SKSR1 identified as key virulence factor in Cryptosporidium by genetic crossing

SKSR1 identified as key virulence factor in Cryptosporidium by genetic crossing | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article SKSR1 identified as key virulence factor in Cryptosporidium by genetic crossing Lihua Xiao, Wei He, Lianbei Sun, Tianyi Hou, Zuiwei Yang, Fuxian Yang, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3993483/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 May, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version 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 used classical genetics to cross two Cryptosporidium parvum isolates of different virulence and used bulked segregant analysis of whole-genome sequence data from the progeny to identify quantitative trait loci (QTL) associated with Cryptosporidium infectivity and virulence. Of the 26 genes in three QTL, two had loss-of-function mutations in the low-virulence isolates. Deletion of the SKSR1 gene or expression of the frame-shift mutant sequence reduced the pathogenicity of infection in vivo . SKSR1 is a polymorphic secretory protein expressed in small granules, secreted into the parasite-host interface, and may cooperate with other secretory proteins in pathogenesis. These results demonstrate that SKSR1 is an important virulence factor in Cryptosporidium , and suggest that the extended SKSR protein family, encoded by variant subtelomeric genes, may contribute to pathogenesis. Biological sciences/Microbiology/Parasitology/Parasite biology Biological sciences/Microbiology/Parasitology/Parasite genetics Cryptosporidium genetic cross linkage mapping bulked segregant analysis virulence factor SKSR1 Full Text Additional Declarations There is NO Competing Interest. Supplementary Files CryGeneticCrossBSASFigure20230227.pdf Supplementary figures CryGeneticCrossBSAStable120240227.pdf Supplementary table1 CryGeneticCrossBSAStable220240227.pdf Supplementary table2 Cite Share Download PDF Status: Published Journal Publication published 20 May, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3993483","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":275470407,"identity":"349abc9c-0b2f-4f60-825f-9364b116a224","order_by":0,"name":"Lihua Xiao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxElEQVRIiWNgGAWjYBACPgbGBgaGCiiPhxgtbGAtZ0jTAgSMbSRpkUhu/PBxXp08/4wExgdv2xjkzQlq4TnYLDlz22HDGTcSmA3ntjEY7mwgpIW9sUGad9uBBIYbCWzSvG0MCQYHCGlhZmz+zTunLkH+RgL7b+K0sDe2SfM2MCcYAG1hJk4Lz8E2yxnHDhtuPPOwWXLOOQnDDYS08EukP77xoaZOXu548sEPb8ps5AnaggRAccogQbz6UTAKRsEoGAW4AQDaOTq2M5EQRQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-8532-2727","institution":"South China Agricultural University","correspondingAuthor":true,"prefix":"","firstName":"Lihua","middleName":"","lastName":"Xiao","suffix":""},{"id":275470408,"identity":"3a5a7356-aeed-4fe1-b13c-61e7f718ae5a","order_by":1,"name":"Wei He","email":"","orcid":"","institution":"South China Agricultural University","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"He","suffix":""},{"id":275470409,"identity":"6074df6c-dc44-4ce3-a55f-e7bd66c4b2de","order_by":2,"name":"Lianbei Sun","email":"","orcid":"","institution":"South China Agricultural University","correspondingAuthor":false,"prefix":"","firstName":"Lianbei","middleName":"","lastName":"Sun","suffix":""},{"id":275470410,"identity":"62beec3a-8d31-4e0a-97ec-00053febbd60","order_by":3,"name":"Tianyi Hou","email":"","orcid":"","institution":"South China Agricultural University","correspondingAuthor":false,"prefix":"","firstName":"Tianyi","middleName":"","lastName":"Hou","suffix":""},{"id":275470411,"identity":"615f36fe-18f7-427a-9583-090f9a55408e","order_by":4,"name":"Zuiwei Yang","email":"","orcid":"","institution":"South China Agricultural University","correspondingAuthor":false,"prefix":"","firstName":"Zuiwei","middleName":"","lastName":"Yang","suffix":""},{"id":275470412,"identity":"5cbb6fb0-0e22-4ce3-a084-ca2d8fe2fbcc","order_by":5,"name":"Fuxian