title: Granzyme-mediated regulation of host defense in the liver in experimental Leishmania donovani infection.
abstract: In the livers of susceptible C57BL/6 (B6) mice infected with Leishmania donovani, CD8(+) T cell mechanisms are required for granuloma assembly, macrophage activation, intracellular parasite killing, and self-cure. Since gene expression of perforin and granzymes A and B (GzmA and GzmB), cytolytic proteins linked to CD8(+) cell effector function, was enhanced in infected liver tissue, B6 mice deficient in these granular proteins were used to gauge host defense roles. Neither perforin nor GzmA was required; however, mice deficient in GzmB (GzmB(-/-), GzmB cluster(-/-), and GzmA×B cluster double knockout [DKO] mice) showed both delayed granuloma assembly and initially impaired control of parasite replication. Since these two defects in B6 mice were limited to early-stage infection, innately resistant 129/Sv mice were also tested. In this genetic setting, expression of both innate and subsequent T (Th1) cell-dependent acquired resistance, including the self-cure phenotype, was entirely derailed in GzmA×B cluster DKO mice. These results, in susceptible B6 mice for GzmB and in resistant 129/Sv mice for GzmA and/or the GzmB cluster, point to granzyme-mediated host defense regulation in the liver in experimental visceral leishmaniasis.
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York, USA hwmurray@med.cornell.edu.
authors.forename: Henry W
authors.initials: HW
authors.lastname: Murray
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Marisa
authors.initials: M
authors.lastname: Mitchell-Flack
authors.affiliation: Shanghai Jiaotong University School of Life Science and Biotechnology, Shanghai, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA Shanghai Jiaotong University School of Life Science and Biotechnology, Shanghai, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Ma
mesh_terms: D000818:Animals; D006099:Granuloma / Q000378:metabolism; D053804:Granzymes / Q000235:genetics / Q000502:physiology*; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis; D020382:Interleukin-18 / Q000096:biosynthesis; D007893:Leishmania donovani / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000469:parasitology; D008099:Liver / Q000276:immunology* / Q000469:parasitology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin / Q000096:biosynthesis / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology
chemical_list: C556062:IL10 protein, mouse; D020382:Interleukin-18; D054353:Perforin; D016753:Interleukin-10; D007371:Interferon-gamma; D053804:Granzymes; C509214:Gzmb protein, mouse; C000597315:granzyme A, mouse