IAI Accepts, published online ahead of print on 18 August 2008

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Infect. Immun. doi:10.1128/IAI.00673-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

CO-INFECTION WITH THE INTESTINAL NEMATODE HELIGMOSOMOIDES POLYGYRUS MARKEDLY REDUCES HEPATIC EGG-INDUCED: IMMUNOPATHOLOGY AND PROINFLAMMATORY CYTOKINES IN MOUSE MODELS OF SEVERE SCHISTOSOMIASIS

Lindsey E. Bazzone, Patrick M. Smith, Laura I. Rutitzky, Mara G. Shainheit, Joseph F. Urban, Tommy Setiawan, Arthur M. Blum, Joel V. Weinstock, and Miguel J. Stadecker^*

Department of Pathology, Tufts University School of Medicine, Boston, MA; Division of Gastroenterology, Tufts Medical Center, Boston, MA; and Diet, Genomic and Immunology Laboratory, Beltsville Human Nutrition Research Center, Beltsville, MD

^* To whom correspondence should be addressed. Email: Miguel.stadecker{at}tufts.edu.

Infection with the trematode helminth Schistosoma mansoni results in a parasite egg-induced, CD4 T cell-mediated, hepato-intestinal granulomatous and fibrosing inflammation that varies greatly in severity, with a higher frequency of milder forms typically occurring in endemic regions. One possible explanation is that in these regions the degree of inflammation is lessened by widespread concurrent infection with gastro-intestinal nematodes. We tested this hypothesis by establishing a murine co-infection model in which mice were given the intestinal nematode parasite Heligmosomoides polygyrus prior to infection with S. mansoni. In CBA mice that naturally display a severe form of schistosomiasis, pre-infection with H. polygyrus caused a marked reduction in schistosome egg-induced hepatic immunopathology, which was associated with a significant decrease in IL-17, IFN-, TNF-, IL-23, IL-6 and IL-1, together with an increase in IL-4, IL-5, IL-10 and TGF-, in mesenteric lymph node cells, purified CD4 T cells, and isolated liver granuloma cells. There also was an increase in liver Ym1 and Foxp3 expression. In another model of high-pathology schistosomiasis induced in BL/6 mice by immunization with schistosome egg Ag in CFA, co-infection with the nematodes also caused a marked inhibition of hepatic immunopathology accompanied by similar shifts in cytokine production. These findings demonstrate that intestinal nematodes prevent Th1 and Th17 cell-mediated inflammation by promoting a strong Th2-polarized environment associated with an increase in alternatively activated macrophages and T regulatory cells, which results in significant amelioration of schistosome-induced immunopathology.

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