{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T19:58:06Z","timestamp":1784231886827,"version":"3.55.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,28]],"date-time":"2021-07-28T00:00:00Z","timestamp":1627430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003852","name":"Regione Campania","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003852","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Clinical features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection seem to differ in children compared to that in adults. It has been hypothesized that the lower clinical severity in children could be influenced by differential expression of the main host functional receptor to SARS-CoV-2, the angiotensin-converting enzyme 2 (ACE2), but data are still conflicting. To explore the origin of age-dependent clinical features of coronavirus disease 2019 (COVID-19), we comparatively evaluated the expression in children and adult subjects of the most relevant mediators of the SARS-CoV-2 infection: ACE2, angiotensin-converting enzyme 1 (ACE1), transmembrane serine protease-2 (TMPRSS2), and neuropilin-1 (NRP1), at upper respiratory tract and small intestine level.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> The expression of <jats:italic>ACE2, ACE1, TMPRSS2<\/jats:italic>, and <jats:italic>NRP1<\/jats:italic> in nasal epithelium and in small intestine epithelium was investigated by quantitative real-time PCR analysis.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> We found no differences in <jats:italic>ACE2, ACE1<\/jats:italic>, and <jats:italic>TMPRSS2<\/jats:italic> expression in the nasal epithelium comparing children and adult subjects. In contrast, nasal epithelium <jats:italic>NRP1<\/jats:italic> expression was lower in children compared to that in adults. Intestinal <jats:italic>ACE2<\/jats:italic> expression was higher in children compared to that in adults, whereas intestinal <jats:italic>ACE1<\/jats:italic> expression was higher in adults. Intestinal <jats:italic>TMPRSS2<\/jats:italic> and <jats:italic>NRP1<\/jats:italic> expression was similar comparing children and adult subjects.<\/jats:p><jats:p><jats:bold>Conclusions:<\/jats:bold> The lower severity of SARS-CoV-2 infection observed in children may be due to a different expression of nasal <jats:italic>NRP1<\/jats:italic>, that promotes the virus interaction with ACE2. However, the common findings of intestinal symptoms in children could be due to a higher expression of <jats:italic>ACE2<\/jats:italic> at this level. The insights from these data will be useful in determining the treatment policies and preventive measures for COVID-19.<\/jats:p>","DOI":"10.3389\/fped.2021.697390","type":"journal-article","created":{"date-parts":[[2021,7,28]],"date-time":"2021-07-28T12:05:49Z","timestamp":1627473949000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":29,"title":["Age-Related Differences in the Expression of Most Relevant Mediators of SARS-CoV-2 Infection in Human Respiratory and Gastrointestinal Tract"],"prefix":"10.3389","volume":"9","author":[{"given":"Roberto","family":"Berni Canani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marika","family":"Comegna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorella","family":"Paparo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo","family":"Cernera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Bruno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Strisciuglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Immacolata","family":"Zollo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonietta Gerarda","family":"Gravina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erasmo","family":"Miele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Cantone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Gennarelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Nocerino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Carucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Giglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felice","family":"Amato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Castaldo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"17846","DOI":"10.1038\/s41598-020-74913-0","article-title":"Gastrointestinal symptoms and fecal nucleic acid testing of children with 2019 coronavirus disease: a systematic review and meta-analysis","volume":"10","author":"Wang","year":"2020","journal-title":"Sci Rep."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e2011335","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":"Parasa","year":"2020","journal-title":"J Am Med Assoc Netw Open."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1892","DOI":"10.1002\/ppul.24885","article-title":"Clinical manifestations of children with COVID-19: a systematic review","volume":"55","author":"de Souza","year":"2020","journal-title":"Pediatr Pulmonol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1038\/s41390-020-1015-2","article-title":"Coronavirus disease 2019 (COVID-19) in children and\/or adolescents: a meta-analysis","volume":"89","author":"Mantovani","year":"2021","journal-title":"Pediatr Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1016\/j.arcped.2020.12.008","article-title":"COVID-19 infection in children: a systematic review and meta-analysis of clinical features and laboratory findings","volume":"28","author":"Mansourian","year":"2021","journal-title":"Arch Pediatr."