ABSTRACT
A key feature of malaria infection is the production of high levels of T N F-α and other pro-inflammatory mediators that are thought to contribute to the systemic and organ-related malaria syndromes. In infection with Plasmodium falciparum , the parasite that causes fatal forms of malaria, the adherence and sequestration of infected erythrocytes in the microvascular beds of vital organs create pathogenic microenvironments and exacerbate the role of pro-inflammatory responses. Available information indicates that the glycosylphosphatidylinositols (GPIs) of P. falciparum are the specific and dominant parasite-associated molecular patterns recognized by the host innate immune system. The parasite GPIs appear to be mainly responsible for the ability of the parasite to induce potent pro-inflammatory re sponses in monocytes and macrophages, thereby playing an important role in malaria patho genesis. The GPI-induced cellular activation is mediated mainly through the recognition of TLR2, involving MyD88-dependent signaling transduction and downstream initiation of ERK, p38 and JN K MAPK and N F-κΒ signaling pathways. The MAPK pathways and N F-κΒ fam ily members differentially regulate the GPI-induced production of various pro-inflammatory cytokines and nitric oxide by macrophages. A comprehensive understanding of how the vari ous signaling cascades of the cells of the host innate immune system induced by the malaria parasite factors regulate a wide range of cellular responses has important implications for the development of immunotherapeutics for severe malaria.
