{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T23:33:01Z","timestamp":1782516781361,"version":"3.54.5"},"reference-count":17,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T00:00:00Z","timestamp":1635120000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T00:00:00Z","timestamp":1635120000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Inflammation"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>\n                    <jats:italic>Abstract<\/jats:italic>\n                    \u2014\n                  <\/jats:title>\n                  <jats:p>The coronavirus SARS-CoV-2 contributes to morbidity and mortality mainly as a result of immune-pathology in the lungs. Recent data has shown multi-system involvement with widespread viral tropism. Here we present a detailed intestinal protein characterisation of SARS-Cov-2 entry molecules ACE2 and TMPRSS2 in patients with inflammatory bowel disease ([IBD]; ulcerative colitis [UC] and Crohn\u2019s disease [CD]) with age- and sex-matched non-IBD controls, and in those with fatal COVID-19 infection.\u00a0In our dataset, ACE2 and TMPRSS2 displayed a membrane enterocyte staining in the ileum (due to presence of brush border\/microvilli) in contrast to a cytoplasmic pattern in the colon. We also showed a high ACE2\/low TMPRSS2 expression pattern in the ileum with a reverse trend in the colon. In UC, colonic ACE2 and TMPRSS2 are cytoplasmic in nature, with significantly higher ACE2 staining intensity compared to non-IBD controls. In inflamed and unaffected IBD mucosa, ileal and colonic enterocyte ACE2 and TMPRSS2 expressions are not modified in the histologic presence of inflammation. We observed immune cells within the lamina propria that expressed ACE2 and TMPRSS2, at higher frequencies in IBD when compared to non-IBD controls. These were identified as plasma cells with multiple myeloma oncogene 1\/interferon regulatory factor 4 (MUM1\/IRF4) expression. We further analysed the gut histology of six fatal COVID-19 cases, with no difference in colonic and ileal ACE2\/TMRPSS2 staining (compared to non-IBD controls) and identified ACE2\u2009+\u2009lamina propria plasma cells. Of interest, in this COVID-19 cohort, there was no histologic evidence gut inflammation despite known evidence of viral tropism within the enterocytes. Our data provides evidence for tissue expression of entry molecules ACE2 and TMPRSS2 including a close apposition to plasma cells \u2014 both pointing towards a role of the gut in the antecedent immune response to SARS-CoV-2 infection.<\/jats:p>","DOI":"10.1007\/s10753-021-01567-z","type":"journal-article","created":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T17:02:27Z","timestamp":1635181347000},"page":"567-572","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Intestinal Protein Characterisation of SARS-CoV-2 Entry Molecules ACE2 and TMPRSS2 in Inflammatory Bowel Disease (IBD) and Fatal COVID-19 Infection"],"prefix":"10.1007","volume":"45","author":[{"given":"Milly J.","family":"McAllister","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Kirkwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaun C.","family":"Chuah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily J.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A.","family":"Cartwright","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clark D.","family":"Russell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Dorward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher D.","family":"Lucas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6014-372X","authenticated-orcid":false,"given":"Gwo-tzer","family":"Ho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,25]]},"reference":[{"key":"1567_CR1","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","volume":"181","author":"M Hoffmann","year":"2020","unstructured":"Hoffmann, M., et al. 2020. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181: 271-280.e278.","journal-title":"Cell"},{"key":"1567_CR2","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1164\/rccm.202008-3265OC","volume":"203","author":"DA Dorward","year":"2021","unstructured":"Dorward, D.A., et al. 2021. Tissue-specific immunopathology in fatal COVID-19. American Journal of Respiratory and Critical Care Medicine 203: 192\u2013201.","journal-title":"American Journal of Respiratory and Critical Care Medicine"},{"key":"1567_CR3","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1136\/gutjnl-2020-320953","volume":"69","author":"H Zhang","year":"2020","unstructured":"Zhang, H., et al. 2020. Digestive system is a potential route of COVID-19: An analysis of single-cell coexpression pattern of key proteins in viral entry process. Gut 69: 1010\u20131018.","journal-title":"Gut"},{"key":"1567_CR4","doi-asserted-by":"crossref","unstructured":"Guo, M., W. Tao, R.A. Flavell, and S. Zhu. 2021. Potential intestinal infection and faecal-oral transmission of SARS-CoV-2.