{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:25:44Z","timestamp":1791919544062,"version":"4.3.4"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,6]],"date-time":"2021-05-06T00:00:00Z","timestamp":1620259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Although millions of patients with underlining\u00a0conditions are treated primarily with anti-TNF-\u03b1 agents, little is known about the safety of this standard therapy during the coronavirus disease-2019 (COVID-19) pandemic. In this study, we investigated the effect of anti-TNF-\u03b1 monoclonal antibodies on the cellular entry mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and increasing the risk of\u00a0COVID-19 development. We focused on the expression of angiotensin-converting enzyme II (ACE2),\u00a0type II transmembrane serine proteases (TMPRSS2)\/TNF-\u03b1 converting enzyme (TACE) ratio. We also\u00a0investigated the involvement of Notch-1 signaling and its downstream influence on IL-6, myeloid cell leukemia sequence-1(MCL-1) in the anti-TNF-\u03b1 mode of action and increased the susceptibility to <jats:italic>Mycobacterium avium subspecies paratuberculosis<\/jats:italic>\u00a0(MAP) infection. Surprisingly, anti-TNF-\u03b1 downregulated ACE2 expression by 0.46-fold and increased TMPRSS2\/TACE ratio by 44% in THP-1 macrophages. Treatment of macrophages with rIL-6 also downregulated ACE2 and increased TMPRSS2\/TACE ratio by 54%.\u00a0Interestingly, anti-TNF-\u03b1 treatment upregulated Notch-1, IL-6, and MCL-1 by 1.3, 1.2, and 1.9-fold, respectively, and increased viability and burden of MAP infection in macrophages. Blocking Notch signaling doubled ACE2 expression, decreased TMPRSS2\/TACE ratio by 38%, and\u00a0reduced MAP viability by 56%. In a small group of patients, ACE2 level was significantly lower in the plasma from rheumatoid arthritis (RA) patients on anti-TNF-\u03b1 treatment compared to healthy control. The data in this critical study demonstrated that through Notch-1\/IL-6 signaling, anti-TNF-\u03b1 agents decreased ACE2 expression and shedding through TMPRSS2\/TACE modulation and increased the susceptibility to infection. Overall, this study warns against anti-TNF-\u03b1 therapy in some patients with underlining inflammatory conditions during the COVID-19 pandemic.\u00a0The findings should impact current guidelines regarding treatment decisions of patients on anti-TNF-\u03b1 during the COVID-19 pandemic.<\/jats:p>","DOI":"10.3389\/fimmu.2021.641295","type":"journal-article","created":{"date-parts":[[2021,5,6]],"date-time":"2021-05-06T05:50:33Z","timestamp":1620280233000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":29,"title":["Anti-TNF-\u03b1 agents Modulate SARS-CoV-2 Receptors and Increase the Risk of Infection Through Notch-1 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