Abstract

Plasmodium parasites must control cysteine protease activity that is critical for hepatocyte invasion by sporozoites, liver stage development, host cell survival and merozoite liberation. Here we show that exoerythrocytic P. berghei parasites express a potent cysteine protease inhibitor (PbICP, P. berghei inhibitor of cysteine proteases). We provide evidence that it has an important function in sporozoite invasion and is capable of blocking hepatocyte cell death. Pre-incubation with specific anti-PbICP antiserum significantly decreased the ability of sporozoites to infect hepatocytes and expression of PbICP in mammalian cells protects them against peroxide- and camptothecin-induced cell death. PbICP is secreted by sporozoites prior to and after hepatocyte invasion, localizes to the parasitophorous vacuole as well as to the parasite cytoplasm in the schizont stage and is released into the host cell cytoplasm at the end of the liver stage. Like its homolog falstatin/PfICP in P. falciparum, PbICP consists of a classical N-terminal signal peptide, a long N-terminal extension region and a chagasin-like C-terminal domain. In exoerythrocytic parasites, PbICP is posttranslationally processed, leading to liberation of the C-terminal chagasin-like domain. Biochemical analysis has revealed that both full-length PbICP and the truncated C-terminal domain are very potent inhibitors of cathepsin L-like host and parasite cysteine proteases. The results presented in this study suggest that the inhibitor plays an important role in sporozoite invasion of host cells and in parasite survival during liver stage development by inhibiting host cell proteases involved in programmed cell death.

Highlights

  • Malaria is caused by apicomplexan parasites of the genus Plasmodium

  • Parasite and host cell cysteine proteases play an important role during the entire life cycle of the Plasmodium parasite

  • Cysteine protease activity is essential for sporozoite egress from oocysts in the mosquito [19], sporozoite invasion of hepatocytes in the vertebrate host [20,21], liver stage development and liberation of exo-erythrocytic merozoites from hepatocytes [16] as well as for invasion, nutrition and egress in the blood stage [18]

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Summary

Introduction

Malaria is caused by apicomplexan parasites of the genus Plasmodium. The infection of the vertebrate host begins with the inoculation of sporozoites into the dermis during blood feeding of an infected Anopheles mosquito [1,2,3,4,5,6,7]. At the end of the liver stage, the parasite induces an unusual form of programmed cell death that facilitates the merozoites leaving the liver and gaining access to the bloodstream [16,17]. Even during this complex liberation process, which includes parasite-dependent host cell death, classical host cell apoptosis is not induced and cell membrane integrity is maintained [16], suggesting that parasite molecules responsible for inhibition of apoptosis are translocated to the host cell cytoplasm, at least during this last phase of parasite development in hepatocytes

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