Association of Malaria-Induced Murine Pregnancy Failure with Robust Peripheral and Placental Cytokine Responses

Abstract

Malarial infection in nonimmune pregnant women is a major risk factor for pregnancy failure. The biological mechanisms that underlie malaria-associated fetal loss, however, are poorly understood. Plasmodium chabaudi AS infection during early pregnancy results in midgestational embryonic loss in naive C57BL/6 mice. To define the immunopathogenesis of this malaria-induced pregnancy compromise, cytokine production in plasma, spleen, and placenta cell culture supernatants during the first 11 days of infection and gestation was studied. In infected pregnant mice, systemic interleukin-1␤ and both systemic and splenic gamma interferon levels were elevated relative to those in uninfected pregnant mice, and gamma interferon was also robustly produced within the placenta 1 to 2 days before malaria-induced fetal loss. Although circulating tumor necrosis factor production was not affected by pregnancy or infection, circulating soluble tumor necrosis factor receptor II was highest in infected pregnant mice, particularly those undergoing abortion, but decreased at the placental level preceding abortion. Systemic levels of interleukin-10 were also high in infected mice at this time point, but this cytokine was not detected at the placental level. Histological examination revealed that trophoblast giant cells of aborting mice phagocytosed infected red blood cells and hemozoin. Furthermore, in vitro-cultured trophoblast cells isolated from embryos on day 7 of gestation phagocytosed P. chabaudi AS-infected red blood cells and secreted tumor necrosis factor. These results suggest that systemic and placenta-level proinflammatory antimalarial immune responses, in the absence of adequate and sustained counterregulatory mechanisms, contribute to pregnancy loss in this model.

MyD88 Signaling Is Directly Involved in the Development of Murine Placental Malaria

“…However, our results indicated that the production of these cytokines in WT infected mice was clearly associated with the observed placental impairment (i.e., inflammation, tissue disorganization, and reduction of vascular space). A possible explanation for the absence of abortions in this study may be the time of infection, which, in contrast to previous studies (47), was chosen to allow the pregnancies to reach term in our murine model (3). In addition to the systemic maternal levels of TNF-␣, the placentas from the infected WT mice showed increased expression of TNF-␣ mRNA.…”

“…In addition to TNF-␣, other proinflammatory cytokines, such as IFN-␥, have been implicated in spontaneous abortion in humans (46). Similarly, murine models developed in an attempt to induce pregnancy failure through malaria infection point to systemic increases in TNF-␣ and IFN-␥ production as a cause of abortions (47,48). In our model system, we did not observe an increase in abortion or reabsorption due to systemic TNF-␣ or IFN-␥ production.…”

Differential roles of inflammation and apoptosis in initiation of mid-gestational abortion in malaria-infected C57BL/6 and A/J mice

“…Advances in understanding of malarial pathogenesis in humans during the early, highly vulnerable phases of pregnancy are few because the affected placenta is unavailable for study. P. chabaudi AS infection in murine pregnancy, which can be easily employed to investigate infection throughout the course of pregnancy [23, 25-27], is therefore highly valuable in identifying the molecular mechanisms underlying the pathogenesis of PM early in gestation.…”

“…Additionally, trophoblast phagocytosis of red blood cells is associated with pregnancy loss in mice infected with P. chabaudi AS [23] as well as P. berghei [24]. Like P. berghei ANKA, P. chabaudi AS -iRBCs have also been reported to accumulate in placental tissue [25].…”

“…Whereas TNF responses to malaria are observed in both strains, levels are quite high in A/J mice [25, 26]; ablation of this response with neutralizing antibodies significantly improves mid-gestational pregnancy success in B6 [26] but not in A/J mice [25], in which higher neutralizing activity may be required. Ultimately, B6 mice recover from this infection, but A/J mice die by gestation day 14 [23, 25]. …”