Unravelling rodent malaria gametocytogenesis to unlock a zoonotic transmission model

Malaria parasite transmission is a uniquely vulnerable to intervention with the simple goal of reducing R below 1. Informed strategies to achieve this require in-depth knowledge of the parasite biology behind transmission - currently impeded by a paucity of tools to study human non-falciparum parasites. Transmission is initiated (commitment) by expression of a transcription factor, AP2-G that directs new transcription programmes that generate male and female gametocytes in the blood ready for ingestion within the female mosquito blood-meal. Expression of ap2-g is tightly regulated through epigenetic mechanisms and responsive to the environment. However, to date we are ignorant of: - the mode of action of the sex-specific developmental programmes initiated by AP2-G - environmental factors that stimulate gametocytogenesis - how and when a sex-specific genome is configured In a ground-breaking programme supported by a wealth of published and unpublished data, we propose to gain unprecedented insights into these issues by establishing a new human infectious model of transmission, Plasmodium knowlesi, in London, Malaysia and Glasgow building on paradigm-shifting research from our existing rodent and human models. Exploiting the gametocytogenesis discovery pipelines in the sophisticated P. berghei and P. falciparum models will permit a comparative integrative approach to understanding and ultimately blocking malaria transmission.