SKSR1 identified as key virulence factor in Cryptosporidium by genetic crossing

Wei He, Lianbei Sun, Tianyi Hou, Zuwei Yang, Fuxian Yang, Shengchen Zhang, Tianpeng Wang, Xinran Wang, Na Li, Yaqiong Guo, L. David Sibley (), Yaoyu Feng () and Lihua Xiao ()
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Wei He: South China Agricultural University
Lianbei Sun: South China Agricultural University
Tianyi Hou: South China Agricultural University
Zuwei Yang: South China Agricultural University
Fuxian Yang: South China Agricultural University
Shengchen Zhang: South China Agricultural University
Tianpeng Wang: South China Agricultural University
Xinran Wang: South China Agricultural University
Na Li: South China Agricultural University
Yaqiong Guo: South China Agricultural University
L. David Sibley: Washington University School of Medicine
Yaoyu Feng: South China Agricultural University
Lihua Xiao: South China Agricultural University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-60088-7

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