HDP—A Novel Heme Detoxification Protein from the Malaria Parasite

Kami Kim,Dewal Jani,Carla Slebodnick,Rana Nagarkatti,Sanjai Kumar,John Andersen,Dharmendar Rathore,Wandy Beatty,Ross Angel

doi:10.1371/journal.ppat.1000053

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.

Highlights

Malaria is the most lethal parasitic disease and a dominant public health issue in more than 100 nations
In P. falciparum parasites, we found that the Heme Detoxification Protein (HDP) gene was actively transcribed during the intraerythrocytic stages of the lifecycle (Fig. S1A)
The native protein was purified by immunoprecipitation from the infected red blood cells (RBC) extracts (Fig. S7B) and though being a dimer, was found to be active, producing Hz at levels comparable to the recombinant protein (Fig. 1C), suggesting that in-vivo, HDP could be involved in Hz production

Summary

Introduction

Malaria is the most lethal parasitic disease and a dominant public health issue in more than 100 nations. While malaria infection begins with the invasion of hepatocytes by the Plasmodium sporozoites inoculated by an infected mosquito, the common clinical symptoms of malaria, which includes high fever, chills and anemia, are due to the subsequent infection and rapid multiplication of the parasite inside the RBC. To sustain its rapid pace of development, the parasite digests host hemoglobin, which represents 90% of the total protein present inside an RBC [1]; approximately 75% of which is degraded during the erythrocytic stages of development [2]. Along with a continuous degradation of hemoglobin, a concomitant detoxification of heme is necessary for an uninterrupted growth and proliferation of the parasite. Heme detoxification is one of the homeostasis processes, performed by a combination of proteins like hemopexin and heme oxygenase [5], whose homologs have not been found in the parasite genome

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Results

Conclusion