“In most of the eukaryotic organisms, from yeasts to mammals, the expression of these proteins depends on a highly conserved transcription factor called HSF1,” explains Alfred Cortés, ICREA researcher at ISGlobal and study coordinator. “However, malaria parasites – which are also eukaryotes – lack the HSF1 gene, although we know that they can survive at febrile temperatures,” he adds.
‘In most severe forms of malaria, the PfAP2-HS gene activates a protective response against high temperatures and other adverse conditions within the host.’
In this study, Cortés and his team set out to investigate how the malaria parasite regulates its response to higher temperatures (or heat shock) despite the absence of HSF1. They observed that a P. falciparum cell line, grown in the laboratory, had lost its capacity to survive when exposed to a temperature of 41.5ºC, and that this was due to a mutation in a gene which they named PfAP2-HS.
They showed that PfAP2-HS acts as a transcription factor that activates the expression of heat shock proteins hsp70-1 and hsp90 by binding to their respective promoters (i.e. the “on-off button” of a gene). They also showed that engineered parasites lacking the PfAP2-HS gene not only had a lower survival when exposed to higher temperatures, but also showed reduced growth at “normal” temperatures of 37ºC.
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“This means that, in addition to its role in the protective heat-shock response, PfAP2-HS is also important for maintaining protein stability in the parasite at basal temperatures,” says Elisabet Tintó-Font, first author of the study. Moreover, absence of PfAP2-HS in P. falciparum led to a higher susceptibility of the parasite to the antimalarial drug artemisinin, due to alterations in protein balance.
The research team found homologues of PfAP2-HS in all Plasmodium species analysed, even in those that infect mice and do not cause fever. “This suggests that, at least in those species, the response orchestrated by AP2-HS could protect against other adverse conditions in the host,” says Cortés. “This is the first transcription factor described in Plasmodium capable of regulating responses to adverse host conditions, including fever. PfAP2-HS acts as “an orchestra director”, coordinating the other proteins involved in the response,” he adds.
Source: Eurekalert
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