ACE2 Helps SARS-CoV-2 Infect Cells, Also Influences Gut Inflammation

Patients receiving anti-inflammatory drugs to treat inflammatory bowel disease have been reported to experience reduced morbidity from COVID-19, and a new study sheds light on the enzyme that is central to the diseases.

The study, published in Gastroenterology, examined the role of angiotensin-converting enzyme 2 (ACE2) in Crohn's disease and ulcerative colitis. In COVID-19, the virus binds to ACE2 as an entry point into the cell.

“ACE2, the enzyme that SARS-COV-2 virus uses to infect human cells, is highly expressed in the bowel,” senior author Dermot P. McGovern, MD, PhD, the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics at Cedars-Sinai Medical Center, told Contagion®. “Its expression is increased with some of the demographic factors associated with worse outcomes in COVID-19, such as obesity and increasing age. There is altered ACE2 expression in patients with inflammatory bowel disease (IBD), and the altered expression is associated with worse outcomes in both types of IBD—Crohn’s disease and ulcerative colitis. The altered ACE2 expression is also associated with response to the anti-cytokine drug infliximab in IBD. These findings raise the possibility that infliximab may have role in treating COVID-19.”

Investigators examined records of 1,000 IBD patients at Cedars-Sinai; Washington University in St. Louis, Missouri; and other North American sites. They found that expression of ACT2 — which typically activates a hormone that helps regulate blood pressure — varied depending on the location and the specific disease. Normalizing the levels of ACE2 with infliximab was associated with improved disease outcomes.

“The biggest surprise for us was in two paradoxes we describe in the study. First, while higher ACE2 expression may be associated with an increased risk of SARS-Cov-2 infection, we found that lower ACE2 levels were associated with worse outcomes in small bowel Crohn’s disease,” McGovern said. “These findings are in keeping with previous data showing a similar phenomenon in lung disease, suggesting ACE2 levels may have paradoxical effects on infection and severity in COVID-19. Second, we observed a paradox between ACE2-related inflammatory signals in small bowel inflammation versus colonic inflammation in patients with IBD. This GI ‘compartmentalization’ of the biology raises intriguing possibilities of developing more targeted therapies for treating IBD depending on disease location. What was not a surprise to us was the ‘intersection’ of biology between infections and immune-mediated diseases, which we have observed in some of our other work.”

While COVID-19 typically attacks the lungs, it also has been known to cause gastrointestinal symptoms, leading some to some to consider the GI tract as a possible alternate route for infection.

“Registry-based studies have suggested that IBD (and psoriasis) patients treated with anti-cytokine therapies such as infliximab may have improved outcomes from COVID-19 in comparison to some of our other therapies, including corticosteroids and mesalamine,” McGovern said. “Our data suggests some possible mechanistic reasons for this clinical observation, and there has been some suggestion that these drugs may have a role in the management of the ‘cytokine storm’ seen in more extreme manifestations of COVID-19.”

The cytokine storm, a sever bout of hyperinflammation, has a devastating effect on COVID-19 patients. Aakriti Gupta, MD, a cardiologist at New York’s Columbia University Irving Medical Center, recently described the devastating snowball effect.

More research is needed to better understand the role of ACE2 both in increasing risk of COVID-19 infection and in assisting with recovery and the possible role of anti-inflammatory drugs in treating COVID-19.

“The National Institutes of Health have recognized the potential importance of our work,” McGovern said. “They awarded us a grant to further study the ACE2 mechanisms, and we hope that this will help us advance our understanding of both COVID-19 and inflammatory bowel diseases. We are also interested in the results of any clinical trials evaluating COVID-19 outcomes with other drug classes used to treat immune-mediated diseases to see if these provide additional support for our findings and provide the impetus to study infliximab as a COVID-19 treatment.”