HDP—A Novel Heme Detoxification Protein from the Malaria Parasite

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Abstract
When malaria parasites infect host red blood cells (RBC) and proteolyze hemoglobin, a unique, albeit poorly understood parasite-specific mechanism, detoxifies released heme into hemozoin (Hz). Here, we report the identification and characterization of a novel Plasmodium Heme Detoxification Protein (HDP) that is extremely potent in converting heme into Hz. HDP is functionally conserved across Plasmodium genus and its gene locus could not be disrupted. Once expressed, the parasite utilizes a circuitous “Outbound–Inbound” trafficking route by initially secreting HDP into the cytosol of infected RBC. A subsequent endocytosis of host cytosol (and hemoglobin) delivers HDP to the food vacuole (FV), the site of Hz formation. As Hz formation is critical for survival, involvement of HDP in this process suggests that it could be a malaria drug target. Each year, more than one million people, most of them children under the age of 5, succumb to malaria, a devastating disease caused by Plasmodium parasites. The parasite resides inside the red blood cells of the host, where, during its development, it proteolyzes vast amounts of host hemoglobin. This degradation also releases heme, which is extremely toxic to the parasite. To protect itself (from the toxic effects of heme), the parasite converts free heme into hemozoin. This parasite-specific mechanism is widely accepted as the weakest link in its lifecycle and is targeted by several of the currently available antimalarial drugs, which prevent hemozoin formation by binding to heme. However, due to an incomplete understanding of the parasite processes that lead to hemozoin formation, a drug that specifically targets the parasite factors responsible for hemozoin production has never been developed. Here we identify and characterize Heme Detoxification Protein, a unique Plasmodium protein, which we show as the potent producer of hemozoin. We demonstrate that this protein is highly conserved across the Plasmodium genus, is extremely efficient in producing hemozoin, and is delivered to the food vacuole, the site of hemozoin formation, via a unique trafficking route. We also demonstrate the critical nature of this protein and suggest that it could be targeted to develop novel antimalarial drugs.

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