Plasmodium male and female gametocytes are responsible for transmission from humans to mosquitoes, thus mediate not only the spread of malaria, but also antimalarial drug resistance. Interrupting transmission is essential for malaria elimination/eradication. Understanding the cell biology of gametocytes is essential to discovering new methods to prevent transmission. However, P. faciparum gametocytes are difficult to culture in vitro, and even harder to successfully transmit to mosquitoes in the laboratory.

My research goal is to accelerate the discovery of new therapeutics that prevent parasite transmission. To achieve this, my group take advantage of the unique culture, insectary and transmission facilities at LSHTM, transgenic manipulation of the parasite, microscopy and high throughput drug screening.

Current research projects:

MMV Transmission-blocking Drug Screening Platform - P. falciparum Dual Gamete Formation Assay (PfDGFA)

 Funded by the MMV, we screen and characterise all new antimalarial molecules in MMV Discovery Portfolio provided by academic partners and industry. Data we generate identifies antimalarial molecules that target gametocytes - i.e. have the capacity to not only cure malaria, but also prevent onward transmission. Molecules with this dual activity are a priority for development. 

                Uniquely, the PfDGFA recognises that gametocytes are sexually dimorphic, have divergent cell biology and that male and female gametocytes have different sensitivities to antimalarial drugs. Consequently, the assay gives a “dual” readout of activity against males and females. Furthermore, by using gamete formation as an assay endpoint, we identify molecules that not only kill gametocytes, but also those that interfere with their fertility, thus maximising the transmission-blocking molecules identified in screens.

Defining the “quiescent” phenotype of P. falciparum gametocytes

P. falciparum mature gametocytes have reached the end of their development in the human and to continue their life cycle, need to be taken up by a mosquito. They have no control over when this may happen, and so to maximise their chances of transmission they become dormant (likely contributing to their insensitivity to most antimalarials). However, gametocytes must be always ready for energetic transformation into gametes within minutes upon uptake by mosquitoes. Using proteomics, metabolomics and transgenic modification, we seek to understand how these two contradictory life styles can be reconciled.

How do gametocytes regulate energy metabolism in their quiescent state?
Notably, gametocytes have an enlarged mitochondrion, but we have recently shown that mitochondrial respiration is unimportant for gametocyte survival. However, mitochondrial ATP is essential for gametogenesis (particularly in the male). We want to understand how the gametocyte controls energy metabolism and how it is used to “fuel” its transformation into gametes.

Using phenotypic imaging to characterise novel transmission blocking molecules

Molecular targets for transmission-blocking drugs are either not known or poorly understood. Traditional resistance generation methods are also not feasible for non-replicating gametocytes. To deconvolve the “targetable cell biology” of gametocytes, we have developed machine learning-based phenotypic imaging methodology enabling us to categorise antimalarial molecules by the visible phenotypic changes they make to the gametocyte. Applying our phenotypic imaging approach to the hits from our high throughput screening, we aim to use transmission-blocking molecules to “tell” us which proteins and pathways are essential for transmission.