Malaria-induced murine pregnancy failure: distinct roles for IFN-gamma and TNF

Although an important role for excessive proinflammatory cytokines in compromise of pregnancy has been established, an immunological basis for malaria-induced fetal loss remains to be demonstrated. In this study, the roles of IFN-gamma and TNF in Plasmodium chabaudi AS-induced fetal loss in mice wer...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2009-10, Vol.183 (8), p.5342-5349
Main Authors: Poovassery, Jayakumar S, Sarr, Demba, Smith, Geoffrey, Nagy, Tamas, Moore, Julie M
Format: Article
Language:English
Subjects:
Animals
Antibodies - immunology
Embryo Loss - immunology
Embryo Loss - parasitology
Female
Interferon-gamma - genetics
Interferon-gamma - immunology
Malaria - complications
Malaria - immunology
Malaria - parasitology
Mice
Mice, Inbred C57BL
Mice, Knockout
Placenta - immunology
Placenta - parasitology
Placenta - pathology
Plasmodium chabaudi
Pregnancy
Pregnancy Complications, Parasitic - immunology
Thromboplastin - immunology
Thromboplastin - metabolism
Tumor Necrosis Factor-alpha - antagonists & inhibitors
Tumor Necrosis Factor-alpha - immunology
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Summary:Although an important role for excessive proinflammatory cytokines in compromise of pregnancy has been established, an immunological basis for malaria-induced fetal loss remains to be demonstrated. In this study, the roles of IFN-gamma and TNF in Plasmodium chabaudi AS-induced fetal loss in mice were directly investigated. Pregnant IFN-gamma(-/-) mice experienced a more severe course of infection compared with intact C57BL/6 mice, characterized by high parasitemia, severe anemia, and marked weight loss. However, fetal loss was delayed in these mice relative to intact controls. Because IFN-gamma(-/-) mice exhibited sustained levels of plasma TNF, the role of this cytokine was examined. Whereas splenic tnf expression in C57BL/6 mice was highest 3 days before peak parasitemia, increased placental expression relative to uninfected mice was sustained, indicating that locally produced TNF may be important in malaria-induced pregnancy failure. Indeed, Ab neutralization of TNF resulted in preservation of embryos until day 12 of gestation, at which point all embryos were lost in untreated mice. Histological analysis revealed that TNF ablation preserved placental architecture whereas placentae from untreated infected mice had widespread hemorrhage and placental disruption, with fibrin thrombi in some maternal blood sinusoids. Consistent with a role for cytokine-driven thrombosis in fetal loss, expression of procoagulant tissue factor was significantly increased in the placentae of infected C57BL/6 mice but was reduced in mice treated with anti-TNF Ab. Together, these results suggest that IFN-gamma contributes to malaria-induced fetal loss and TNF is a critical factor that acts by inducing placental coagulopathy.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.0901669