Concerted action of perforin and granzymes is critical for the elimination of Trypanosoma cruzi from mouse tissues, but prevention of early host death is in addition dependent on the FasL/Fas pathway

Abstract

CTL and NK cells are critical for resistance to acute Trypanosoma cruzi infection, but are also implicated in the pathology induced by this intracellular protozoan parasite. Here we explore to what extent the two main cytolytic pathways of CTL and NK cells, i.e. the granule exocytosis and the Fas ligand (FasL)/Fas pathways, are responsible for the elimination of parasites from mouse tissues and control of organ pathology. For this purpose we have employed mouse strains with targeted gene defects in one or more components - including perforin, granzyme A and granzyme B, and Fas - of either of the two cytolytic pathways, and we used the highly pathogenic T. cruzi strain Tulahuen. We show that parasites are effectively cleared from infected tissues independently of the FasL/Fas pathway by the concerted action of perforin and the two granzymes. However, prevention of pathology and early host death is critically dependent in addition on an operational FasL/Fas interaction. Thus, in contrast to C57B/6 (B6) wild-type mice, mouse strains with deficiencies in either the FasL/Fas or the perforin/granzyme pathway similarly suffer from early death, independently of their differential capacity to control parasite growth; this finding indicates that the two cytolytic pathways control distinct but vital processes during infection with T. cruzi.