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However, the precise molecular mechanisms underlying this process have yet to be elucidated. In this study, IFN\u2010\u03b3 knockout mice were infected with a virulent\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Cryptosporidium parvum<\/jats:italic>\n                    <\/jats:styled-content>\n                    IId isolate, and intestinal pathological changes and microvillus alterations were monitored throughout the infection. The results showed that\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>C. parvum<\/jats:italic>\n                    <\/jats:styled-content>\n                    invasion induced both intestinal and microvillus damage in the host. Ileum tissues were collected at the early, peak, and late stages of infection for transcriptome sequencing and analysis. Differential expression and enrichment analyses revealed significant downregulation of genes associated with microvilli, lipid metabolism, and fatty acid metabolism during the peak and late stages of infection. A gene co\u2010expression network constructed using the Pearson correlation coefficient further identified that two epithelial cell transcription factors,\n                    <jats:italic>HNF4\u03b1<\/jats:italic>\n                    and\n                    <jats:italic>HNF4\u03b3<\/jats:italic>\n                    , were downregulated after\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>C. parvum<\/jats:italic>\n                    <\/jats:styled-content>\n                    infection, along with multiple microvillus\u2010related genes showing at least a two\u2010fold decrease in expression, such as\n                    <jats:italic>Vil1<\/jats:italic>\n                    ,\n                    <jats:italic>Cdhr2<\/jats:italic>\n                    , and\n                    <jats:italic>Ush1c<\/jats:italic>\n                    . The role of HNF4\u03b1 in\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>C. parvum<\/jats:italic>\n                    <\/jats:styled-content>\n                    \u2010induced microvillus damage was validated in\u00a0vitro. Activation of HNF4\u03b1 using an agonist promoted\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>C. parvum<\/jats:italic>\n                    <\/jats:styled-content>\n                    growth in Caco\u20102 cells. These findings reveal that\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>C. parvum<\/jats:italic>\n                    <\/jats:styled-content>\n                    infection interferes with HNF4\u03b1 expression, leading to reduced expression of brush border and related genes and ultimately resulting in microvillus damage. This study provides new insights and directions for further research on the interaction between\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>C. parvum<\/jats:italic>\n                    <\/jats:styled-content>\n                    and the host. Elucidating this HNF4\u03b1 mediated mechanism not only deepens our understanding of host\u2013parasite interactions but also highlights potential therapeutic targets for alleviating\n                    <jats:italic>Cryptosporidium<\/jats:italic>\n                    \u2010induced intestinal injury.\n                  <\/jats:p>","DOI":"10.1096\/fj.202600309r","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T13:55:24Z","timestamp":1778594124000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Downregulation of\n                    <scp>HNF4\u03b1<\/scp>\n                    Mediates Microvillus Damage During\n                    <scp>\n                      <i>Cryptosporidium parvum<\/i>\n                    <\/scp>\n                    Infection"],"prefix":"10.1096","volume":"40","author":[{"given":"Chaowei","family":"Luo","sequence":"first","affiliation":[{"name":"State Key Laboratory of Animal Disease Control and Prevention, Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine South China Agricultural University  Guangzhou China"},{"name":"College of Agriculture and Biological Science Dali University  Dali China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhua","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Disease Control and Prevention, Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine South China Agricultural University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengchen","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Disease Control and Prevention, Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine South China Agricultural University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongping","family":"Tang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Disease Control and Prevention, Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine South China Agricultural University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9958-1295","authenticated-orcid":false,"given":"Yaqiong","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Disease Control and Prevention, Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine South China Agricultural University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Disease Control and Prevention, Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine South China Agricultural University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoyu","family":"Feng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Disease Control and Prevention, Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine South China Agricultural University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8532-2727","authenticated-orcid":false,"given":"Lihua","family":"Xiao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Disease Control and Prevention, Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine South China Agricultural University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8720-8979","authenticated-orcid":false,"given":"Rui","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Disease Control and Prevention, Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine South China Agricultural University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(19)30076-2"},{"key":"e_1_2_12_3_1","first-page":"691","article-title":"Global, Regional, and National Age\u2010Sex\u2010Specific Burden of Diarrhoeal Diseases, Their Risk Factors, and Aetiologies, 1990\u20102021, for 204 Countries and Territories: A Systematic Analysis for the Global Burden of Disease Study 2021","volume":"1473","author":"Collaborators G. 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