We are finally unravelling the mystery of what causes severe covid-19

We are finally unravelling the mystery of what causes severe covid-19

By Mark Anderson

A computer graphic representation of the molecular structure of bradykininHANK MORGAN/SCIENCE PHOTO LIBRARY
An out-of-control human peptide called bradykinin could be responsible for some of the varied and sometimes deadly symptoms seen in people who have contracted the coronavirus. We already have drugs to control bradykinin, which are being tested as treatments for people with covid-19.
Bradykinin normally helps to regulate blood pressure, and in some people, the coronavirus seems to be pushing bradykinin production into overdrive. This would create a kind of “bradykinin storm” in the body that may lead to a number of symptoms common in covid-19.
Renuka Roche at Eastern Michigan University says such a storm could explain many aspects of covid-19 that seem disjointed, such as muscle pain, women sometimes having milder illness than men, and African Americans being more likely to develop complications.


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In July, a team led by Daniel Jacobson at the Oak Ridge National Laboratory in Tennessee published a study in which they mined gene expression data in samples of lung fluid from nine people with covid-19 in China, and compared them with samples from a control group that didn’t have the disease. They found an over-expression of genes that are responsible for bradykinin production, along with under-expression of genes that produce enzymes to keep bradykinin levels in check.
Because bradykinin dilates blood vessels and makes them more permeable, high levels of bradykinin could lead to fluid leakage in a blood-vessel-rich environment like the lungs. It can also break down the blood-brain barrier, suggesting a possible pathway for some of the coronavirus’s puzzling neurological symptoms.
Josef Penninger at the University of British Columbia in Canada says the bradykinin hypothesis makes sense given what we know about the way the coronavirus works in the body. The virus invades human cells via ACE2 receptors, which, he says, also help keep bradykinin levels in check. But with the virus reducing the availability of these receptors, bradykinin levels could get out of control.
Jacobson’s team also discovered an overexpression of genes in coronavirus patients’ lungs that encode for a substance called hyaluronic acid. When hyaluronic acid mixes with liquid, such as the fluids that blood vessels may be dumping into the lungs, it turns gelatinous. This could explain the coronavirus’s most notorious severe symptom: difficulty breathing, the group says.
Fortunately, drugs that help regulate hyaluronic acid and bradykinin predate covid-19. In 2011, the US Food and Drug Administration approved the anti-inflammatory drug icatibant for acute attacks of the hereditary genetic disease angioedema, a condition that involves its own bradykinin storms.

In July, a team led by Roger Brüggemann at Radboud University Medical Center in the Netherlands did a preliminary trial of icatibant on nine Dutch coronavirus patients who were being treated with oxygen for difficulty breathing. The team found a reduction in the need for oxygen supplementation in eight of those people.
Studies are now under way in the US and Europe to test another bradykinin signal-blocking drug called lanadelumab.
“We hope … once this is completed, it will be the next step towards a multinational study involving several hundreds of patients,” says Brüggemann.
Journal reference: eLife, DOI: 10.7554/eLife.59177
Journal reference: JAMA Network Open, DOI: 10.1001/jamanetworkopen.2020.17708
Journal reference: FASEB, DOI: 10.1096/fj.202000967

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