Intracellular Protozoan Parasites of Humans: The Role of Molecular Chaperones in Development and Pathogenesis

Addmore      Shonhai; Alexander      G. Maier; Jude      M. Przyborski; Gregory      L. Blatch

Abstract

Certain kinetoplastid (Leishmania spp. and Trypanosoma cruzi) and apicomplexan parasites (Plasmodium falciparum and Toxoplasma gondii) are capable of invading human cells as part of their pathology. These parasites appear to have evolved a relatively expanded or diverse complement of genes encoding molecular chaperones. The gene families encoding heat shock protein 90 (Hsp90) and heat shock protein 70 (Hsp70) chaperones show significant expansion and diversity (especially for Leishmania spp. and T. cruzi), and in particular the Hsp40 family appears to be an extreme example of phylogenetic radiation. In general, Hsp40 proteins act as co-chaperones of Hsp70 chaperones, forming protein folding pathways that integrate with Hsp90 to ensure proteostasis in the cell. It is tempting to speculate that the diverse environmental insults that these parasites endure have resulted in the evolutionary selection of a diverse and expanded chaperone network. Hsp90 is involved in development and growth of all of these intracellular parasites, and so far represents the strongest candidate as a target for chemotherapeutic interventions. While there have been some excellent studies on the molecular and cell biology of Hsp70 proteins, relatively little is known about the biological function of Hsp70-Hsp40 interactions in these intracellular parasites. This review focuses on intracellular protozoan parasites of humans, and provides a critique of the role of heat shock proteins in development and pathogenesis, especially the molecular chaperones Hsp90, Hsp70 and Hsp40.

Keywords: Heat shock proteins, Hsp40, Hsp70, Hsp90, Leishmania, molecular chaperone, Plasmodium falciparum, Trypanosoma cruzi, Toxoplasma gondii, desiccation, pH, oxidative stress, antigenic variation, virulence, ER, Grp94, TRAP1, homeostasis, HPD, kinetoplastids, apicomplexa, T. cruzi, HIV, L. major, temperature, geldanamycin, amplification, LPG, SGT, L. tarentolae, secretory proteins, 46kDa, PDI, mRNA, RNAi, VSG, DNA, Merozoites, Saccharomyces cerevisiae, PV, Falcipain-2Heat shock proteins, Hsp40, Hsp70, Hsp90, Leishmania, molecular chaperone, Plasmodium falciparum, Trypanosoma cruzi, Toxoplasma gondii, desiccation, pH, oxidative stress, antigenic variation, virulence, ER, Grp94, TRAP1, homeostasis, HPD, kinetoplastids, apicomplexa, T. cruzi, HIV, L. major, temperature, geldanamycin, amplification, LPG, SGT, L. tarentolae, secretory proteins, 46kDa, PDI, mRNA, RNAi, VSG, DNA, Merozoites, Saccharomyces cerevisiae, PV, Falcipain-2