Abstract
The Plasmodium subtilisin‐like serine protease SUB1 is expressed in hepatic and both asexual and sexual blood parasite stages. SUB1 is required for egress of invasive forms of the parasite from both erythrocytes and hepatocytes, but its subcellular localisation, function, and potential substrates in the sexual stages are unknown. Here, we have characterised the expression profile and subcellular localisation of SUB1 in Plasmodium berghei sexual stages. We show that the protease is selectively expressed in mature male gametocytes and localises to secretory organelles known to be involved in gamete egress, called male osmiophilic bodies. We have investigated PbSUB1 function in the sexual stages by generating P. berghei transgenic lines deficient in PbSUB1 expression or enzyme activity in gametocytes. Our results demonstrate that PbSUB1 plays a role in male gamete egress. We also show for the first time that the PbSUB1 substrate PbSERA3 is expressed in gametocytes and processed by PbSUB1 upon gametocyte activation. Taken together, our results strongly suggest that PbSUB1 is not only a promising drug target for asexual stages but could also be an attractive malaria transmission‐blocking target.
Highlights
Malaria is a devastating disease with 216 million cases globally and 445,000 lethal outcomes in 2016 (Organization WH, 2017), mainly in children under the age of 5
To assess whether the endogenous PbSUB1 proteolytic activity was inhibited as anticipated in the SUB1/prod line, we preliminarily investigated whether proteolytic processing of the parasitophorous vacuole (PV) protein PbSERA3, known to be a substrate of PbSUB1 during egress of merozoites from P. berghei liver schizonts (Tawk et al, 2013), occurred in the sexual stages
We investigated the subcellular localisation of the protease in the sexual stages, showing that PbSUB1 is expressed in male gametocytes and localises to specialised secretory organelles called male osmiophilic bodies (MOBs), previously shown to be involved in the exflagellation process (Olivieri et al, 2015; Tachibana et al, 2018)
Summary
Malaria is a devastating disease with 216 million cases globally and 445,000 lethal outcomes in 2016 (Organization WH, 2017), mainly in children under the age of 5. After an initial reproductive cycle in the liver, malaria parasites invade erythrocytes, where they either multiply asexually by forming schizonts or differentiate into gamete precursors called gametocytes. Secretory organelles called osmiophilic bodies (OBs) followed by inside‐out disruption of the parasitophorous vacuole membrane (PVM) and erythrocyte membrane (Ponzi et al, 2009; Sologub et al, 2011; Talman et al, 2011). This entire process is crucial for fertilisation and zygote formation and represents a major bottleneck in the Plasmodium life cycle, involving an approximate 300‐fold loss of parasite abundance (Kuehn & Pradel, 2010). Our results strongly suggest that PbSUB1 is a promising drug target for asexual stages but could be an attractive malaria transmission‐blocking target
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