Shining a Light on Dense Granules – A Biochemical, Genetic and Cell Biological Investigation of an Essential but Understudied Compartment of the Malaria Parasite

Malaria is a significant infectious disease of tropical and sub-tropical regions that is caused by six species of Apicomplexan parasites of the genus Plasmodium. With 228 million cases and an estimated 619,000 mortalities worldwide in 2021 (1), this disease is endemic in developing countries in which the transmission vector, species of the Anopheles mosquito, most commonly A. gambiae, is found. Further, malaria is a major cause of mortality in children, with 65% of cases occurring in those under the age of 5 (2). Between 2000 and 2019 rates of malaria fatality decreased steadily, with a 10% increase in mortality in 2020 followed by a slight decline in 2021 (1). However, the disease remains a major global health burden and new insights into the pathogenesis of the disease are needed if new interventions are to be developed. The clinical symptoms of malaria are caused by invasion, replication within, and destruction of host red blood cells by the Plasmodium parasite. Invasion of the host cell by the parasite requires the highly regulated secretion of proteins from three specialised secretory organelles: micronemes, rhoptries, and dense granules (DGs). Microneme and rhoptry proteins function in host cell recognition attachment and invasion and establishment of the parasitophorous vacuole (PV), respectively, in Plasmodium spp. (3,4). DGs are speculated to be required for the erythrocyte remodelling that enables parasite survival and replication within the host cell post invasion, with known proteins functioning in transport of parasite effector proteins into the erythrocyte (5) and alteration of host cell mechanical properties (6). Host erythrocyte remodelling by the parasite is a process that may be exploited for development of drugs capable of inhibiting parasite growth and replication, blocking further cycles of infection. Very little is known about Plasmodium DGs, therefore shedding light on the biogenesis, protein composition and function of DGs in Plasmodium may aid drug development efforts. This project aims to address these questions in Plasmodium falciparum using molecular biological and bioinformatics techniques.