A key regulator gene
Infection by Plasmodium falciparum, which causes one of the most severe forms of malaria in humans, is characterised by periodic fevers (each time parasites are released into the bloodstream after completing a cycle of reproduction). This is because fever is an important element of our body’s response against pathogens—by affecting the stability of cellular proteins, it can reduce parasite growth. In turn, many organisms have developed defence mechanisms (called heat-shock proteins) to survive at increased temperatures. “In most organisms, from yeasts to mammals, the expression of these proteins depends on a highly conserved transcription factor called HSF1,” explains Alfred Cortés, who has been studying the biology of P. falciparum for many years. “However, malaria parasites—which are also eukaryotes—lack the HSF1 gene, although we know that they can survive at febrile temperatures,” he adds.
Cortés and his team set out to investigate how the malaria parasite regulates its response to higher temperatures. They found that it all depends on a key regulator gene called PfAP2-HS, which activates the expression of heat-shock proteins. Parasites that had a mutation in that gene lost their capacity to survive in the lab when cultured at 41.5oC. Surprisingly, these parasites also showed reduced growth at temperatures of 37oC and were more susceptible to the antimalarial drug artemisinin.
“This means that, in addition to its protective role against heat, PfAP2-HS is also important for maintaining protein stability in the parasite at normal body temperatures,” says Elisabet Tintó-Font, lead author of the study. In fact, 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 is the first transcription factor described in Plasmodium capable of regulating responses to fever and other adverse conditions in the host. It acts as an ‘orchestra director’, coordinating the other proteins involved in the response,” says Cortés.