{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T18:27:45Z","timestamp":1786559265042,"version":"build-2736575974"},"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007830","name":"Kitasato University","doi-asserted-by":"publisher","award":["COVID-19 All Kitasato Project"],"award-info":[{"award-number":["COVID-19 All Kitasato Project"]}],"id":[{"id":"10.13039\/501100007830","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is frequently associated with gastrointestinal manifestations; however, intestinal immune responses following SARS-CoV-2 infection remain incompletely understood. This study aimed to characterize eosinophil-associated intestinal immune responses in SARS-CoV-2-infected\n                      <jats:italic>K18-hACE2<\/jats:italic>\n                      transgenic mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Small intestinal tissues from infected mice were analyzed using cytokine and chemokine PCR arrays, qRT-PCR, immunohistochemistry, and histological analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SARS-CoV-2 infection was associated with marked upregulation of\n                      <jats:italic>Il5<\/jats:italic>\n                      mRNA in small intestinal tissues, along with increased expression of eosinophil-related cytokines and chemokines, including\n                      <jats:italic>Ccl24<\/jats:italic>\n                      and\n                      <jats:italic>Ccl11<\/jats:italic>\n                      . Immunohistochemical analyses showed eosinophil accumulation in the lamina propria, accompanied by increased signals for eosinophil-associated granule proteins, including major basic protein and eosinophil peroxidase. Additional qRT-PCR analyses showed increased expression of\n                      <jats:italic>Prg2<\/jats:italic>\n                      and\n                      <jats:italic>Epx<\/jats:italic>\n                      , further supporting eosinophil granule protein-associated responses. Charcot-Leyden crystals and increased\n                      <jats:italic>Galectin-10<\/jats:italic>\n                      expression were also observed. Temporal analyses showed an acute\n                      <jats:italic>Il5<\/jats:italic>\n                      \/\n                      <jats:italic>Ccl24<\/jats:italic>\n                      -related response followed by delayed\n                      <jats:italic>Ccl11<\/jats:italic>\n                      upregulation during later stages.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These findings indicate that SARS-CoV-2 infection is associated with eosinophil-associated intestinal immune responses in\n                      <jats:italic>K18-hACE2<\/jats:italic>\n                      mice. Although eosinophil activation or intestinal allergy was not directly demonstrated, this study supports virus-associated eosinophil-related intestinal responses as a possible framework for understanding allergy-like intestinal immune alterations during SARS-CoV-2 infection.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0355607","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T17:32:23Z","timestamp":1786555943000},"page":"e0355607","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Eosinophil-associated intestinal immune responses following SARS-CoV-2 infection in K18-hACE2 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and the digestive system: A comprehensive review","volume":"9","author":"M-K Wang","year":"2021","journal-title":"World J Clin Cases"},{"issue":"6","key":"pone.0355607.ref002","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2020.11335","article-title":"Prevalence of Gastrointestinal Symptoms and Fecal Viral Shedding in Patients With Coronavirus Disease 2019: A Systematic Review and Meta-analysis","volume":"3","author":"S Parasa","year":"2020","journal-title":"JAMA Netw Open"},{"issue":"1","key":"pone.0355607.ref003","doi-asserted-by":"crossref","first-page":"147","DOI":"10.14309\/ajg.0000000000001541","article-title":"Prevalence of Gastrointestinal Symptoms in Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Results of the Prospective Controlled Multinational GI-COVID-19 Study","volume":"117","author":"G Marasco","year":"2022","journal-title":"Am J 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