Johns Hopkins Bloomberg School of Public Health, Department of Molecular Microbiology and Immunology and Malaria Research Institute, 615N. Wolfe St., Baltimore, MD, 21205, USA.
Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, 42988, Republic of Korea.
Nat Commun. 2021 Nov 19;12(1):6773. doi: 10.1038/s41467-021-27109-7.
After inoculation by the bite of an infected mosquito, Plasmodium sporozoites enter the blood stream and infect the liver, where each infected cell produces thousands of merozoites. These in turn, infect red blood cells and cause malaria symptoms. To initiate a productive infection, sporozoites must exit the circulation by traversing the blood lining of the liver vessels after which they infect hepatocytes with unique specificity. We screened a phage display library for peptides that structurally mimic (mimotope) a sporozoite ligand for hepatocyte recognition. We identified HP1 (hepatocyte-binding peptide 1) that mimics a ~50 kDa sporozoite ligand (identified as phospholipid scramblase). Further, we show that HP1 interacts with a ~160 kDa hepatocyte membrane putative receptor (identified as carbamoyl-phosphate synthetase 1). Importantly, immunization of mice with the HP1 peptide partially protects them from infection by the rodent parasite P. berghei. Moreover, an antibody to the HP1 mimotope inhibits human parasite P. falciparum infection of human hepatocytes in culture. The sporozoite ligand for hepatocyte invasion is a potential novel pre-erythrocytic vaccine candidate.
被感染的蚊子叮咬后，疟原虫孢子进入血液并感染肝脏，每个受感染的细胞产生数千个裂殖子。裂殖子进而感染红细胞并引起疟疾症状。为了引发有效的感染，孢子必须在离开循环系统后穿过肝脏血管的血液内层，然后以独特的特异性感染肝细胞。我们从噬菌体展示文库中筛选出能够模拟（模拟表位）疟原虫孢子与肝细胞识别相关配体的肽段。我们鉴定出 HP1（肝细胞结合肽 1），它模拟了约 50 kDa 的疟原虫孢子配体（鉴定为磷脂翻转酶）。此外，我们还表明 HP1 与约 160 kDa 的肝细胞膜假定受体（鉴定为氨基甲酰磷酸合成酶 1）相互作用。重要的是，用 HP1 肽免疫小鼠可部分保护其免受啮齿动物寄生虫伯氏疟原虫的感染。此外，针对 HP1 模拟表位的抗体可抑制人疟原虫在培养的人肝细胞中的感染。这种用于肝细胞入侵的孢子配体可能是一种新型的红细胞前期疫苗候选物。
