A new paper published in Nature Communications adds further evidence to the bradykinin storm theory of COVID-19’s viral pathogenesis — a theory that was posited two years ago by a team of researchers at the Department of Energy’s Oak Ridge National Laboratory.

At the height of the pandemic, ORNL systems biologist Dan Jacobson and his team used ORNL’s Summit supercomputer to analyze gene-expression data of lung cells from COVID-19 patients. Their research suggested that genes related to some of the body’s systems that are responsible for controlling blood pressure, fluid balance and inflammation appear to be excessively dysregulated, or impaired, in the lung cells of those infected with the virus. In a paper published in eLife, the team predicted that overproduction of bradykinin — the compound that dilates blood vessels and makes them permeable — could be the source of COVID-19 symptoms such as excessive accumulation of fluid in the lungs, fatigue, nausea and decreased cognitive function.

That theory has been further supported in a new study conducted by Jacobson and his colleagues in ORNL’s Biosciences, Computational Sciences and Engineering, and Neutron Scattering Divisions in collaboration with Soichi Wakatsuki, a professor of photon science at Stanford University’s SLAC National Accelerator Laboratory. Wakatsuki’s team was able to prove experimentally that the virus’s main protease, 3CLpro, binds to the NF-κB Essential Modulator, or NEMO. The subsequent cleavage of NEMO means it dysregulates NF-κB, which is a protein complex that helps regulate the immune system’s response to infection — and its dysregulation can contribute to a bradykinin storm, just as the ORNL team’s pathogenesis model had predicted.