title: Apicomplexan parasite, Eimeria falciformis, co-opts host tryptophan catabolism for life cycle progression in mouse.
abstract: The obligate intracellular apicomplexan parasites, e.g. Toxoplasma gondii and Plasmodium species, induce an IFNγ-driven induction of host indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of tryptophan catabolism in the kynurenine pathway. Induction of IDO1 supposedly depletes cellular levels of tryptophan in host cells, which is proposed to inhibit the in vitro growth of auxotrophic pathogens. In vivo function of IDO during infections, however, is not clear, let alone controversial. We show that Eimeria falciformis, an apicomplexan parasite infecting the mouse caecum, induces IDO1 in the epithelial cells of the organ, and the enzyme expression coincides with the parasite development. The absence or inhibition of IDO1/2 and of two downstream enzymes in infected animals is detrimental to the Eimeria growth. The reduced parasite yield is not due to a lack of an immunosuppressive effect of IDO1 in the parasitized IDO1(-/-) or inhibitor-treated mice because they did not show an accentuated Th1 and IFNγ response. Noticeably, the parasite development is entirely rescued by xanthurenic acid, a by-product of tryptophan catabolism inducing exflagellation in male gametes of Plasmodium in the mosquito mid-gut. Our data demonstrate a conceptual subversion of the host defense (IFNγ, IDO) by an intracellular pathogen for progression of its natural life cycle. Besides, we show utility of E. falciformis, a monoxenous parasite of a well appreciated host, i.e. mouse, to identify in vivo factors underlying the parasite-host interactions.
authors.affiliation: Department of Molecular Parasitology, Humboldt University, 10115 Berlin, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Schmid
authors.forename: Maik J
authors.initials: MJ
authors.lastname: Lehmann
authors.forename: Richard
authors.initials: R
authors.lastname: Lucius
authors.forename: Nishith
authors.initials: N
authors.lastname: Gupta
mesh_terms: D000818:Animals; D003048:Coccidiosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009033:Culicidae / Q000469:parasitology; D004539:Eimeria / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*; D014364:Tryptophan / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014977:Xanthurenates / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014977:Xanthurenates; C028330:xanthurenic acid; D007371:Interferon-gamma; D014364:Tryptophan