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1002\/jmv.26398","article-title":"A systematic review and meta-analysis of children with coronavirus disease 2019 (COVID-19)","volume":"93","author":"Cui","year":"2020","journal-title":"J Med Virol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"431","DOI":"10.3389\/fped.2020.00431","article-title":"Clinical characteristics of children with COVID-19: a meta-analysis","volume":"8","author":"Ding","year":"2020","journal-title":"Front Pediatr."},{"key":"B8","doi-asserted-by":"publisher","first-page":"104715","DOI":"10.1016\/j.jcv.2020.104715","article-title":"Prevalence, clinical characteristics, and outcomes of pediatric COVID-19: a systematic review and meta-analysis","volume":"135","author":"Badal","year":"2021","journal-title":"J Clin Virol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"B10","doi-asserted-by":"publisher","first-page":"11727","DOI":"10.1073\/pnas.2003138117","article-title":"Cell entry mechanisms of SARS-CoV-2","volume":"117","author":"Shang","year":"2020","journal-title":"Proc Natl Acad Sci USA."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2427","DOI":"10.1001\/jama.2020.8707","article-title":"Nasal gene expression of angiotensin-converting enzyme 2 in children and adults","volume":"323","author":"Bunyavanich","year":"2020","journal-title":"J Am Med Assoc."},{"key":"B12","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1101\/2020.05.21.109124","article-title":"Intestinal inflammation modulates the expression of ACE2 and TMPRSS2 and potentially overlaps with the pathogenesis of SARS-CoV-2-related disease","volume":"160","author":"Su\u00e1rez-Fari\u00f1as","year":"2021","journal-title":"Gastroenterology"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.omtm.2020.05.013","article-title":"Airways expression of SARS-CoV-2 receptor, ACE2, and TMPRSS2 is lower in children than adults and increases with smoking and COPD","volume":"18","author":"Saheb","year":"2020","journal-title":"Mol Ther Methods Clin Dev."},{"key":"B14","doi-asserted-by":"publisher","first-page":"20143085","DOI":"10.1098\/rspb.2014.3085","article-title":"Evolution of the immune system in humans from infancy to old age","volume":"282","author":"Simon","year":"2015","journal-title":"Proc Biol Sci."},{"key":"B15","first-page":"264","article-title":"Clinico-pathogenesis of COVID-19 in children","volume":"57","author":"Pandit","year":"2020","journal-title":"Indian J Biochem Biophys"},{"key":"B16","doi-asserted-by":"publisher","first-page":"379","DOI":"10.3390\/pathogens10030379","article-title":"The impact of angiotensin-converting enzyme 2 (ACE2) expression on the incidence and severity of COVID-19 infection","volume":"10","author":"Kaseb","year":"2021","journal-title":"Pathogens."},{"key":"B17","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1126\/science.abd2985","article-title":"Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity","volume":"370","author":"Cantuti-Castelvetri","year":"2020","journal-title":"Science."},{"key":"B18","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1126\/science.abd3072","article-title":"Neuropilin-1 is a host factor for SARS-CoV-2 infection","volume":"370","author":"Daly","year":"2020","journal-title":"Science."},{"key":"B19","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.ando.2020.04.005","article-title":"'Drugs, COVID-19' working group of the French Society of Pharmacology, Therapeutics. Renin-angiotensin-aldosterone system and COVID-19 infection","volume":"81","author":"Alexandre","year":"2020","journal-title":"Ann Endocrinol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"4825","DOI":"10.1111\/bph.15082","article-title":"Hypothesis for pathobiology and treatment of COVID-19: the centrality of ACE1\/ACE2 imbalance","volume":"177","author":"Sriram","year":"2020","journal-title":"Br J Pharmacol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2465","DOI":"10.3201\/eid2610.201315","article-title":"COVID-19 National Emergency Response Center, Epidemiology and Case Management Team. Contact tracing during coronavirus disease outbreak, South Korea, 2020","volume":"26","author":"Park","year":"2020","journal-title":"Emerg Infect Dis"},{"key":"B22","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1136\/archdischild-2020-319910","article-title":"Role of children in household transmission of COVID-19","volume":"106","author":"Kim","year":"2020","journal-title":"Arch Dis Child"},{"key":"B23","doi-asserted-by":"publisher","first-page":"011101","DOI":"10.7189\/jogh.10.011101","article-title":"The role of children in transmission of SARS-CoV-2: a rapid review","volume":"10","author":"Li","year":"2020","journal-title":"J Glob Health."},{"key":"B24","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1001\/jamapediatrics.2020.4573","article-title":"Mytton, OT; Bonell C, Melendez-Torres GJ, Ward J, Hudson L, et al. Susceptibility to SARS-CoV-2 infection among children and adolescents compared with adults: a systematic review and meta-analysis","volume":"175","author":"Viner","year":"2021","journal-title":"J Am Med Assoc Pediatr."