"A number of overlapping inflammatory pathways between COVID-19 and IBD imply that some of the pre-existing IBD medications, like IL-12/23 inhibitors or TNF inhibitors, could be repurposed for use in COVID-19 patients," Dr. Saurabh Mehandru of Icahn School of Medicine at Mount Sinai, in New York City, told Reuters Health by email.
SARS-CoV-2 initiates infection by attaching the receptor-binding domain of the viral spike (S) protein to epithelial angiotensin-converting enzyme-2 (ACE2), which is expressed by intestinal epithelial cells as well as lung epithelial cells. Cleavage of the S protein by transmembrane serine protease 2 (TMPRSS2) then facilitates viral entry into the host cell.
Dr. Mehandru and colleagues examined potential areas of intersection between the uninflamed and inflamed gastrointestinal tract and COVID-19 disease using endoscopy specimens, peripheral blood and biopsies from individuals with and without IBD.
ACE2 was widely expressed in the small intestinal surface epithelium but only inconsistently in the colon of healthy individuals. In contrast, TMPRSS2 was more robustly expressed in the colon.
Ileal ACE2 mRNA expression decreased significantly with inflammation, whereas rectal ACE2 mRNA expression increased significantly with inflammation, compared with uninflamed tissue from IBD patients or non-IBD controls.
In both ileal and colon biopsies, TMPRSS2 expression increased in the presence of inflammation, although the effect sizes were small.
Nonbiological IBD medications reduced ACE2 and TMPRSS2 gene expression in the inflamed colon and rectum but not in the ileum, the researchers report in Gastroenterology.
Among biologic medications, infliximab reduced ACE2 expression in the inflamed colon, whereas ustekinumab increased ACE2 and TMPRSS2 in the inflamed colons of treatment responders.
Gene-set-variation analysis revealed that genes upregulated with inflammation or positively associated with disease measures or associated with the risk of IBD were significantly enriched with genes upregulated by SARS-CoV-2 infection of lung epithelial cells.
The majority of pathways and cell-type enrichments associated with a response to COVID-19 were immune oriented, with the most striking related to innate immune signaling via interferon and interleukin-6.
There was significant overlap between many of the genes associated with IBD therapy and IBD inflammation or COVID-19 infection, and COVID-19 upregulated genes decreased significantly after four weeks of ustekinumab treatment.
"The effect of IBD medications on ACE2 is complex and region-specific," Dr. Mehandru said. "However, inflammation is detrimental to the pathogenesis of COVID-19. Therefore, in COVID-19 patients with IBD, the treatment of IBD-related intestinal inflammation should proceed according to existing clinically indicated paradigms."
"The multiple points of intersection in COVID-19 transcriptional profiles and those of IBD-associated inflammation were very interesting," he said. "Even though COVID-19 is a 'new disease,' there is great value in comparing it with some of the pre-existing inflammatory diseases in order to better understand disease pathogenesis and to define therapeutic targets."
By Will Boggs MD
SOURCE: https://bit.ly/30p2gHa Gastroenterology, online September 24, 2020.
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