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As rate\u2010limiting steps for virus entry, modulation of ACE2 and\/or TMPRSS2 may decrease SARS\u2010CoV\u20102 infectivity and COVID\u201019 severity. In silico modeling suggested the natural bioactive flavonoid quercetin can bind to ACE2 and a recent randomized clinical trial demonstrated that oral supplementation with quercetin increased COVID\u201019 recovery. A range of cultured human cells were assessed for co\u2010expression of ACE2 and TMPRSS2. Immortalized Calu\u20103 lung cells, cultured and matured at an air\u2013liquid interface (Calu\u20103\u2010ALIs), were established as the most appropriate. Primary bronchial epithelial cells (PBECs) were obtained from healthy adult males (\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u20096) and cultured under submerged conditions to corroborate the outcomes. Upon maturation or reaching 80% confluence, respectively, the Calu\u20103\u2010ALIs and PBECs were treated with quercetin, and mRNA and protein expression were assessed by droplet digital PCR and ELISA, respectively. SARS\u2010CoV\u20102 infectivity, and the effects of pre\u2010 and co\u2010treatment with quercetin, was assessed by median tissue culture infectious dose assay. Quercetin dose\u2010dependently decreased ACE2 and TMPRSS2 mRNA and protein in both Calu\u20103\u2010ALIs and PBECs after 4\u2009h, while TMPRSS2 remained suppressed in response to prolonged treatment with lower doses (twice daily for 3\u2009days). Quercetin also acutely decreased ADAM17 mRNA, but not ACE, in Calu\u20103\u2010ALIs, and this warrants further investigation. Calu\u20103\u2010ALIs, but not PBECs, were successfully infected with SARS\u2010CoV\u20102; however, quercetin had no antiviral effect, neither directly nor indirectly through downregulation of ACE2 and TMPRSS2. Calu\u20103\u2010ALIs were reaffirmed to be an optimal cell model for research into the regulation of ACE2 and TMPRSS2, without the need for prior genetic modification, and will prove valuable in future coronavirus and respiratory infectious disease work. However, our data demonstrate that a significant decrease in the expression of ACE2 and TMPRSS2 by a promising prophylactic candidate may not translate to infection prevention.\n                  <\/jats:p>","DOI":"10.1002\/biof.2084","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T00:54:08Z","timestamp":1718672048000},"page":"1268-1286","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The flavonoid quercetin decreases\n                    <scp>ACE2<\/scp>\n                    and\n                    <scp>TMPRSS2<\/scp>\n                    expression but not\n                    <scp>SARS\u2010CoV<\/scp>\n                    \u20102 infection in cultured human lung cells"],"prefix":"10.1002","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6579-7995","authenticated-orcid":false,"given":"Michael James","family":"Houghton","sequence":"first","affiliation":[{"name":"Department of Nutrition, Dietetics and Food Monash University, BASE Facility  Notting Hill VIC Australia"},{"name":"Victorian Heart Institute Monash University, Victorian Heart Hospital  Clayton VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eglantine","family":"Balland","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Dietetics and Food Monash University, BASE Facility  Notting Hill VIC Australia"},{"name":"Monash Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology Monash University  Clayton VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew James","family":"Gartner","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology University of Melbourne at The Peter Doherty Institute for Infection and Immunity  Melbourne VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belinda Jane","family":"Thomas","sequence":"additional","affiliation":[{"name":"Centre for Innate Immunity and Infectious Diseases Hudson Institute of Medical Research  Clayton VIC Australia"},{"name":"Monash Lung and Sleep, Monash Health, Monash Medical Centre  Clayton VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanta","family":"Subbarao","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology University of Melbourne at The Peter Doherty Institute for Infection and Immunity  Melbourne VIC Australia"},{"name":"WHO Collaborating Centre for Reference and Research on Influenza The Peter Doherty Institute for Infection and Immunity  Melbourne VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Williamson","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Dietetics and Food Monash 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