Investigating the molecular mechanism of Glycosylphosphatidylinositol-dependent signalling and its implication in the development of severe malaria pathology

• Applicant: Privatdozent Faustin Kamena, Ph.D.
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 242246532

The glcosylsphosphatidylinositol anchor (GPI) is the most important glycoconjugate in Plasmodium falciparum and serves as membrane anchor for several essential proteins at every stage of the life cycle of the parasite. In addition, GPI was found to be one the main toxins involved in the development of severe malaria pathology. Stimulation of macrophages in vitro with plasmodial GPIs leads to an overwhelming secretion of pro-inflammatory cytokines presumably through Toll-like receptors 2 and 4 (TLR2/4). However, the molecular mechanism how plasmodial GPIs affect the development of malaria pathology remains largely unsolved. Although numerous evidences for the involvement of TLR2/4 in the development of severe malaria pathology have been generated, the levels of pro-inflammatory cytokines appear to be dispensable for the development of experimental cerebral malaria (ECM) in a mouse model. In addition, stimulation of host cells with GPIs from different parasites, although they signal through the same receptors, can lead to different cellular responses. It is possible therefore that plasmodial GPI might stimulate additional processes other than pro-inflammatory reaction that are relevant for the development of malaria pathology. Importantly, as observed in our preliminary work, the repertoire of GPI interacting proteins might still be incomplete. The goal of the proposed project is to investigate additional aspects of plasmodial GPI interaction with the host. More specifically the transfer of plasmodial GPI to the membrane of host cell, especially of the erythrocytes, and its consequences for the development of malaria pathology will be extensively investigated. The project also aims at systematically identifying and characterising novel GPI-binding proteins on host cells. The proposed project addresses a fundamental aspect on the development of malaria pathology and should provide a solid basis for understanding the molecular mechanism of interaction between Plasmodium falciparum and its host.

• DFG Programme: Research Grants