasmodium infection by trophoblasts represents a foetus‐protective response that counteracts the pro‐inflammatory effects of the maternal immune system (Pandya & Penha‐Gonçalves, ).…”