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 transmissionblocking drug discovery.