\u00a0Nature Reviews Gastroenterology & Hepatology 18: 269\u2013283.","DOI":"10.1038\/s41575-021-00416-6"},{"key":"1567_CR5","doi-asserted-by":"publisher","first-page":"1398","DOI":"10.1136\/gut.2008.148395","volume":"57","author":"CL Noble","year":"2008","unstructured":"Noble, C.L., et al. 2008. Regional variation in gene expression in the healthy colon is dysregulated in ulcerative colitis. Gut 57: 1398\u20131405.","journal-title":"Gut"},{"key":"1567_CR6","doi-asserted-by":"publisher","first-page":"1151.e1152","DOI":"10.1053\/j.gastro.2020.05.030","volume":"159","author":"JK Nowak","year":"2020","unstructured":"Nowak, J.K., et al. 2020. Age, inflammation, and disease location are critical determinants of intestinal expression of SARS-CoV-2 receptor ACE2 and TMPRSS2 in inflammatory bowel disease. Gastroenterology 159: 1151.e1152-1154.e1152.","journal-title":"Gastroenterology"},{"key":"1567_CR7","doi-asserted-by":"publisher","first-page":"287.e220","DOI":"10.1053\/j.gastro.2020.09.029","volume":"160","author":"M Suarez-Farinas","year":"2021","unstructured":"Suarez-Farinas, M., et al. 2021. Intestinal inflammation modulates the expression of ACE2 and TMPRSS2 and potentially overlaps with the pathogenesis of SARS-CoV-2-related disease. Gastroenterology 160: 287.e220-301.e220.","journal-title":"Gastroenterology"},{"key":"1567_CR8","first-page":"591","volume":"33","author":"M Gajendran","year":"2020","unstructured":"Gajendran, M., et al. 2020. Inflammatory bowel disease amid the COVID-19 pandemic: Impact, management strategies, and lessons learned. Annals of Gastroenterology 33: 591\u2013602.","journal-title":"Annals of Gastroenterology"},{"key":"1567_CR9","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1093\/ibd\/izaa085","volume":"26","author":"JF Burgueno","year":"2020","unstructured":"Burgueno, J.F., et al. 2020. Expression of SARS-CoV-2 entry molecules ACE2 and TMPRSS2 in the gut of patients with IBD. Inflammatory Bowel Diseases 26: 797\u2013808.","journal-title":"Inflammatory Bowel Diseases"},{"key":"1567_CR10","doi-asserted-by":"crossref","unstructured":"Verstockt, B., et al. 2020\u00a0Intestinal receptor of SARS-CoV-2 in inflamed IBD tissue seems downregulated by HNF4A in ileum and upregulated by interferon regulating factors in colon. Journal of Crohn's and Colitis\u00a015: 485\u2013498.","DOI":"10.1093\/ecco-jcc\/jjaa185"},{"key":"1567_CR11","doi-asserted-by":"publisher","first-page":"809.e807","DOI":"10.1053\/j.gastro.2020.10.041","volume":"160","author":"AA Potdar","year":"2021","unstructured":"Potdar, A.A., et al. 2021. Altered intestinal ACE2 levels are associated with inflammation, severe disease, and response to anti-cytokine therapy in inflammatory bowel disease. Gastroenterology 160: 809.e807-822.e807.","journal-title":"Gastroenterology"},{"key":"1567_CR12","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1002\/path.1570","volume":"203","author":"I Hamming","year":"2004","unstructured":"Hamming, I., et al. 2004. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 203: 631\u2013637.","journal-title":"J Pathol"},{"key":"1567_CR13","doi-asserted-by":"publisher","first-page":"e9610","DOI":"10.15252\/msb.20209610","volume":"16","author":"F Hikmet","year":"2020","unstructured":"Hikmet, F., et al. 2020. The protein expression profile of ACE2 in human tissues. Mol Syst Biol 16: e9610.","journal-title":"Mol Syst Biol"},{"key":"1567_CR14","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1053\/j.gastro.2020.07.067","volume":"160","author":"JM Penninger","year":"2021","unstructured":"Penninger, J.M., M.B. Grant, and J.J.Y. Sung. 2021. The role of angiotensin converting enzyme 2 in modulating gut microbiota, intestinal inflammation, and coronavirus infection. Gastroenterology 160: 39\u201346.","journal-title":"Gastroenterology"},{"key":"1567_CR15","doi-asserted-by":"crossref","unstructured":"Gaebler, C., et al. (2021) Evolution of antibody immunity to SARS-CoV-2. Nature 591: 639\u2013644.","DOI":"10.1038\/s41586-021-03207-w"},{"key":"1567_CR16","doi-asserted-by":"publisher","first-page":"1296.e1299","DOI":"10.1016\/j.immuni.2020.11.017","volume":"53","author":"JP Bernardes","year":"2020","unstructured":"Bernardes, J.P., et al. 2020. Longitudinal multi-omics analyses identify responses of megakaryocytes, erythroid cells, and plasmablasts as hallmarks of severe COVID-19. Immunity 53: 1296.e1299-1314.e1299.","journal-title":"Immunity"},{"key":"1567_CR17","doi-asserted-by":"crossref","unstructured":"Sterlin, D., et al. (2021) IgA dominates the early neutralizing antibody response to SARS-CoV-2.\u00a0Science Translational Medicine 13.","DOI":"10.1126\/scitranslmed.abd2223"}],"container-title":["Inflammation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10753-021-01567-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10753-021-01567-z\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10753-021-01567-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T02:17:02Z","timestamp":1648174622000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10753-021-01567-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,25]]},"references-count":17,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,4]]}},"alternative-id":["1567"],"URL":"https:\/\/doi.org\/10.1007\/s10753-021-01567-z","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-495949\/v1","asserted-by":"object"}]},"ISSN":["0360-3997","1573-2576"],"issn-type":[{"value":"0360-3997","type":"print"},{"value":"1573-2576","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,25]]},"assertion":[{"value":"7 May 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 August 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 September 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 October 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"DECLARATIONS"}},{"value":"East of Scotland Research Ethical Approval No 20\/ES\/0061 and No 16\/ES\/0084.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical Approval"}},{"value":"All human subjects have consented via ethical approvals above.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"All human subjects have consented for publication of research data via ethical approvals above.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}