Defining the signature of deformable and infectious Plasmodium falciparum gametocytes

<ns3:p> Background One of the major challenges for malaria elimination is combating the highly efficient spread of the disease. Despite progress in understanding the development of malaria transmission stages, there remain many unanswered questions about how gametocytes progress from being immature to infectious. In <ns3:italic>Plasmodium falciparum,</ns3:italic> immature gametocytes are rigid and sequester outside of circulation in the extravascular space of the bone marrow, while deformable, mature stages are found in circulation and transmitted to mosquitoes. It is currently unclear whether deformable gametocytes are immediately infectious to mosquitoes, or whether they undergo activation upon release into circulation. Methods We used a combination of phenotypic assays and transcriptional analysis to define the transition from immature non-infectious to mature infectious gametocyte. Specifically, we associated gene expression with distinct phenotypic traits: gametocyte deformability assessed by microsphere filtration, and gametocyte infectivity assessed by exflagellation and mosquito feeding assays. Conclusions Our data revealed major transcriptional differences between unfiltered and deformable gametocytes, but high similarity between deformable and infectious gametocytes. In combination with exflagellation and transmission results upon mosquito feeding assays, this suggests that deformable gametocytes are immediately infectious upon release from the bone marrow. The transcriptional analysis revealed a comprehensive set of infectivity markers that can be utilized to track gametocytes during their development and serve as diagnostic tools to map the human infectious reservoir. </ns3:p>