In malaria parasites, while the clinical symptoms are caused by asexual parasites that replicate within the red blood cells, sexual forms are the only ones capable of transmitting the infection to mosquitoes. Targeting this small population of sexually differentiated parasites would provide an extremely powerful malaria control method overcoming limitations in vector control and antimalarials.
During gametocyte developmental pathway, there are two distinct cellular decisions at molecular level: first, commitment to sexual differentiation and, then, determination of the parasite into one sex or the other. Although several genes have been found to have sex-specific roles, the molecular basis of the sex-determining mechanisms of Plasmodium and the relation of this decision with the sexual commitment pathway is completely unknown. It has also been suggested that sex-determination is a flexible phenotype that can be influenced by environmental variation to maximise parasite fitness and, consequently, transmission. However, the mechanisms underlying on the process of environment sensing and the molecular players involved remain unclear.
Malaria is the most lethal parasitic disease in the world causing more than 600000 deaths of children under 5 years old in 2021, with approximately half of the human population exposed to be infected every day by one of the five Plasmodium species able to affect humans. The current scenario to combat this health and social burden is that the deadliest parasite responsible for this disease, P. falciparum, has developed resistance to all antimalarials individually, so the most potent treatment is based in combination of two different drugs while there are no promising alternatives in last phases of clinical trials. Therefore, searching for novel alternatives to tackle malaria infections is clearly needed. We have focused on using cutting-edge technologies, such as single-cell transcriptomics (scRNAseq), to expand and unravel sexual determination and differentiation, two essential steps for the parasite life cycle that are still largely unknown. That could lead to discover attractive drug targets that could block transmission to mosquitoes and, then, alleviate the burden of this disease.
In this proposal, we have applied innovative approaches to uncover the pathway of sex-determination in P. falciparum, in both lab-adapted parasites and wild parasite populations. Specifically to:
- Determine the earliest events in sex determination using scRNAseq in a lab-adapted P. falciparum strain (NF54)
- Understand determinants of malaria sexual determination in wild parasites by harnessing the power of scRNAseq
- Identify factors that influence determination into male or female gametocytes in natural parasite populations obtained from infected carriers.
