title: Gamma Interferon-Regulated Chemokines in Leishmania donovani Infection in the Liver.
abstract: In the livers of C57BL/6 mice, gamma interferon (IFN-γ) 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-γ-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-/-mice were used as CXCL16-deficient surrogates) indicated that individual IFN-γ-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-/-mice) and Sb was fully active (in CXCL10-/-, CCL2-/-, and CCL5-/-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.
authors: Department of Medicine, Weill Cornell Medical College, New York, New York, USA hwmurray@med.cornell.edu.
authors: Henry W
authors: HW
authors: Murray
authors: Center for Immunology and Inflammatory Diseases, Division of Rheumatology & Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Andrew D
authors: AD
authors: Luster
authors: Shanghai Jiaotong University School of Life Science and Biotechnology, Shanghai, China.
authors: Hua
authors: H
authors: Zheng
authors: Shanghai Jiaotong University School of Life Science and Biotechnology, Shanghai, China.|Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA.
authors: Xiaojing
authors: X
authors: Ma
mesh_terms: D000818:Animals; D018925:Chemokines / Q000276:immunology*; D005260:Female; D006099:Granuloma / Q000276:immunology / Q000469:parasitology; D007371:Interferon-gamma / Q000276:immunology*; D007893:Leishmania donovani / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000276:immunology*; D008099:Liver / Q000469:parasitology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018925:Chemokines; D007371:Interferon-gamma
keywords: Leishmania donovani; chemokines; granuloma; pentavalent antimony; visceral leishmaniasis