Life-threatening malaria is accompanied by intermittent high fever and shaking chills, produced by the release of the malarial parasite, Plasmodium falciparum, into the bloodstream at the end of each cycle of asexual reproduction in red blood cells. The high temperatures ought to kill the parasites, but they don’t. How the parasite survives these high fevers has been a mystery until now.

This has been particularly confounding because Plasmodium’s genetic material lacks a transcription factor to activate the expression of protective chaperone proteins upon heat shock that keep proteins functional in their native folded states even at high temperatures.

Alfred Cortés, PhD, is ICREA researcher at ISGlobal and corresponding author of the study

“In most of the eukaryotic organisms, from yeasts to mammals, the expression of these proteins [chaperones] depends on a highly conserved transcription factor called HSF1,” says Alfred Cortés, PhD, ICREA researcher at ISGlobal. “However, malaria parasites—which are also eukaryotes—lack the HSF1 gene, although we know that they can survive at febrile temperatures.”

In a new study published in Nature Microbiology, Cortés and his team of scientists at ISGlobal, Barcelona Institute of Global Health, identify a transcription factor (PfAP2-HS) that controls the protective heat-shock response in the parasite.

The study is reported in an article titled, “A heat-shock response regulated by the PfAP2-HS transcription factor protects human malaria parasites from febrile temperatures” and is co-funded by the European Regional Development Fund, NIH/NIAID, and the European Social Fund.

The study is based on their fortuitous observation that a P. falciparum cell line in their laboratory lost its capacity to survive when exposed to a temperature of 41.5ºC. When they probed into the underlying cause, they established that this was due to a mutation in the gene PfAP2-HS.

At high temperatures, PfAP2-HS induces expression of chaperone proteins hsp70-1 and hsp90. The authors show the transcription factor primarily binds at a sequence in the hsp70-1 promoter called the “tandem G-box DNA motif.”

Of therapeutic relevance is the researchers’ finding that when the malaria parasite lacks PfAP2-HS, it is no longer adept at surviving at 37°C/98.6°F (normal physiological temperature) compared to 35°C/95°F, and if it does survive, it experiences severe growth defects.

“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, PhD, first author of the study.

Parasites lacking PfAP2-HS are more sensitive to imbalances in the dynamic regulation of the proteome (proteostasis). Artemisinin, the frontline antimalarial drug, is believed to act by disrupting the balance of the proteome. Absence of PfAP2-HS in the malarial parasite results in increased susceptibility of the parasite to artemisinin.

“We propose that PfAP2-HS contributes to the maintenance of proteostasis under basal conditions and upregulates specific chaperone-encoding genes at febrile temperatures to protect the parasite against protein damage,” the authors note.

The research team also identify proteins comparable to PfAP2-HS in other Plasmodium species, 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 Plasmodiumcapable of regulating responses to adverse host conditions, including fever. PfAP2-HS acts as ‘an orchestra director’, coordinating the other proteins involved in the response,” says Cortés.

The study settles the long-standing question of whether the transcriptional machinery of malaria parasites can respond to changes in the host environment.

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