Abstract
Blocking malaria transmission is critical to malaria control programs but remains a major challenge especially in endemic regions with high levels of asymptomatic infections. New strategies targeting the transmissible sexual stages of the parasite, called gametocytes, are needed. This review focuses on P. falciparum gametocytogenesis in vivo and in vitro. Highlighting advances made elucidating genes required for gametocyte production and identifying key questions that remain unanswered such as the factors and regulatory mechanisms that contribute to gametocyte induction, and the mechanism of sequestration. Tools available to begin to address these issues are also described to facilitate advances in our understanding of this important stage of the life cycle.
Highlights
Half of the world’s population is still at risk of malaria (WHO, 2020)
Of particular interest are the roles of LysoPC and bone marrow and spleen sequestration, as well as quantifying gametocyte-committed rings and their maturation to gametocytes in asymptomatic and symptomatic individuals
Understanding the factors contributing to the infectious reservoir will be important to design control strategies for malaria elimination
Summary
Half of the world’s population is still at risk of malaria (WHO, 2020). Through the 1980s and 1990s, the spread of P. falciparum parasites resistant to chloroquine, the mainstay of treatment since the 1950s, across Africa increased the annual malaria mortality rate above one million (Nuwaha, 2001). To more directly evaluate clinical conditions closer to the time of initial sexual differentiation, blood samples from malaria patients were maintained in culture for 8 days in the presence of N-acetyl glucosamine (NAG) to block asexual growth and monitor gametocyte production (Usui et al, 2019) This approach revealed that 76% of the samples produced gametocytes, but the number of ring-stage parasites that differentiate sexually, referred to as the gametocyte conversion rate (GCR), varied from 0–78%. It is difficult to test this directly in humans, but the recently validated biomarkers for early sexually-committed ring-stage parasites can be used to assess the in vivo relationship between sexually-committed-rings and circulating gametocyte levels 10-11 days later This information can be used to determine the association between gametocyte maturation in vivo and different clinical factors, including hematopoiesis, parasitemia, and fever as well as other factors recently found to influence gametocytogenesis in vitro. The feedback pathway that regulates the upregulation of PfPMT in response to low choline levels is unknown
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