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Abstract
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 infectionduring pregnancy, our understanding of the molecular and immunologic mechanisms involved infetal loss is limited. This has been due in part to the absence of an adequate system to carry outmechanistic studies during pregnancy. To overcome this limitation a model system wasdeveloped in this study by infecting pregnant C57BL/6 mice with Plasmodium chabaudi AS. Inthis model, P. chabaudi AS -infected pregnant B6 mice experienced parasitemia, anemia andweight change comparable to infected nonpregnant mice. Although the infection was not lethalto the mother, the fetal outcome was poor. Aborting mice experienced high placental parasitemiacompared to peripheral blood. Additionally, fetal loss was associated with elevated levels ofproinflammatory cytokines IFN-, TNF- and IL-1 in the plasma. Since both IFN- and TNF-are known embryotoxic agents, experiments using gene knockout mice and antibody ablationwere performed to identify the role of these cytokines in malaria-induced fetal loss. Despiteexperiencing a more severe course of infection, IFN--/- mice had improved pregnancy success.Since IFN- knockout mice also experienced fetal loss and had TNF-, a known embryo toxicagent, in their plasma at the time of abortion, the effect of in vivo neutralization of TNF- onpregnancy success in P. chabaudi AS-infected wild-type pregnant mice was tested. Whereas IgGtreated infected mice aborted their embryos by gestation day 11, infected, pregnant mice treatedwith anti-TNF- antibody retained their pregnancies and had viable embryos in their uteri on day12 post infection. It is possible that the proinflammatory cytokines are mediating theirdetrimental effects on the fetus through initiating a clotting cascade in the uterus. Placentalsections from aborting mice had wide spread hemorrhage and fibrin thrombi formation in thematernal blood sinusoids. Furthermore, the levels of procoagulants tissue factor and plasminogenactivator inhibitor-1 were upregulated in the uteri from aborting mice. In addition to maternalcells, fetal cells may also be contributing to the local placental pathology. Fetal trophoblast cellsexhibited phagocytosis of iRBCs in vivo and secreted TNF- in the culture medium followingphagocytosis of iRBCs in vitro.Taken together the results from this study suggest that TNF- is a critical factor inmalaria-induced fetal loss. TNF- produced by both maternal and fetal cells at the placental levelmay be contributing to tissue injury through initiating a clotting cascade in the placenta, leadingto loss of blood supply to fetus and ultimately fetal death.