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

TitleGamma Interferon-Regulated Chemokines in Leishmania donovani Infection in the Liver.
Publication TypeJournal Article
Year of Publication2017
AuthorsMurray HW, Luster AD, Zheng H, Ma X
JournalInfect Immun
Volume85
Issue1
Date Published2017 Jan
ISSN1098-5522
KeywordsAnimals, Chemokines, Female, Granuloma, Interferon-gamma, Leishmania donovani, Leishmaniasis, Visceral, Liver, Mice, Mice, Inbred C57BL, T-Lymphocytes
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.

DOI10.1128/IAI.00824-16
Alternate JournalInfect Immun
PubMed ID27795366
PubMed Central IDPMC5203646
Grant ListR01 AI083219 / AI / NIAID NIH HHS / United States
R01 CA069212 / CA / NCI NIH HHS / United States

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