},{"key":"B25","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real time quantitative PCR and the 2 (-Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e13168","DOI":"10.1111\/acel.13168","article-title":"Individual variation of the SARS-CoV-2 receptor ACE2 gene expression and regulation","volume":"19","author":"Chen","year":"2020","journal-title":"Aging Cell."},{"key":"B27","doi-asserted-by":"publisher","first-page":"321334","DOI":"10.1136\/archdischild-2020-321334","article-title":"Nasal expression of SARS-CoV-2 entry receptors in newborns","volume":"2020","author":"Heinonen","year":"2021","journal-title":"Archiv Dis Childh"},{"key":"B28","doi-asserted-by":"publisher","first-page":"2166","DOI":"10.1016\/j.lfs.2005.09.038","article-title":"Age- and gender-related difference of ACE2 expression in rat lung","volume":"78","author":"Xie","year":"2006","journal-title":"Life Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"6731093","DOI":"10.1155\/2016\/6731093","article-title":"Age-associated changes in the vascular renin-angiotensin system in mice","volume":"2016","author":"Yoon","year":"2016","journal-title":"Oxid Med Cell Longev."},{"key":"B30","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1038\/s41368-020-0074-x","article-title":"High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa","volume":"12","author":"Xu","year":"2020","journal-title":"Int J Oral Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/s40249-020-00662-x","article-title":"Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues","volume":"9","author":"Li","year":"2020","journal-title":"Infect Dis Poverty."},{"key":"B32","doi-asserted-by":"publisher","first-page":"640073","DOI":"10.3389\/fmed.2021.640073","article-title":"New insights into the physiopathology of COVID-19: SARS-CoV-2-associated gastrointestinal illness","volume":"8","author":"Devaux","year":"2021","journal-title":"Front Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"116537","DOI":"10.1016\/j.molliq.2021.116537","article-title":"Molecular basis of the new COVID-19 target neuropilin-1 in complex with SARS-CoV-2 S1 C-end rule peptide and small-molecule antagonists","volume":"335","author":"Klaewkla","year":"2021","journal-title":"J Mol Liq"},{"key":"B34","doi-asserted-by":"publisher","first-page":"e105114","DOI":"10.15252\/embj.2020105114","article-title":"SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells","volume":"39","author":"Lukassen","year":"2020","journal-title":"EMBO J."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e317","DOI":"10.1097\/INF.0000000000002843","article-title":"COVID-19 Pediatric network. Gastrointestinal symptoms in severe COVID-19 children","volume":"39","author":"Giacomet","year":"2020","journal-title":"Pediatr Infect Dis J."},{"key":"B36","doi-asserted-by":"publisher","first-page":"118075","DOI":"10.1016\/j.lfs.2020.118075","article-title":"The dual impact of ACE2 in COVID-19 and ironical actions in geriatrics and pediatrics with possible therapeutic solutions","volume":"257","author":"Behl","year":"2020","journal-title":"Life Sci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"24620","DOI":"10.1073\/pnas.2012358117","article-title":"Reduced development of COVID-19 in children reveals molecular checkpoints gating pathogenesis illuminating potential therapeutics","volume":"117","author":"Steinman","year":"2020","journal-title":"Proc Natl Acad Sci USA."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1001\/jamapediatrics.2020.1467","article-title":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents a systematic review","volume":"2","author":"Castagnoli","year":"2020","journal-title":"J Am Med Assoc Pediatr."},{"key":"B39","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s13601-020-00362-7","article-title":"Nrf2-interacting nutrients and COVID-19: time for research to develop adaptation strategies","volume":"10","author":"Bousquet","year":"2020","journal-title":"Clin Transl Allergy."},{"key":"B40","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41586-020-03065-y","article-title":"Genetic mechanisms of critical illness in COVID-19","volume":"591","author":"Pairo-Castineira","year":"2021","journal-title":"Nature."},{"key":"B41","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1136\/gutjnl-2020-323020","article-title":"Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19","volume":"70","author":"Yeoh","year":"2021","journal-title":"Gut."}],"updated-by":[{"DOI":"10.3389\/fped.2021.790285","type":"corrigendum","label":"Corrigendum","source":"publisher","updated":{"date-parts":[[2021,11,10]],"date-time":"2021-11-10T00:00:00Z","timestamp":1636502400000}}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2021.697390\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,10]],"date-time":"2021-11-10T13:12:13Z","timestamp":1636549933000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2021.697390\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,28]]},"references-count":41,"alternative-id":["10.3389\/fped.2021.697390"],"URL":"https:\/\/doi.org\/10.3389\/fped.2021.697390","relation":{"corrigendum":[{"id-type":"doi","id":"10.3389\/fped.2021.790285","asserted-by":"object"}]},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,28]]},"article-number":"697390"}}