Supercomputer Analyzes Lung Fluid Cells from Coronavirus Infected Patients to Repurpose Drugs for COVID-19 Treatment

Summit is currently the most powerful supercomputer in the US, with a theoretical peak performance of 200 petaflops, or 200 quadrillion calculations per second. The researchers required the power of Summit to run 2.5 billion correlation calculations that helped them understand the normal regulatory circuits and relationships for the genes of interest. With Summit, the team completed the calculations in one week rather than spending months doing them on a desktop computer.

Their computational analyses suggest that genes related to one of the body’s systems responsible for lowering blood pressure-the bradykinin system-appear to be excessively “turned on” in the lung fluid cells of those with the virus. Based on their analyses, the team posits that bradykinin-the compound that dilates blood vessels and makes them permeable-is overproduced in the body of COVID-19 patients; related systems either contribute to overproduction or cannot slow the process. Excessive bradykinin leads to leaky blood vessels, allowing fluid to build up in the body’s soft tissues.

Much attention has focused on what is known as the cytokine storm, a severe reaction in which the body releases an excess of cytokines, a variety of small proteins that help regulate the immune system. However, the researchers believe that a bradykinin storm may instead be to blame for much of the viral pathogenesis. The bradykinin storm could explain the wide variety of symptoms experienced by COVID-19 patients, such as muscle pain, fatigue, nausea, vomiting, diarrhea, headaches, and decreased cognitive function. Similar symptoms are also experienced by patients with other bradykinin-related conditions such as hereditary angioedema, a genetic condition that is characterized by episodes of severe swelling throughout the body.

The team also uncovered that an enzyme that forestalls the bradykinin cascade-the angiotensin-converting enzyme, known as ACE-was less expressed in COVID-19 patients. At least 10 existing drugs are known to act on the specific pathways studied by the researchers, although large-scale clinical trials are needed to determine whether they might be effective at treating COVID-19. Additionally, the lungs of COVID-19 patients are known to have an increased amount of hyaluronic acid, a gooey substance found in connective tissues that can trap around 1,000 times its own weight in water to form a hydrogel. The team also found that genes in the cells of COVID-19 patients increased the production of the substance and decreased its breakdown. The findings suggest that further experimental study of drug compounds known to slow the synthesis of hyaluronic acid and the mechanisms involved in the process is warranted.

The researchers also used the Compute and Data Environment for Science, or CADES, at ORNL to determine which genes in the RAS-bradykinin pathways have vitamin D binding sites. The results of their analyses might help scientists determine through experimentation which parts of these pathways could potentially be influenced by vitamin D. Because vitamin D helps regulate the RAS and vitamin D deficiencies have already been associated with more severe illness in COVID-19 patients, the researchers believe that it's another molecule worth further study.

“This is one of those rare times where you can really tie everything back to a eureka moment,” said Dan Jacobson, staff scientist in ORNL’s Biosciences Division, who led the study. “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.”

“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,” added Jacobson.

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Oak Ridge National Laboratory