Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington, USA.
Department of Pediatrics, University of Washington, Seattle, Washington, USA.
mBio. 2022 Oct 26;13(5):e0222722. doi: 10.1128/mbio.02227-22. Epub 2022 Sep 26.
Cyclin-dependent kinases (CDKs) and cyclins are critical cell cycle regulators in eukaryotes. In this study, we functionally characterized a CDK-related kinase (CRK5) of the human malaria parasite Plasmodium falciparum. P. falciparum CRK5 (CRK5) was expressed in asexual blood stages and sexual gametocyte stages, but showed male gametocyte- specific expression. In contrast to previous findings, we showed that gene deletion parasites grew normally as asexual stages and underwent normal gametocytogenesis to stage V gametocytes. However, parasites showed a severe defect in male gametogenesis, which was evident by a significant reduction in the emergence of male gametes (exflagellation). This defect caused a severe reduction of parasite transmission to the mosquito. Genetic crosses performed using sex-specific sterile transgenic parasites revealed that parasites suffered a defect in male fertility but female gametes were fertile. Taken together, these results demonstrate that CRK5 is a critical sexual stage kinase which regulates male gametogenesis and transmission to the mosquito. Gametocytes are parasite sexual stages which differentiate from asexually replicating parasites. These stages are necessary for the completion of sexual phase of the parasite life cycle. Inside the mosquito midgut, gametocytes rapidly get activated to form fertilization competent gametes. These stages present a bottleneck in the parasite life cycle. In this study, we demonstrate that PCRK5 is important for male gametogenesis and therefore regulates parasite transmission to the mosquito. Our study identifies PCRK5 as a potential target for the development of drugs to block malaria transmission.
细胞周期蛋白依赖性激酶（CDKs）和细胞周期蛋白是真核生物细胞周期的关键调节因子。在这项研究中，我们对人类疟疾寄生虫疟原虫的一种 CDK 相关激酶（CRK5）进行了功能表征。疟原虫 CRK5（CRK5）在无性血期和有性配子体期表达，但表现出雄性配子体特异性表达。与之前的发现相反，我们表明基因缺失 寄生虫在无性阶段正常生长，并经历正常的配子发生，形成 V 期配子体。然而， 寄生虫在雄性配子发生中表现出严重缺陷，这表现在雄性配子（出芽）的出现显著减少。这种缺陷导致寄生虫向蚊子的传播严重减少。使用性特异性不育转基因寄生虫进行的遗传杂交表明， 寄生虫雄性不育，但雌性配子是可育的。总之，这些结果表明 CRK5 是一种关键的性阶段激酶，它调节雄性配子发生和向蚊子的传播。配子体是寄生虫的有性阶段，由无性复制的寄生虫分化而来。这些阶段是完成寄生虫生命周期的有性阶段所必需的。在蚊子的中肠内，配子体迅速被激活形成有受精能力的配子。这些阶段是寄生虫生命周期中的一个瓶颈。在这项研究中，我们表明 PCRK5 对雄性配子发生很重要，因此调节寄生虫向蚊子的传播。我们的研究确定 PCRK5 是开发药物阻断疟疾传播的潜在靶点。
