Executive Summary : | Exosomes or extracellular vesicles (EVs) are reported to be released from infected cells, and are potentially relevant to the infection process and to the host immune response during infection. Recent reports have been shown that exosomes are released from the host cells, in response to infection or stimulated by parasite, including Trypanosoma, Leishmania, Toxoplasma, and Trichomonas, and the released exosomes can in turn affect the host immune responses. Interestingly, when the host cells were pre-treated with Leishmania derived EVs followed by Leishmania parasites infection, resulted in the reduction of pro-inflammatory cytokines release such as IL-8, TNF, and IL-12 with an increased release of anti-inflammatory cytokine IL-10, compared to the untreated cells. These studies have advanced the understanding of the importance of host and parasite derived EVs in malaria pathogenesis and provided the supporting evidence for malaria exosomes as potential biomarkers and therapeutic tools. Initial studies focused on the EVs of host cell origin reported that the EVs are associated with malaria with their role in cerebral pathogenesis, as increased levels of endothelial-derived EVs were present in the serum of patients with severe cerebral malaria. Recently, a better understanding of the content of host derived exosomes during severe malaria was achieved based on proteomic analysis of EVs from mice with cerebral malaria. Similarly, the presence of endothelial cell EVs in P. falciparum infection likely reflects the involvement of the secreted exosomes in the development of cytoadherent-dependent severe disease symptoms. Most of the studies suggests a potential targeted effect of exosomes on host cell function, which could have important implications for the understanding of progression of the disease and have implicated the role of EVs in the development of drug resistance by the parasites. However, despite their unequivocal roles of exosomes in malaria progression, little progress has been made in targeting exosome biogenesis, release and/or uptake as novel treatment for malaria. Exploring the EVs generation and secretion mechanism and studying EVs inhibition in P. falciparum infected cultures may prove to be an effective therapeutical strategy to limit the development of the parasites and can combat drug resistance. In this proposed study, we are going to study extensively the EVs produced during P. falciparum infection, we are going to profile both the production and composition of the EVs produced during different stages of P. falciparum erythrocytic cycle in in vitro conditions. After analyzing the composition of exosomes released, we are going to use an array of exosome inhibitors to check their ability to inhibit the growth and development of the P. falciparum parasites. In addition, we will use infected RBC-derived EVs as a new platform to test new drugs against malaria, the first to the use exosome inhibitors as new therapeutic agents. |