Section Cellular and Applied Infection Biology
   

 

email: gabriele.pradel(at)molbiotech.rwth-aachen.de

42B, Room 159

Worringerweg 1

D-52074 Aachen

Phone: 0049 241 8028123

Fax: 0049 241 871062

research interests

Malaria: Transmission blocking strategies

Malaria is the most prevalent tropical disease in the world, with 225 million new cases reported each year and an annual death toll of one million people. Disease treatment and control measures are undermined by the spread of drug resistance, particularly in populations of Plasmodium falciparum, the agent responsible for malaria tropica. Guidelines released by the WHO recommend artemisinin-based combination therapies in order to combat drug-resistant malaria. Furthermore, efforts in drug discovery and vaccine development are encouraged to focus on the transmission-blocking activity of vaccine and drug candidates. This is needed to eliminate all parasites that have entered the sexual pathway and which would continue the parasite life-cycle in the mosquito vector. Transmission-blocking strategies therefore provide a stopgap measure against the transmission of drug-resistant genotypes from the human to the mosquito. Parasite transmission from humans to mosquitoes is mediated by sexual precursor cells, the intraerythrocytic gametocytes, which in the midgut of the mosquito become activated due to environmental stimuli and transform into fertile gametes. The egress of the gametocytes, from the enveloping host erythrocyte is triggered by stimuli of the mosquito midgut and involves the rupture of two membranes, the erythrocyte membrane and the membrane of the parasitophorous vacuole. Gametocyte egress is crucial for the formation of gametes, but the underlying molecular mechanisms are up to date not well understood. The sexual stages are the only life-cycle stages of the malaria parasite that are able to establish an infection in the mosquito and thus play an important role for spread of the tropical disease. They are considered bottleneck stages with an approximate 300-fold loss in the abundance during transmission to the mosquito. They are also the only stages within the parasite´s life cycle that for more than 1 day are extracellularly exposed to a hostile environment, which includes mosquito midgut factors as well as human immune defense components present in the blood meal. When entering the midgut of the blood-feeding mosquito, the malaria parasite therefore on the one hand has to receive signals indicating the transmission to the invertebrate host, thereby activating fertilization, but on the other hand has to simultaneously prepare for protection. It is the aim of the Pradel lab to investigate the molecular and cellular interplay of P. falciparum parasites during gametocyte development and transmission to the mosquito. In detail we want to investigate:
• Proteostasis in gametocytes.
• Membrane-associated adhesion proteins and the inner membrane complex of gametocytes.
• The molecular mechanisms of gametocyte egress following transmission to the mosquito midgut.
• The cellular interactions between gametes during fertilization in the mosquito midgut.
• The molecular mechanisms that gametes utilize to protect from midgut factors.

 

Plasmodium falciparum gametocytes expressing Pfs230 (green). Erythrocytes counterstained with Evans Blue (red).

Formation of nanotubes in activated Plasmodium falciparum gametocytes. Gametocytes labeled with anti-Pfs230 (green), erythrocytes counterstained with Evans Blue (red).

Plasmodium falciparum gametocyte 2 min post-activation.