Yang","email":"","orcid":"","institution":"South China Agricultural University","correspondingAuthor":false,"prefix":"","firstName":"Fuxian","middleName":"","lastName":"Yang","suffix":""},{"id":275470413,"identity":"7c435cc3-0bea-42e8-b147-a56dcbb8762b","order_by":6,"name":"Shengchen Zhang","email":"","orcid":"","institution":"South China Agricultural University","correspondingAuthor":false,"prefix":"","firstName":"Shengchen","middleName":"","lastName":"Zhang","suffix":""},{"id":275470414,"identity":"ce988b80-c9d0-4f96-93aa-b065dcd162ea","order_by":7,"name":"Tianpeng Wang","email":"","orcid":"","institution":"South China Agricultural University","correspondingAuthor":false,"prefix":"","firstName":"Tianpeng","middleName":"","lastName":"Wang","suffix":""},{"id":275470415,"identity":"f8cf0d59-218e-4311-9298-1caeb932ef2d","order_by":8,"name":"Na Li","email":"","orcid":"","institution":"South China Agricultural University","correspondingAuthor":false,"prefix":"","firstName":"Na","middleName":"","lastName":"Li","suffix":""},{"id":275470416,"identity":"025ea119-744b-4c40-8f03-35aa07f2a130","order_by":9,"name":"Yaqiong Guo","email":"","orcid":"","institution":"South China Agricultural University","correspondingAuthor":false,"prefix":"","firstName":"Yaqiong","middleName":"","lastName":"Guo","suffix":""},{"id":275470417,"identity":"cd1dfd85-c8c6-4a40-b82c-5a663e3b75ab","order_by":10,"name":"L. 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Although \u003cem\u003eCryptosporidium \u003c/em\u003eisolates exhibit significant differences in infectivity and virulence, the genetic determinants for these traits are not clear. In this study, we used classical genetics to cross two \u003cem\u003eCryptosporidium parvum\u003c/em\u003e isolates of different virulence and used bulked segregant analysis of whole-genome sequence data from the progeny to identify quantitative trait loci (QTL) associated with \u003cem\u003eCryptosporidium \u003c/em\u003einfectivity and virulence. Of the 26 genes in three QTL, two had loss-of-function mutations in the low-virulence isolates. Deletion of the \u003cem\u003eSKSR1 \u003c/em\u003egene or expression of the frame-shift mutant sequence reduced the pathogenicity of infection \u003cem\u003ein vivo\u003c/em\u003e. SKSR1 is a polymorphic secretory protein expressed in small granules, secreted into the parasite-host interface, and may cooperate with other secretory proteins in pathogenesis. These results demonstrate that SKSR1 is an important virulence factor in \u003cem\u003eCryptosporidium\u003c/em\u003e, and suggest that the extended SKSR protein family, encoded by variant subtelomeric genes, may contribute to pathogenesis.\u003c/p\u003e","manuscriptTitle":"SKSR1 identified as key virulence factor in Cryptosporidium by genetic crossing","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-01 11:03:56","doi":"10.21203/rs.3.rs-3993483/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"9c183203-2343-4f3e-8e82-c9cb09f6779c","owner":[],"postedDate":"March 1st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":29039389,"name":"Biological sciences/Microbiology/Parasitology/Parasite biology"},{"id":29039390,"name":"Biological sciences/Microbiology/Parasitology/Parasite genetics"}],"tags":[],"updatedAt":"2025-05-21T07:07:53+00:00","versionOfRecord":{"articleIdentity":"rs-3993483","link":"https://doi.org/10.1038/s41467-025-60088-7","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2025-05-20 04:00:00","publishedOnDateReadable":"May 20th, 2025"},"versionCreatedAt":"2024-03-01 11:03:56","video":"","vorDoi":"10.1038/s41467-025-60088-7","vorDoiUrl":"https://doi.org/10.1038/s41467-025-60088-7","workflowStages":[]},"version":"v1","identity":"rs-3993483","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3993483","identity":"rs-3993483","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}