Contrasting CTL responses in protective and non-protective models of malaria (45.3)

Protracted sterile protection conferred by a P. yoelii genetically attenuated parasite (PyGAP) vaccine was found to be completely dependent on CD8+ T lymphocytes. Immunization studies with perforin and IFN-γ knock out mice indicated that the protection was largely dependent on perforin as compared to IFN-γ. Both liver and spleen CD8+ T cells from PyGAP immunized mice induced massive apoptosis of liver stage (LS)-infected hepatocytes in vitro without the release of detectable IFN-γ and TNF-a, which directly correlated with GAP vaccine efficacy in vivo. Most importantly, we demonstrated that CD8+ T cells isolated from naïve mice that had survived wild-type P. yoelii sporozoite infection targeted mainly sporozoite-traversed and uninfected hepatocytes, revealing an immune evasion strategy that might have been used by wild-type parasites to subvert host immune responses. Differential processing of the parasite antigens in liver of immunized or naturally infected mice may be responsible for contrasting outcomes of their CTL responses. A controversial role of circumsporozoite protein (CSP) in host immune protection versus immune evasion against malaria is also highlighted by our findings. This research was supported by SBRI innovation grant.