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Granzyme-mediated regulation of host defense in the liver in experimental Leishmania donovani infection.

TitleGranzyme-mediated regulation of host defense in the liver in experimental Leishmania donovani infection.
Publication TypeJournal Article
Year of Publication2015
AuthorsMurray HW, Mitchell-Flack M, Zheng H, Ma X
JournalInfect Immun
Volume83
Issue2
Pagination702-12
Date Published2015 Feb
ISSN1098-5522
KeywordsAnimals, Granuloma, Granzymes, Immunity, Innate, Inflammation, Interferon-gamma, Interleukin-10, Interleukin-18, Leishmania donovani, Leishmaniasis, Visceral, Liver, Macrophage Activation, Macrophages, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Perforin, T-Lymphocytes, Cytotoxic, Th1 Cells
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.

DOI10.1128/IAI.02418-14
Alternate JournalInfect Immun
PubMed ID25452549
PubMed Central IDPMC4294235
Grant ListR01 AI083219 / AI / NIAID NIH HHS / United States
5R01AI083219 / AI / NIAID NIH HHS / United States

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