High fever could temporarily reduce malaria transmission

The fever experienced by people with malaria exposes parasites to high temperatures within blood cells. This heat can lead to the accumulation of damaged proteins inside the parasite and trigger protective mechanisms against thermal stress.

A study led by the Barcelona Institute for Global Health (ISGlobal), a center supported by the “la Caixa” Foundation, reveals that Plasmodium falciparum is unable to activate these heat-response mechanisms when it is in the gametocyte stage, the phase responsible for transmitting infection from humans to mosquitoes. The findings, published in PLOS Pathogens, suggest that patients with a high fever could become temporarily noninfectious.

If a mosquito were to bite them during this period, it might not acquire the parasite and therefore would not transmit the disease to other people.

Malaria affects around 260 million people every year and causes roughly 600,000 deaths. P. falciparum is responsible for the most severe form of the disease and for the majority of fatal cases.

After the bite of an infected Anopheles mosquito, the parasites travel to the liver, where they multiply. They then invade red blood cells and begin a replication cycle that repeats approximately every 48 hours. During each cycle, a small proportion of the parasites transform into gametocytes, the only stage capable of infecting a mosquito and therefore essential for malaria transmission.

How and when does P. falciparum activate the thermal stress response?

Fever episodes caused by malaria usually last several hours and can reach 41°C (106°F), temperatures high enough to cause the accumulation of misfolded proteins and threaten the parasite’s survival.

To cope with this damage, the Heat Shock Response (HSR) is activated, a mechanism that protects the cell’s proteins. This response triggers the production of chaperone proteins, which act as “molecular assistants,” helping damaged proteins repair themselves and regain their structure. As in other organisms, HSR is a fundamental survival mechanism in malaria parasites. Until now, however, it was unclear under which conditions it becomes activated.

The research team developed a new protocol to expose parasites to thermal stress using a water bath instead of an incubator, allowing for more precise temperature control and the study of very short heat exposures. Using this method, they observed that just 10 minutes of exposure is enough to activate the HSR.

In P. falciparum, the HSR is controlled by AP2-HS, a transcription factor that regulates the activation of genes involved in the heat response. “We found that the AP2-HS-controlled response is activated very easily. Even moderate increases in temperature, which do not threaten the parasite’s survival, are enough to trigger this protective mechanism,” explains Neus Ràfols, researcher at ISGlobal and first author of the study. These findings suggest that parasites use the HSR in a “preventive” way, which is more efficient than activating it once damage has already occurred.

The HSR is also activated following treatment with the drug DHA

When the research team treated parasites with dihydroartemisinin, or DHA (the active compound in artemisinin and its derivatives, which are the main drugs used against malaria), they also observed activation of the HSR.

These findings point to the HSR as a protective mechanism against different forms of stress that damage parasite proteins, not just thermal stress. However, parasites with truncated forms (incomplete versions) of the AP2-HS protein are more sensitive to thermal stress, although not to DHA. This may be because DHA affects many different molecules within the parasite, not only proteins.

Gametocytes at intermediate or advanced developmental stages do not activate the HSR

Unlike other stages in the parasite’s life cycle, only stage I gametocytes are able to activate the AP2-HS-dependent HSR. More developed gametocytes lose this ability. “Our findings suggest that fever could temporarily reduce the ability of a person with malaria to transmit the infection. Although the parasite appears to enhance transmission under stress conditions, mature gametocytes are particularly sensitive to high temperatures,” explains Alfred Cortés, ICREA researcher at ISGlobal and coordinator of the study.

“Future studies will need to confirm whether this effect occurs during natural infections and determine whether there is a threshold temperature above which patients become temporarily noninfectious,” concludes Cortés.

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Gaby Clark

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Andrew Zinin

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