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and TNF1,2
*Center for Tropical and Emerging Global Diseases; and
Department of Infectious Diseases and
Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602
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-
and TNF in Plasmodium chabaudi AS-induced fetal loss in mice were directly investigated. Pregnant IFN-–/– 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-–/– 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- contributes to malaria-induced fetal loss and TNF is a critical factor that acts by inducing placental coagulopathy.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Institutes of Health Grant HD046860 to J.M.M. The content is solely the responsibility of the authors and does not necessarily represent the official views of National Institute of Child Health and Human Development or the National Institutes of Health.
2 Portions of these data were presented at the 54th Annual Meeting of the American Society of Tropical Medicine and Hygiene, 2005, Washington DC, and the Keystone Malaria: Immunology, Pathogenesis and Vaccine Perspectives Meeting, June 2008, Alpbach, Austria.
3 Current address: Department of Microbiology, Carver College of Medicine, University of Iowa, IA 52240.
4 Address correspondence and reprint requests to Dr. Julie M. Moore, Department of Infectious Diseases, Center for Tropical and Emerging Global Diseases, Paul Coverdell Center Room 330, University of Georgia, 500 DW Brooks Drive, Athens, GA, 30602. E-mail address: julmoore{at}uga.edu
5 Abbreviations used in this paper: TF, tissue factor; ED, experiment day; IHC, immunohistochemistry; INP, infected nonpregnant; IP, infected pregnant; iRBC, infected red blood cell; UP, uninfected pregnant.
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