Book excerpt: The pathogenesis of Plasmodium falciparum is associated with inability of the host to adequately clear parasitized-erythrocytes and excessive pro-inflammatory cytokine response to infection. The combination of these events can culminate in the development of severe and cerebral malaria (CM). We also investigated mechanism of host induced excessive inflammatory response to malaria infection and demonstrated that PfGPI exposure leads to JNK2 activation resulting in TNF-alpha production in vitro. In vivo, JNK2-/- mice infected with P. berghei ANKA had lower circulating TNF-alpha levels and higher survival compared to JNK1-/- or JNK2 +/+ infected mice. We investigated the mechanisms by which adverse innate immune responses contribute to pathogenesis of severe malaria. CD36 has been shown to mediate the sequestration of PEs to vascular endothelium. Using macrophages isolated from CD36+/+ and CD36 -/- mice, we show that CD36 plays an important role in the uptake of ring- and schizont-stage PEs. In vivo, CD36 -/- mice infected with P. chabaudi chabaudi AS had an early impaired inflammatory response, early peak parasitemia and higher parasite burden which resulted in higher mortality than CD36 +/+ mice. We then investigated whether modulating host immune responses improve outcome in an experimental CM model. We showed that rosiglitazone treated mice infected with P. berghei had significantly lower circulating TNF-alpha and higher TGF-beta production with increased survival rate compared to control mice, thus suggesting that modulating host immune responses leads to a better outcome in mice infected with lethal P. berghei malaria. In summary, we show that CD36 is an important receptor involved in activation of early immune response essential for control and clearance of malaria infection. In addition, a dysregulated innate immune response leads to the development of severe and CM, and modulation of host innate immune response is crucial in the effective resolution of experimental CM. Finally, we investigated the role of complement in the development of CM. Using C5+/+, C5 -/- and congenic mice, we found C5 and its active product C5a contributes to development of CM. C5-/- mice were protected from the development of CM and survived longer than C5 +/+ mice. Neutralization of C5a activity using monoclonal antibody protected susceptible mice resulted in increased survival.