Now, researchers at the National Institutes of Health (NIH) have shed light on how malaria parasites sidestep the host's fever response. The investigators report in the journal Nature Communications that the parasite hijacks the red blood cell's cellular defenses to protect its own proteins from the detrimental effects of excessive heat.
"Our findings reveal the molecular mechanism that underlies malaria parasites' remarkable tolerance of host body temperature," said senior investigator Louis Miller, Ph.D., of the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH. "The strategy deployed by malaria parasites, which involves commandeering the host's protein defense mechanism, represents an important target for development of new therapies to treat malaria."
Falciparum malaria is a mosquito-borne disease caused by the protozoan parasite Plasmodium falciparum. The World Health Organization estimates that, in 2020, there were approximately 241 million new cases of malaria and 627,000 deaths attributable to the disease worldwide. People most commonly infected are young children in sub-Saharan Africa.
Inside the human body, the parasite exists in two main forms, in the liver and in red blood cells. The liver-stage parasite is not typically sensitive to elevated body temperature. However, the asexual form of the parasite that resides inside red blood cells — the blood-stage parasite — typically can be killed when the body temperature rises above the normal range of 36.5 to 37.5 degrees Celsius (97.7 to 99.5 degrees Fahrenheit).
In 2018, Dr. Miller and his colleagues developed a rapid diagnostic test to identify individuals who have the P. falciparum variant that exhibits unusually high tolerance of febrile temperatures. In the present study, the researchers characterized the molecular basis for this thermal tolerance.
The team found that heat-resistant parasites have elevated levels of a chaperone protein called PfHsp70-x. Production of this protein is normally curtailed when the temperature inside red blood cells exceeds 37.5 C (99.5 F). However, the researchers uncovered a mechanism by which these heat-resistant parasites ensure ongoing production of the PfHsp70-x chaperone.
Elevated levels of PfHsp70-x protect the parasite's proteins against heat-induced damage, keeping the parasites alive and replicating even when the body temperature rises. The chaperone's ability to safeguard parasitic proteins is rooted in its interaction with a host cell protein called Hsp90, a key component of the cell's heat-shock response pathway.
"Malaria parasites have hijacked the host's cell defense mechanism to protect themselves from the damaging effects of a fever," said Dr. Miller. "Our findings reveal the molecular choreography by which the parasites exploit this defense route, creating an opportunity for innovative therapies to disarm the chaperone and block parasite growth."
