Immunopathogenesis of malaria during murine pregnancy
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Malaria during pregnancy is detrimental to the health of both mother and her unborn child. Although malaria-induced fetal loss is one of the most severe consequences of malarial infection during pregnancy, our understanding of the molecular and immunologic mechanisms involved in fetal loss is limited. This has been due in part to the absence of an adequate system to carry out mechanistic studies during pregnancy. To overcome this limitation a model system was developed in this study by infecting pregnant C57BL/6 mice with Plasmodium chabaudi AS. In this model, P. chabaudi AS -infected pregnant B6 mice experienced parasitemia, anemia and weight change comparable to infected nonpregnant mice. Although the infection was not lethal to the mother, the fetal outcome was poor. Aborting mice experienced high placental parasitemia compared to peripheral blood. Additionally, fetal loss was associated with elevated levels of proinflammatory cytokines IFN-γ, TNF-α and IL-1β in the plasma. Since both IFN-γ and TNF-α are known embryotoxic agents, experiments using gene knockout mice and antibody ablation were performed to identify the role of these cytokines in malaria-induced fetal loss. Despite experiencing a more severe course of infection, IFN-γ-/- mice had improved pregnancy success. Since IFN-γ knockout mice also experienced fetal loss and had TNF-α, a known embryo toxic agent, in their plasma at the time of abortion, the effect of in vivo neutralization of TNF-α on pregnancy success in P. chabaudi AS-infected wild-type pregnant mice was tested. Whereas IgG treated infected mice aborted their embryos by gestation day 11, infected, pregnant mice treated with anti-TNF-α antibody retained their pregnancies and had viable embryos in their uteri on day 12 post infection. It is possible that the proinflammatory cytokines are mediating their detrimental effects on the fetus through initiating a clotting cascade in the uterus. Placental sections from aborting mice had wide spread hemorrhage and fibrin thrombi formation in the maternal blood sinusoids. Furthermore, the levels of procoagulants tissue factor and plasminogen activator inhibitor-1 were upregulated in the uteri from aborting mice. In addition to maternal cells, fetal cells may also be contributing to the local placental pathology. Fetal trophoblast cells exhibited phagocytosis of iRBCs in vivo and secreted TNF-α in the culture medium following phagocytosis of iRBCs in vitro. Taken together the results from this study suggest that TNF-α is a critical factor in malaria-induced fetal loss. TNF-α produced by both maternal and fetal cells at the placental level may be contributing to tissue injury through initiating a clotting cascade in the placenta, leading to loss of blood supply to fetus and ultimately fetal death.