Granzyme-Mediated Regulation of Host Defense in the Liver in Experimental Leishmania donovani Infection |
| |
| Authors: | Henry W. Murray Marisa Mitchell-Flack Hua Zheng Xiaojing Ma |
| |
| Affiliation: | aDepartment of Medicine, Weill Cornell Medical College, New York, New York, USA;bDepartment of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA;cShanghai Jiaotong University School of Life Science and Biotechnology, Shanghai, China |
| |
| 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. |
| |
| Keywords: | |
|
|
