Journal
NATURE MICROBIOLOGY
Volume 4, Issue 1, Pages 144-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41564-018-0291-7
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Funding
- Spanish Ministry of Economy and Competitiveness (MINECO)/Agencia Estatal de Investigacion (AEI) [SAF2013-43601-R, SAF2016-76190-R]
- European Regional Development Fund (ERDF, European Union)
- Secretary for Universities and Research under the Department of Economy and Knowledge of the Catalan Government [2014 SGR 485]
- Secretary for Universities and Research [2011-BP-B 00060]
- FPU fellowship from the Spanish Ministry of Education, Culture and Sports [FPU014/02456]
- WCM internal startup funds
- NSF CAREER award [DBI-10549646]
- LLS SCOR [7006-13, 7012016]
- Hirschl Trust Award
- Starr Cancer Consortium [I6-A618]
- NIH [1R01CA194547]
- WCM graduate fellowships
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Human to vector transmission of malaria requires that some blood-stage parasites abandon asexual growth and convert into non-replicating sexual forms called gametocytes. The initial steps of gametocytogenesis remain largely uncharacterized. Here, we study this part of the malaria life cycle in Plasmodium falciparum using PfAP2-G, the master regulator of sexual conversion, as a marker of commitment. We demonstrate the existence of PfAP2-G-positive sexually committed parasite stages that precede the previously known committed schizont stage. We also found that sexual conversion can occur by two different routes: the previously described route in which PfAP2-G-expressing parasites complete a replicative cycle as committed forms before converting into gametocytes upon re-invasion, or a direct route with conversion within the same cycle as initial PfAP2-G expression. The latter route is linked to early PfAP2-G expression in ring stages. Reanalysis of published single-cell RNA-sequencing (RNA-seq) data confirmed the presence of both routes. Consistent with these results, using plaque assays we observed that, in contrast to the prevailing model, many schizonts produced mixed plaques containing both asexual parasites and gametocytes. Altogether, our results reveal unexpected features of the initial steps of sexual development and extend the current view of this part of the malaria life cycle.
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