Gamma Interferon-Regulated Chemokines in Leishmania donovani Infection in the Liver

Abstract

In the livers of C57BL/6 mice, gamma interferon (IFN-␥) controls intracellular Leishmania donovani infection and the efficacy of antimony (Sb) chemotherapy. Since both responses usually correlate with granulomatous inflammation, we tested six prominently expressed, IFN-␥-regulated chemokines-CXCL9, CXCL10, CXCL13, CXCL16, CCL2, and CCL5-for their roles in (i) mononuclear cell recruitment and granuloma assembly and maturation, (ii) initial control of infection and self-cure, and (iii) responsiveness to Sb treatment. Together, the results for the L. donovani-infected livers of chemokine-deficient mice (CXCR6 Ϫ/Ϫ mice were used as CXCL16-deficient surrogates) indicated that individual IFN-␥-induced chemokines have diverse affects and (i) may be entirely dispensable (CXCL13, CXCL16), (ii) may promote (CXCL10, CCL2, CCL5) or downregulate (CXCL9) initial granuloma assembly, (iii) may enhance (CCL2, CCL5) or hinder (CXCL10) early parasite control, (iv) may promote granuloma maturation (CCL2, CCL5), (v) may exert a granuloma-independent action that enables self-cure (CCL5), and (vi) may have no role in responsiveness to chemotherapy. Despite the near absence of tissue inflammation in early-stage infection, parasite replication could be controlled (in CXCL10 Ϫ/Ϫ mice) and Sb was fully active (in CXCL10 Ϫ/Ϫ , CCL2 Ϫ/Ϫ , and CCL5 Ϫ/Ϫ mice). These results characterize chemokine action in the response to L. donovani and also reemphasize that (i) recruited mononuclear cells and granulomas are not required to control infection or respond to Sb chemotherapy, (ii) granuloma assembly, control of infection, and Sb's efficacy are not invariably linked expressions of the same T cell-dependent, cytokine-mediated antileishmanial mechanism, and (iii) granulomas are not necessarily hallmarks of protective antileishmanial immunity.KEYWORDS chemokines, visceral leishmaniasis, Leishmania donovani, granuloma, pentavalent antimony I n visceral leishmaniasis, a disseminated protozoal infection, tissue macrophages in the liver, spleen, and bone marrow are targeted and support intracellular parasite replication. In the susceptible host, experimental Leishmania donovani infection in the liver does not come under control nor are parasites killed until either chemotherapy is given or T cell-dependent, multi-cytokine-driven mechanisms emerge and macrophage activation is induced. In the livers of infected wild-type (WT) C57BL/6 (B6) and BALB/c mice, this immunoinflammatory response is usually associated with mononuclear cell recruitment to and granuloma assembly at parasitized Kupffer cells (1-8). In the granulomatous environment, this T cell-and cytokine-mediated response also directs self-cure in initially susceptible B6 and BALB/c mice and, in addition, regulates the intracellular efficacy of conventional antileishmanial chemotherapy, pentavalent antimony (Sb) (2, 4, 6, 7, 9-11).

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