The transcription factor T-bet regulates parasitemia and promotes pathogenesis during Plasmodium berghei ANKA murine malaria (43.16)

Abstract

Abstract CD4+ T cells are required for the pathogenesis of experimental cerebral malaria (ECM) during the induction phase of disease in mice. Using the Plasmodium berghei ANKA murine model of ECM and mice deficient for the transcription factor T-bet (the master regulator of Th1 cells) on the C57BL/6 background, we demonstrate that while Th1 CD4+ T cells play a role in the regulation of parasite burden, they also promote the pathogenesis of ECM possibly by invoking a robust proinflammatory response. We find that while 100% (10/10) of wildtype mice developed ECM by day 9 post-infection, only 30% (3/10) of T-bet deficient mice succumbed to disease during the cerebral phase of infection (p=0.000058). In addition, T-bet deficient mice had higher parasitemia than wildtype controls during the ECM phase of disease (17.7 +/- 3.1% verses 10.9 +/- 1.5%). These results indicate that T-bet dependent regulation of parasite burden may promote pathogenesis in this murine model of ECM. We are also investigating the effect of T-bet on protective immunity in the P. yoelii NL murine model and the P. chabaudi AS model during the acute and clearance phases and in recrudescence. In depth analysis of immune cells and cytokines is currently being performed to better understand how Th1 CD4+ T cells mediate their protective as well as pathogenic functions during malaria infection.