Plasmodium falciparum, the human pathogen responsible for the most dangerous malaria infection, survives and develops in mature erythrocytes through the export of proteins needed for remodelling of the host cell. Molecular chaperones of the heat shock protein (Hsp) family are prominent members of the exportome, including a number of Hsp40s and a Hsp70. PFA0660w, a type II Hsp40, has been shown to be exported and possibly form a complex with PfHsp70-x in the infected erythrocyte cytosol. However, the chaperone properties of PFA0660w and its interaction with human and parasite Hsp70s are yet to be investigated. Recombinant PFA0660w was found to exist as a monomer in solution, and was able to significantly stimulate the ATPase activity of PfHsp70-x but not that of a second plasmodial Hsp70 (PfHsp70-1) or a human Hsp70 (HSPA1A), indicating a potential specific functional partnership with PfHsp70-x. Protein binding studies in the presence and absence of ATP suggested that the interaction of PFA0660w with PfHsp70-x most likely represented a co-chaperone/chaperone interaction. Also, PFA0660w alone produced a concentration-dependent suppression of rhodanese aggregation, demonstrating its chaperone properties. Overall, we have provided the first biochemical evidence for the possible role of PFA0660w as a chaperone and as co-chaperone of PfHsp70-x. We propose that these chaperones boost the chaperone power of the infected erythrocyte, enabling successful protein trafficking and folding, and thereby making a fundamental contribution to the pathology of malaria.

Background and Aim The many pharmacological potentials of Stachytarpheta cayennensis (L.C. Rich) Vahl, especially in managing central nervous system disorders, hypertension, diabetes and infections, have made it a subject of abuse, necessitating the need to ascertain its safety. This study therefore investigated the toxic effects of the leaf extract of S. cayennensis in rats following acute and 28-day repeated doses in male and female rats. Experimental procedure Acute and repeated dose studies were conducted in male and female groups of rats (135–150 g), using OECD 423 and 407 Tests guidelines respectively. Functional observational battery, and body weights were monitored. Blood samples were analysed for haematological and plasma biochemical indices. Organs (brain, kidneys and liver) specimen were collected and weighed. Kidney and liver specimen were subjected to histopathological analysis. Results and conclusion The LD 50 of the extract was greater than 5000 mg/kg, p.o. (24 h) suggesting that the extract may be non-toxic. However, following single and repeated doses, the results revealed varying degree of significant (p < 0.05) changes in biochemical and heamatological indices, as well as in relative body weight and organ-body and organ-brain weight ratios. Also, histological assessment revealed evidence of liver and kidney toxicities and recovery was incomplete, as signs of toxicities were still evident after 21 days of recovery. Therefore, the extract is potentially harmful to vital organs with evidence of sex differential adverse effects and non-reversible forms of toxicity, especially with repeated usage, necessitating the need to avoid indiscriminate use.

The survival of the human malaria parasite Plasmodium falciparum under the physiologically distinct environments associated with their development in the cold-blooded invertebrate mosquito vectors and the warm-blooded vertebrate human host requires a genome that caters to adaptability. To this end, a robust stress response system coupled to an efficient protein quality control system are essential features of the parasite. Heat shock proteins constitute the main molecular chaperone system of the cell, accounting for approximately two percent of the malaria genome. Some heat shock proteins of parasites constitute a large part (5%) of the ‘exportome’ (parasite proteins that are exported to the infected host erythrocyte) that modify the host cell, promoting its cyto-adherence. In light of their importance in protein folding and refolding, and thus the survival of the parasite, heat shock proteins of P. falciparum have been a major subject of study. Emerging evidence points to their role not only being cyto-protection of the parasite, as they are also implicated in regulating parasite virulence. In undertaking their roles, heat shock proteins operate in networks that involve not only partners of parasite origin, but also potentially functionally associate with human proteins to facilitate parasite survival and pathogenicity. This review seeks to highlight these interplays and their roles in parasite pathogenicity. We further discuss the prospects of targeting the parasite heat shock protein network towards the developments of alternative antimalarial chemotherapies.

Malaria, an infectious disease caused by Plasmodium spp, is one of the world's most dangerous diseases, accounting for more than half a million deaths yearly. The long years of co-habitation between the parasite and its hosts (human and mosquito), is a testimony to the parasite's ability to escape the immune system and develop drug resistance mechanisms. Currently, an important search area for improved pharmacotherapy are molecular chaperones of the heat shock protein family, abundant in Plasmodium falciparum and contributing to its continuous survival and development. Thus far, small molecule inhibitor studies on P. falciparum Hsp70s and Hsp90s have indicated that they are promising antimalarial targets. However, not much attention has been given to Hsp40s as potential antimalarial drug targets. Hsp40s are known to function as chaperones by preventing protein aggregation, and as co-chaperones, by regulating the chaperone activities of Hsp70s to ensure proper protein folding. There are only a limited number of reviews on Hsp40s as drug targets, and the few reviews on plasmodial Hsp40s tend to focus largely on the intra-erythrocytic stage of the parasite life cycle. Therefore, this review will summarize what is known about Hsp40s throughout the malaria parasite life cycle, and critically evaluate their potential to serve as new avenues for antimalarial drug discovery.