A novel and divergent role of granzyme A and B in resistance to helminth infection. Mus musculus

Granzyme (gzm) A and B, proteases of NK cells and T killer cells, mediate cell death, but also cleave extracellular matrices, inactivate intracellular pathogens and induce cytokines. Moreover, macrophages, T helper 2 cells, regulatory T cells, mast cells and B cells can express gzms. We recently reported gzm induction in human filarial infection. Here we show that in rodent filarial infection with Litomosoides sigmodontis worm loads were significantly reduced in gzmAxB and gzmB knock out (ko) mice, but enhanced in gzmA ko compared to wildtype (wt) mice. GzmA/B deficiency was associated with a defense-promoting Th2 cytokine and antibody shift and enhanced early inflammation gene expression, whereas gzmA deficiency was linked with alternatively activated macrophages and reduced inflammation. This suggests a novel and divergent role for gzms in helminth infection with gzmA contributing to resistance and gzmB promoting susceptibility. Keywords: knock out vs wild type Overall design: Two different knock out mice groups (Granzyme AxB KO and Granzyme A KO) and one wild type group were compared. PLECs were isolated from 6 mice/group (gzmAxB ko, gzmA ko, wt mice) and two mice were pooled/group, yielding 9 samples.