Adapt or Die: Targeting Unique Transmission-Stage Biology for Malaria Elimination

Abstract

Plasmodium parasites have a complex life cycle that includes development in the human host as well as the Anopheles vector. Successful transmission of the parasite between its host and vector therefore requires the parasite to balance its investments in asexual replication and sexual reproduction, varying the frequency of sexual commitment to persist within the human host and generate future opportunities for transmission. The transmission window is extended further by the ability of stage V gametocytes to circulate in peripheral blood for weeks, whereas immature stage I to IV gametocytes sequester in the bone marrow and spleen until final maturation. Due to the low gametocyte numbers in blood circulation and with the ease of targeting such life cycle bottlenecks, transmission represents an efficient target for therapeutic intervention. The biological process of Plasmodium transmission is a multistage, multifaceted process and the past decade has seen a much deeper understanding of the molecular mechanisms and regulators involved. Clearly, specific and divergent processes are used during transmission compared to asexual proliferation, which both poses challenges but also opportunities for discovery of transmission-blocking antimalarials. This review therefore presents an update of our molecular understanding of gametocyte and gamete biology as well as the status of transmission-blocking activities of current antimalarials and lead development compounds. By defining the biological components associated with transmission, considerations for the development of new transmission-blocking drugs to target such untapped but unique biology is suggested as an important, main driver for transmission-blocking drug discovery.

Novel secretory organelles of parasite origin ‐ at the center of host‐parasite interaction

“…[153] During the maturation of the gametocytes (stages I-IV) within the bone marrow and the spleen cords, both parasite and host RBC require remodeling which eventually leads to the development of sickle-or scythe-shaped parasites, hence the name P. falciparum (Latin falx "sickle or scythe"), while the host RBC is reduced to a thin background layer called Laveran's bib. [33,154] Once the gametocytes have matured to stage V, they have to leave their hiding places towards the peripheral blood of their intermediate host.…”

Genotyping Plasmodium falciparum gametocytes using amplicon deep sequencing

“…During the erythrocytic stage of the malaria parasite in humans, a fraction of asexual parasites differentiates into gametocytes [ 1 ]. Gametocytes are the sexual form of the parasite transmitted from humans to mosquitoes and are an important target for interventions that interrupt human-to-mosquito transmission [ 1 , 2 ]. Polyclonal Plasmodium falciparum infections are prevalent in high transmission settings [ 3 – 6 ].…”

Machine Learning Approaches Identify Chemical Features for Stage-Specific Antimalarial Compounds

“…This process is uniquely prolonged among the laverinia species (falciparum and reichenowi) and can take ∼10–12 days until mature (stage V) male and female gametocytes are produced as the only forms to support transmission. Identifying gametocytocidal activity is, therefore, more complicated compared to screening for ABS-inhibiting compounds , due to the limited and time-consuming production of gametocyte populations and the typical need for complementary, orthogonal assays to interrogate the effect of a compound on the differentiated biology associated with transmissible stages …”