Chaperone expression profiles correlate with distinct physiological states of Plasmodium falciparum in malaria patients

Abstract

BackgroundMolecular chaperones have been shown to be important in the growth of the malaria parasite Plasmodium falciparum and inhibition of chaperone function by pharmacological agents has been shown to abrogate parasite growth. A recent study has demonstrated that clinical isolates of the parasite have distinct physiological states, one of which resembles environmental stress response showing up-regulation of specific molecular chaperones.MethodsChaperone networks operational in the distinct physiological clusters in clinical malaria parasites were constructed using cytoscape by utilizing their clinical expression profiles.ResultsMolecular chaperones show distinct profiles in the previously defined physiologically distinct states. Further, expression profiles of the chaperones from different cellular compartments correlate with specific patient clusters. While cluster 1 parasites, representing a starvation response, show up-regulation of organellar chaperones, cluster 2 parasites, which resemble active growth based on glycolysis, show up-regulation of cytoplasmic chaperones. Interestingly, cytoplasmic Hsp90 and its co-chaperones, previously implicated as drug targets in malaria, cluster in the same group. Detailed analysis of chaperone expression in the patient cluster 2 reveals up-regulation of the entire Hsp90-dependent pro-survival circuitries. In addition, cluster 2 also shows up-regulation of Plasmodium export element (PEXEL)-containing Hsp40s thought to have regulatory and host remodeling roles in the infected erythrocyte.ConclusionIn all, this study demonstrates an intimate involvement of parasite-encoded chaperones, PfHsp90 in particular, in defining pathogenesis of malaria.

Hsp70s and J Proteins of Plasmodium Parasites Infecting Rodents and Primates: Structure, Function, Clinical Relevance, and Drug Targets

“…It has been shown to be significantly upregulated in P. falciparum isolates from malaria patients [20]. It has been shown to be significantly upregulated in P. falciparum isolates from malaria patients [20].…”

“…It has been shown to occur in a common complex with PfHsp70-1 suggesting a possible direct or indirect interaction [80]. In addition, Pfj4 was upregulated in parasites isolated from clinical samples [20]. While the role of this J protein is not well understood, it has been suggested to be involved in cytoprotection against thermal stress, protein translocation across membranes, DNA replication and repair, and translation initiation [80].…”

“…These stresses often lead to protein misfolding and aggregation and therefore affect cellular protein homeostasis. Hsps have received widespread research attention in various cellular systems and have been shown to be intimately involved in malaria pathogenesis [11,[18][19][20]. A major constituent of this chaperone complement are heat shock proteins (Hsps).…”

Estudo estrutural e funcional da co-chaperona SGT de <i>Leishmania braziliensis</i>

“…Os efeitos nocivos dessas condições são minimizados pela superexpressão de chaperonas moleculares. Além de atuarem na homeostase proteica, essas proteínas possibilitam a adaptação e diferenciação celular, desempenhando importantes papéis na sobrevivência, virulência e proliferação parasitárias (Pallavi et al, 2010;Shonhai et al, 2011). A inibição das Hsp90 em Leishmania donovani, por exemplo, causa interferências no crescimento celular e na diferenciação parasitária (Wiesgigl e Clos, 2001a;Pallavi et al, 2010).…”

“…Além de atuarem na homeostase proteica, essas proteínas possibilitam a adaptação e diferenciação celular, desempenhando importantes papéis na sobrevivência, virulência e proliferação parasitárias (Pallavi et al, 2010;Shonhai et al, 2011). A inibição das Hsp90 em Leishmania donovani, por exemplo, causa interferências no crescimento celular e na diferenciação parasitária (Wiesgigl e Clos, 2001a;Pallavi et al, 2010). Ainda em L. donovani, a SGT é essencial para o crescimento e viabilidade da forma promastigota do parasito, interagindo dentro da célula com outras co-chaperonas (HIP e HOP) e formando um grande complexo com as Hsp70 e Hsp90 (Ommen et al, 2010).…”