Person:

Catteruccia, Flaminia

Every year the bites of Anopheles mosquitoes kill hundreds of thousands of people, mostly young African children, by transmitting deadly Plasmodium falciparum malaria parasites. Since the turn of the century, efforts to prevent transmission of these parasites via the mass distribution of insecticide-treated bed nets have been extremely successful, causing an unprecedented reduction in malaria deaths1. However, resistance to insecticides has become widespread in Anopheles populations2-4, threatening a global resurgence of the disease and making the generation of effective new malaria control tools an urgent public health priority. Here, we show that development of P. falciparum can be rapidly and completely blocked when Anopheles gambiae females uptake low concentrations of specific antimalarials from treated surfaces, simulating contact with a bed net. Mosquito exposure to atovaquone prior to or shortly after P. falciparum infection causes full parasite arrest in the female midgut, preventing transmission of infection. Similar transmission-blocking effects are achieved with other cytochrome B inhibitors, demonstrating that parasite mitochondrial function is a good target for parasite killing. Incorporating these effects into a model of malaria transmission dynamics predicts that the inclusion of Plasmodium inhibitors on mosquito nets would significantly mitigate the global health impact of insecticide resistance. This study identifies a powerful new strategy for blocking Plasmodium transmission by Anopheles females, with promising implications for malaria eradication efforts.

Insects, unlike vertebrates, are widely believed to lack male-biased sex steroid hormones1. In the malaria mosquito Anopheles gambiae, the ecdysteroid 20-hydroxyecdysone (20E) appears to have evolved to both control egg development when synthesized by females2 and to induce mating refractoriness when sexually transferred by males3. Because egg development and mating are essential reproductive traits, understanding how Anopheles females integrate these hormonal signals can spur the design of new malaria control programs. Here we reveal that these reproductive functions are regulated by distinct sex steroids through a sophisticated network of ecdysteroid-activating/inactivating enzymes. We identify a male-specific oxidized ecdysteroid, 3-dehydro-20E (3D20E), which safeguards paternity by turning off female sexual receptivity following its sexual transfer and activation by dephosphorylation. Notably, 3D20E transfer also induces expression of a reproductive gene that preserves egg development during Plasmodium infection, ensuring fitness of infected females. Female-derived 20E does not trigger sexual refractoriness but instead licenses oviposition in mated individuals once a 20E-inhibiting kinase is repressed. Identifying this male-specific insect steroid hormone and its roles in regulating female sexual receptivity, fertility and interactions with Plasmodium parasites suggests the possibility for reducing the reproductive success of malaria-transmitting mosquitoes.