According to a new study led by the Barcelona Institute for Global Health (ISGlobal), A gene called PfAP2-HS allows the malaria parasite to defend itself from febrile temperatures of the host's body. Most organisms have a defence mechanism against increased temperatures: the expression of heat-shock proteins (HSP), which act as chaperones. In most of the eukaryotic organisms, from yeasts to mammals, the expression of these proteins depends on a highly conserved transcription factor called HSF1. However, malaria parasites which are also eukaryotes, lack the HSF1 gene, although we know that they can survive at febrile temperatures.
So how the malaria parasite regulates its response to higher temperatures despite the absence of HSF1? Researchers 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.
Functions ot PfAP2-HS gene:
- Protective heat-shock response: 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.
- Maintaining protein stability: PfAP2-HS is also important for maintaining protein stability in the parasite at basal temperatures. 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.
References:
- Elisabet Tintó-Font, Lucas Michel-Todó, Timothy J. Russell, Núria Casas-Vila, David J. Conway, Zbynek Bozdech, Manuel Llinás, Alfred Cortés. A heat-shock response regulated by the PfAP2-HS transcription factor protects human malaria parasites from febrile temperatures. Nature Microbiology, Aug. 16, 2021; DOI: 10.1038/s41564-021-00940-w
