Deciphering the IFN-γ-mediated immunopathology during Plasmodium yoelii N67C infection

Abstract

Abstract Immune response plays an important role in controlling malaria infection; however, excessive inflammatory response can lead to severe disease. Here we investigate the mechanism of pathogenesis in mice after infection with a virulent rodent malaria parasite, Plasmodium yoelii nigeriensis strain N67C. Previous studies showed that C57BL/6-infected mice display high parasitemia, strong pro-inflammatory response, culminating in extensive splenic damage and host lethality at around 7 days post-infection. The present work aims to characterize the cellular and molecular events associated with host immune-mediated pathology in response to N67C parasite. Mice were infected with 106 infected red blood cells by intraperitoneal injection. C57BL/6-infected mice develop progressive inflammation in the spleen, characterized by intense cellular death and up-regulation of pro-inflammatory cytokines (notably IFNγ, IL-6, CCL2 and CXCL1). Interestingly, we identified splenic CD4+ and CD8+ T cells as major sources of IFN-γ as early as day 4 post-infection. Additionally, we demonstrated that IFN-γ was a major mediator of splenic pathology because its absence or blockade prolonged host survival and prevented excessive host inflammatory response. Moreover, by employing chimeric mice, we showed that the absence of IFN-γ receptor in the non-hematopoietic compartment protected mice from early death. Elucidation of this IFN-γ signaling mechanism may enable further development of interventions to decrease human morbidity and mortality associated with severe malaria.