New Pathway For Malaria Infection Discovered

The new research findings are the first to describe a molecular link between cholesterol metabolism and malaria infection, and the new data could lead to new approaches for the treatment of malaria including use of RNAi therapeutics.

“Malaria represents a major global health concern accounting for approximately two million deaths per year. Nevertheless, the molecular mechanisms for the parasite’s pathophysiology have remained poorly understood,” said Maria Mota, Ph.D., Director of the Malaria research Unit at the IMM. “Our current studies advance the potential for new therapies as we have discovered an important molecular link between the earliest stages of infection and a critical host gene.”

The published report by Rodrigues, Hannus and Prudêncio et al. (Cell Host & Microbe 4, 271-282; 2008) describes the results of studies to investigate 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. In the study, the liver-expressed gene, SR-BI, was identified as a critical host factor for the liver infection stage of malaria using a systematic RNAi screen of known lipoprotein pathway components in a cultured human cell-based infection assay.

These finding were then confirmed in animal models of malaria infection using small interfering RNAs (siRNAs), the molecules that mediate RNAi, specific for SR-BI silencing. SR-BI is well-known as the major liver receptor for high density lipoproteins (HDL), where it plays a key role in the transfer of cholesterol from the bloodstream to hepatocytes. In addition to studies using RNAi-mediated gene silencing, the pathophysiological relevance of SR-BI’s requirement for malaria infection was confirmed by a comprehensive series of experiments using synthetic small molecule inhibitor compounds, blocking monoclonal antibodies, SR-BI over-expression with transgenic mice, and SR-BI loss of function with knock-out mice. As such, this study establishes the first clear molecular link between malaria infection and cholesterol uptake pathways, thus describing a new therapeutic strategy in the fight against this devastating parasitic disease.

“All of these studies not only demonstrate the power of our RNAi-based discovery platform, but most importantly, they open brand new interventional routes for developing novel treatments for malaria and other major parasitic diseases now devastating some of the world’s most vulnerable populations,” said Dr. Christophe Echeverri, CEO/CSO of Cenix. “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. 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.”

“We’re very pleased to participate in the research efforts initiated at the IMM with Cenix,” said Victor Kotelianski, Senior Vice-President and Distinguished Alnylam Fellow. “We feel particularly gratified that our core technology for systemic therapeutic gene silencing with RNAi therapeutics has played an important role in advancing the characterization of novel targets to confront this killer disease, and we look forward to further supporting ongoing efforts to tackle malaria and other major threats to global health.”

The current work results from an ongoing malaria research program started by the IMM group and their longstanding collaboration with Cenix, announced in 2005 to apply high-throughput RNAi technologies for discovery of host factor genes involved in malaria infection. This work was extended to include Alnylam’s technologies for in vivo delivery of siRNAs. Together, the collaborators have established a major new platform to drive the systematic, genomics-driven discovery and validation of novel human host genes offering clear therapeutic or prophylactic potential for halting malaria infection at its earliest liver stage, before onset of the disease’s symptomatic blood stage.

Driven by Dr. Mota’s ongoing malaria research and the efforts at Cenix and Alnylam, the partners are also seeking opportunities to further scale-up the use of this platform to extend the present screen over the rest of the human genome, and to broaden the reach of these capabilities beyond malaria, tackling other parasitic diseases of major relevance to global health, including so-called neglected diseases of the developing world.