The malaria parasite is able to detect changes in its host’s environment and respond by increasing the production of sexual forms capable of being transmitted to mosquitoes . A study led by the Barcelona Institute for Global Health (ISGlobal), an institution supported by the ”la Caixa” Foundation, identifies the molecular mechanism underlying this process . The findings, published in Nature Microbiology , answer what has been one of the major unanswered questions in malaria research for decades.
During infection in human blood, the malaria parasite Plasmodium falciparum faces two competing demands: on the one hand, it must multiply to sustain the infection; on the other, some parasites must develop into sexual forms known as gametocytes in order to be transmitted to other people through mosquitoes . Whether to continue multiplying or become gametocytes is the key decision in the life cycle of P. falciparum , the parasite responsible for most severe cases of malaria .
It has long been known that the parasite can detect changes in its host’s environment , such as fever or shortages of specific nutrients, and adjust its production of gametocytes accordingly : when conditions become unfavourable, it is advantageous for the parasite to invest more resources in transmission to a mosquito in order to infect another human host.
A single mechanism for responding to different types of stress
In recent years, researchers have identified regulators such as gdv1 and ap2-g , which play a central role in initiating the formation of gametocytes . It was also known that stressful conditions for the parasite, such as nutrient limitation, promote gametocyte production , but the molecular mechanism triggering this response remained unknown.
To uncover it, the research team combined genomics, epigenomics, transcriptomics, proteomics and genetic engineering. Parasites were exposed separately to three stress conditions: nutrient limitation, treatment with the antimalarial drug DHA, and a simulated fever episode . The researchers then analysed which genes were activated, which proteins increased in abundance, and how the organisation of chromatin—the structure that regulates access to DNA—changed. The same experiments were also carried out in parasites in which the regulators involved in the process had been genetically modified.
“All three stimuli activated the same regulatory pathway . They all triggered similar changes in the gdv1 and ap2-g genes,” explains Elisabet Tintó , ISGlobal researcher and first author of the study.
GDV1 and gdv1-as : switching sexual development on and off
The study, supported by CaixaResearch, shows that the stress response does not simply involve switching genes on, but also reorganising heterochromatin , a form of DNA packaging that keeps certain genes silenced. The system also includes its own built-in control mechanism. Once activated, GDV1 triggers conversion into gametocytes , while simultaneously inducing the production of gdv1-as , an RNA molecule that represses gdv1 activity. This regulatory feedback loop acts as a braking system: it enables a rapid response to stress while preventing GDV1 expression from remaining active for longer than necessary, which could otherwise prove lethal for the parasite.
AP2-HS: a control hub for responding to the environment
The study also reveals that AP2-HS, a protein that regulates gene expression , acts as the control hub that enables the parasite to respond to different types of stress . Its role is crucial: when it detects stressful conditions, AP2-HS activates GDV1 expression , thereby initiating gametocyte production. At the same time, AP2-HS also activates other stress-survival mechanisms, revealing this gene as a key factor in the resilience of malaria parasites.
“When we deleted the ap2-hs gene, the parasites completely lost their ability to develop into gametocytes, even under stressful conditions such as fever, DHA treatment or nutrient limitation. Moreover, the few gametocytes that began to develop failed to become viable,” explains Tintó .
“This work helps answer a question that had remained unresolved for years: how the parasite adapts its life cycle to a changing environment and produces the transmissible forms that are essential for its survival at the population level ,” says Alfred Cortés , ICREA researcher at ISGlobal and coordinator of the study.
Reference
Tintó-Font, E., Casas-Vila, N., Martínez-Guardiola, C., Pérez-Cantero, A., Ràfols, N., Nyarko, P. B., & Cortés, A. (2026). AP2-HS and a GDV1 regulatory feedback loop mediate environmental induction of sexual conversion in Plasmodium falciparum . Nature Microbiology . https://doi.org/10.1038/s41564-026-02473-6
Nature Microbiology
Experimental study
Cells
The authors declare that they have no competing interests.