Cenix BioScience, Alnylam Pharmaceuticals, and the Instituto de Medicina Molecular (IMM) report finding a molecular connection between cholesterol metabolism and malaria infection. The team discovered and validated in vivo the scavenger receptor BI (SR-BI), a major regulator of cholesterol uptake by the liver, as a host factor for malaria infection.
The investigators were evaluating a decade-old hypothesis that lipoprotein clearance pathways in the human host may somehow impact the infection of liver cells by malaria-causing Plasmodium parasites. SR-BI is well-known as the major liver receptor for HDL, where it plays a role in the transfer of cholesterol from the bloodstream to hepatocytes.
They used a systematic RNAi screen of known lipoprotein pathway components in a cultured human cell-based infection assay.
The research group reports also confirming their findings in animal models of malaria infection using siRNAs specific for SR-BI silencing. Additionally, the pathophysiological relevance of SR-BI's requirement for malaria infection was confirmed by a series of experiments using synthetic small molecule inhibitor compounds, blocking mAbs, SR-BI overexpression with transgenic mice, and SR-BI loss of function with knock-out mice, the team adds.
SR-BI is a major liver receptor for HDL, where it plays a key role in the transfer of cholesterol from the bloodstream to hepatocytes.
“The various SR-BI-inhibitor molecules demonstrated in this study as having anti-malarial activity, including siRNAs, small synthetic molecules, and antibodies, all represent interesting candidates for the development of novel prophylactic options,” notes Christophe Echeverri, Ph.D., CEO/CSO of Cenix. “Importantly, their equally novel host factor-based mechanism of action promises an inherently more powerful interventional strategy against the emergence of resistant strains of malarial parasites, as compared to existing parasite-targeted therapies.”
The results appears in the September issue of Cell Host & Microbe.