A potential new drug target for treating COVID-19 has been uncovered by scientists using gene expression analysis and the nation’s fastest supercomputer. The team, led by Dan Jacobson of the Department of Energy’s Oak Ridge National Laboratory, found that genes in the bradykinin system were excessively activated in the lung fluid cells of COVID-19 patients.
The bradykinin system is one of several responsible for lowering blood pressure, and its involvement might explain the cytokine storm reaction that is characteristic of the disease. Jacobson’s team analyzed genes from cells in the lung fluid of nine COVID-19 patients compared with 40 control patients. Their results were published in eLife.
“If we can block this pathogenesis in severe patients, we can keep the human response from going overboard and give their immune system time to fight off the virus so they can recover,” Jacobson said.
Scientists are keen to find already approved drugs that can be repurposed for COVID-19 patients. But that hinges on the ability to uncover appropriate targets and researchers are still far from having a thorough understanding of how SARS-CoV-2 is acquired and progresses. It appears that the virus’s entry point is angiotensin-converting enzyme 2 (ACE2), which is a component of the renin-angiotensin system (RAS). Bradykinin is a potent part of the vasopressor system that induces hypotension and vasodilation. It is regulated by ACE and enhanced by angiotensin.
To see which genes were normally co-expressed or turned on or off at the same time, Jacobson’s team compared the genes of COVID-19 patients against a control group and analyzed population-scale gene expression data. They had 17,000 samples from the control patients.
The team observed a critical imbalance in RAS, including decreased expression of ACE in combination with increases in ACE2, renin (REN) , angiotensin (AGT), key RAS receptors (AGTR2, AGTR1), kinogen (KNG) and the kallikrein enzymes (KLKB1, many of KLK-1-15) that activate it, and both bradykinin receptors (BDKRB1, BDKRB2). The authors report that this very atypical pattern of the RAS should elevate bradykinin levels in multiple tissues and systems and that likely causes increases in vascular dilation, vascular permeability and hypotension. These bradykinin-driven outcomes may explain many of the symptoms being observed in COVID-19.
The team proposes that bradykinin is overproduced in the body of COVID-19 patients and that related systems either contribute to overproduction or cannot slow the process. Excessive bradykinin then leads to leaky blood vessels, allowing fluid to build up in the body’s soft tissues.
As a result, Jacobson’s team thinks a bradykinin storm is to blame for much of SARS-CoV-2’s pathogenesis. If their disease model is accurate and substantiated, it may mean that existing medicines could be repurposed to slow the progress of COVID-19 infection. At least ten existing drugs act on the pathways Jacobson’s team studied.
“We believe that when you take the inhibition at the top of this pathway off, you end up with an out-of-control cascade that leads to an opening up of the blood vessels, causing them to leak,” Jacobson said. “If that happens in the lung, that’s not good. Immune cells that are normally contained in the blood vessels flood into the surrounding infected tissue, causing inflammation.”
Jacobson attributes their findings in part to a “eureka moment.” He says, “I was looking at data, and I suddenly saw some very distinct patterns happening in the pathways of the renin-angiotensin and bradykinin systems. That led us to do a deep dive of the gene families of the blood pressure regulatory system.”
