He Wei, Sun Lianbei, Hou Tianyi, Yang Zuwei, Yang Fuxian, Zhang Shengchen, Wang Tianpeng, Wang Xinran, Li Na, Guo Yaqiong, Sibley L David, Feng Yaoyu, Xiao Lihua
State Key Laboratory for Animal Disease Control and Prevention, Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
School of Biology and Agriculture, Shaoguan University, Shaoguan, China.
Nat Commun. 2025 May 20;16(1):4694. doi: 10.1038/s41467-025-60088-7.
Cryptosporidium is a major cause of severe diarrhea. Although Cryptosporidium isolates exhibit significant differences in infectivity and virulence, the genetic determinants for these traits are not clear. In this study, we use classical genetics to cross two Cryptosporidium parvum isolates of different virulence and use bulk segregant analysis of whole-genome sequences from the progeny to identify quantitative trait loci (QTL) associated with Cryptosporidium infectivity and virulence. Of the 23 genes in three QTL, two have loss-of-function mutations in the low-virulence isolates, including the SKSR1 gene encoding a variant secretory protein. Deletion of the SKSR1 gene or expression of the frame-shifted sequence reduces the pathogenicity of the virulent isolate. SKSR1 is expressed in small granules and secreted into the parasite-host interface during invasion. These results demonstrate that SKSR1 is an important virulence factor in Cryptosporidium, and suggest that the extended SKSR protein family, encoded by clusters of subtelomeric genes, may contribute to pathogenesis.
隐孢子虫是严重腹泻的主要病因。尽管隐孢子虫分离株在感染性和毒力方面表现出显著差异，但这些性状的遗传决定因素尚不清楚。在本研究中，我们运用经典遗传学方法，使两种不同毒力的微小隐孢子虫分离株杂交，并对后代的全基因组序列进行混合分组分析，以鉴定与隐孢子虫感染性和毒力相关的数量性状基因座（QTL）。在三个QTL中的23个基因中，有两个在低毒力分离株中存在功能丧失突变，包括编码一种可变分泌蛋白的SKSR1基因。删除SKSR1基因或表达移码序列会降低强毒株的致病性。SKSR1在小颗粒中表达，并在入侵过程中分泌到寄生虫-宿主界面。这些结果表明，SKSR1是隐孢子虫中的一个重要毒力因子，并提示由亚端粒基因簇编码的扩展SKSR蛋白家族可能与发病机制有关。
