Mesalamine Reduces Intestinal ACE2 Expression Without Modifying SARS-CoV-2 Infection or Disease Severity in Mice

• DOI: 10.1101/2021.07.23.453393
• Publication Date: 2021-07-24T03:35:17Z
• Authors: David M. Alvarado; Juhee Son; Larissa B. Thackray; Michael S. Diamond; Siyuan Ding; Matthew A. Ciorba
• Keywords: Coronavirus; TMPRSS2

Abstract Introduction Coronavirus Disease 2019 (COVID-19) is an ongoing public health crisis that has sickened or precipitated death in millions. The etiologic agent of COVID-19, Severe Acute Respiratory Syndrome 2 (SARS-CoV-2), infects the intestinal epithelium, and can induce GI symptoms similar to human inflammatory bowel diseases (IBD). An international surveillance epidemiology study (SECURE-IBD) reported standardized mortality ratio trends higher IBD patients (1.5-1.8) mesalamine/sulfasalazine therapy correlates with poor outcome. goal our was experimentally address relationship between mesalamine SARS-CoV-2 entry, replication, and/or pathogenesis. Methods Viral infection performed a chimeric vesicular stomatitis virus expressing spike protein EGFP (VSV-SARS-CoV-2) derived from infectious cDNA clone 2019n-CoV/USA_WA1/2020. Primary ileal spheroids healthy donors were grown as 3D on 2D transwells. We assessed effect 10 mM (Millipore Sigma) viral RNA levels, well expression receptor angiotensin II-converting enzyme (ACE2), Transmembrane Serine Protease (TMPRSS2), TMPRSS4, Cathepsin B (CTSB) CTSL by qRT-PCR. 8-12 week old K18-ACE2 treated orally PBS at 200 mg/kg daily. Mice inoculated intranasally 1×10 3 FFU SARS-CoV-2. weighed daily titers determined 7 days post (dpi) For entry model, VSV-SARS-CoV-2 injected into ligated loop anesthetized mice tissues harvested 6 hours post-infection. Results found no change levels epithelial cells response mesalamine. Expression ACE2 reduced following treatment enteroids, while increased. receiving lost weight rates compared vehicle control. Mesalamine did not load lung, heart, dpi. Pretreatment modulate mice. Conclusions alter pathogenesis vitro mouse models. concurrently increasing ileum organoids.