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Gastrointestinal Nematode Infection Exacerbates Malaria-Induced Liver Pathology¹

Immunology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom

Mixed parasite infections are common in many parts of the world, but little is known of the effects of concomitant parasite infections on the immune response or severity of clinical disease. We have used the nonlethal malaria infection model of Plasmodium chabaudi AS in combination with the gastrointestinal nematode Heligmosomoides bakeri polygyrus to investigate the impact of nematode infections on malarial morbidity and antimalarial immunity. The data demonstrate that wild-type C57BL/6 mice coinfected with both parasites simultaneously exhibit a striking increase in mortality, while mice deficient in IFN- or IL-23 survive coinfection. The increase in mortality in wild-type mice was associated with severe liver pathology characterized by extensive coagulative necrosis and an increase in hepatic IFN-, IL-17, and IL-22 mRNA expression. This is the first demonstration of increased malaria-associated pathology associated with a switch toward a proinflammatory environment, involving not only IFN- but also the IL-17/IL-23 axis, as a result of coinfection with a gastrointestinal helminth.

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 study was funded by the Wellcome Trust (Grant GR067320).

² Address correspondence and reprint requests to Dr. Helena Helmby, Immunology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, U.K. E-mail address: helena.helmby{at}lshtm.ac.uk

³ Abbreviations used in this paper: LT, lymphotoxin; WT, wild type; p.i., postinfection; AST, aspartate aminotransferase; LBP, LPS-binding protein; P.c., P. chabaudi; H.p., H. polygyrus; KO, knockout.