Anopheles gambiae Cryptochrome 1: A novel regulator of malaria parasite infection in the mosquito

Malaria is caused by Plasmodium parasites that are transmitted between humans by Anopheles mosquitoes. Plasmodium’s journey through the mosquito involves extensive interactions with the midgut tissue, representing a bottleneck of infection, since most parasites succumb to the mosquito's immune responses. Proteomic data on midgut eluents helped us to identify an intriguing Plasmodium antagonist function of the Cryptochrome 1 (CRY1). CRY1 is enriched on the surface of P. falciparum-infected midguts, and its silencing renders the mosquito more permissive to parasite infection. Moreover, the administration of a CRY ligand in the sucrose meal, which has been shown to stabilize CRY proteins, results in a significant oocyst decrease. Using in vitro and in vivo techniques, we validated that the chemical exhibits no direct antiparasitic activity, hence corroborating CRY1’s ability to modulate P. falciparum infection. CRY1 is a known photoreceptor in the circadian phototransduction pathway, while its implication in oxidative stress has also been documented. Besides that, accumulating evidence also indicates light-independent functions. Our data so far corroborate that the CRY1-mediated influence on the parasite infection in the mosquito is independent of the circadian clock, as with dsRNA-mediated silencing the CRY1 expression in the brain (central circadian clock) remained unaffected, while silencing TIMELESS, which interacts with CRY1 in the presence of light, also does not affect oocyst numbers. Additionally, the expression of several ROS-related and immune genes was altered in the CRY1-silenced and KL001-fed mosquitoes upon blood-feeding.