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by Leishmania chagasi: Importance for Parasite Survival in Macrophages 1
,,
* Interdisciplinary Immunology PhD Program, Departments of
Internal Medicine and
Microbiology, University of Iowa, Iowa City, IA 52242;
Veterans Affairs Medical Center, Iowa City, IA 52240;
¶ Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706; and
|| Departamento de Bioquimica, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
TGF-
is a potent regulatory cytokine that suppresses expression of inducible NO synthase and IFN-
, and suppresses Th1 and Th2 cell development. We examined whether functionally active TGF- is present in the local environment surrounding the invading protozoan Leishmania chagasi. Our prior data showed that TGF- levels are significantly increased in L. chagasi-infected mice. In the current study, we found TGF- was also abundant in bone marrows of humans with acute visceral leishmaniasis but not in those of uninfected controls. Furthermore, L. chagasi infection caused an increase in biologically active TGF- in human macrophage cultures without changing the total TGF-. Therefore, we investigated the means through which leishmania could augment activated but not total TGF-. Incubation of latent TGF- with Leishmania sp. promastigotes caused active TGF- to be released from the latent complex. In contrast, the nonpathogenic protozoan Crithidia fasciculata could not activate TGF-. TGF- activation by leishmania was prevented by inhibitors of cysteine proteases and by the specific cathepsin B inhibitor CA074. Physiologic concentrations of TGF- inhibited killing of intracellular L. chagasi in macrophages, although the phagocytosis-induced respiratory burst remained intact. In contrast, supraphysiologic concentrations of TGF- had no effect on parasite survival. We hypothesize that the combined effect of abundant TGF- stores at extracellular sites during infection, and the ability of the parasite to activate TGF- in its local environment, leads to high levels of active TGF- in the vicinity of the infected macrophage. Locally activated TGF- could, in turn, enhance parasite survival through its effects on innate and adaptive immune responses.
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