Dong Yuemei, Kang Seokyoung, Sandiford Simone L, Pike Andrew, Simões Maria L, Ubalee Ratawan, Kobylinski Kevin, Dimopoulos George
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Department of Biomedical Sciences, Institute of Tropical Medicine Antwerp, Antwerp, Belgium.
Nat Microbiol. 2025 Apr;10(4):841-854. doi: 10.1038/s41564-025-01947-3. Epub 2025 Mar 6.
The Plasmodium infection cycle in mosquitoes relies on numerous host factors in the vector midgut, which can be targeted with therapeutics. The mosquito prefoldin complex is needed to fold proteins and macromolecular complexes properly. Here we show that the conserved Anopheles mosquito prefoldin (PFDN)-chaperonin system is a potent transmission-blocking target for multiple Plasmodium species. Silencing any prefoldin subunit or its CCT/TRiC partner via RNA interference reduces Plasmodium falciparum oocyst loads in the mosquito midgut, as does co-feeding mosquitoes with PFDN6-specific antibody and gametocytes. Inhibition of the PFDN-CCT/TRiC chaperonin complex results in the loss of epithelial and extracellular matrix integrity, which triggers microorganism-mediated anti-Plasmodium immune priming and compromises the parasite's laminin-based immune evasion. Mouse malaria transmission-blocking vaccine and antibody co-feeding assays support its potential as a multispecies transmission-blocking target for P. falciparum and Plasmodium vivax. Further study is needed to determine the potential of this system as a transmission-blocking vaccine target.
疟原虫在蚊子体内的感染周期依赖于媒介中肠中的众多宿主因子，这些因子可用治疗药物作为靶点。蚊子的预折叠蛋白复合体是正确折叠蛋白质和大分子复合体所必需的。在此，我们表明，保守的按蚊预折叠蛋白（PFDN）伴侣蛋白系统是多种疟原虫物种有效的传播阻断靶点。通过RNA干扰沉默任何预折叠蛋白亚基或其伴侣蛋白CCT/TRiC，可减少恶性疟原虫在蚊子中肠的卵囊数量，给蚊子同时喂食PFDN6特异性抗体和配子体也有同样效果。抑制PFDN-CCT/TRiC伴侣蛋白复合体导致上皮细胞和细胞外基质完整性丧失，从而引发微生物介导的抗疟原虫免疫启动，并损害寄生虫基于层粘连蛋白的免疫逃避。小鼠疟疾传播阻断疫苗和抗体同时喂食试验支持其作为恶性疟原虫和间日疟原虫多物种传播阻断靶点的潜力。需要进一步研究来确定该系统作为传播阻断疫苗靶点的潜力。
