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Pulmonary inflammation in severe covid-19 can be caused by an aggressive protein.
The HMGB1 protein causes the body’s immune system to overreact. But the antibodies that attack the protein have already been developed in animal tests.
– This work that I think can save lives, says researcher Ulf Andersson.
He has been researching the HMGB1 protein for 20 years with his American colleague Kevin Tracey.
– No one has wanted to invest a penny in developing this as a drug. Suddenly we get hit by covid-19, and then all the pieces of the puzzle are done well, says Ulf Andersson, a senior professor in the Karolinska Institute’s Department of Women’s and Children’s Health.
Photo: PETER WIXTRÖM
“If the antibody works in covid-19, it will likely work against other serious viruses as well,” says Ulf Andersson.
Andersson and Tracey’s research shows how the HMGB1 protein causes pneumonia in severe viral infections. Is that how it works:
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Covid-19 difficult leads to extensive cell death in the lungs. When cells die, DNA, RNA, histones, and other substances that the HMGB1 protein groups together are called danger molecules (“Dangerous Molecules”), which in turn bind to the RAGE receptor.
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In the next step, the mixture enters the purification system of the lung cells, the so-called lysosomes, which normally break down the molecules into small parts.
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But if there is too much HMGB1, the system may crash. The protein works at high concentrations as a detergent and makes holes in the lysosome membranes. The danger molecules then leak to another part of the cells, the cytoplasm, and create a production of cytokines that cause inflammation.
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The process can be so strong that researchers describe it as a cytokine storm. It results in powerful inflammation that often leads to the death of the patient.
The cells explode and create a cytokine storm.
Not only that. When lung cancer cells die, the HMGB1 protein is released on a much larger scale in male mice than in female mice, the researchers found. When lung cells in female mice die from pneumonia, they shrink without releasing HMGB1. In males, on the other hand, cells explode, initiating the process leading to the cytokine storm.
– May be the reason more men die on covid-19, says Ulf Andersson.
Under the direction of Ulf Andersson and Kevin Tracey, an antibody has been developed that hinders the progression of the protein in mice, a so-called HMGB1 inhibitor. The next step is to have the antibody tested in humans.
– If what I think is HMGB1 is crucial to the strength of the inflammation, then this can be as good as any other, Andersson says.
Hope for global testing
Even better is that an antibody-based medicine could have a wide range of uses:
– If our antibody works on covid-19, it will likely work against other serious viruses as well, says Andersson.
Along with hopes for a specific HMGB1 inhibitor, several drugs are already approved for other effects, which at the same time suppress HMGB1’s ability to cause inflammation. These include chloroquine, heparin, and substances like nicotine and statins.
Ulf Andersson now hopes that doctors around the world will test them against covid-19 to a greater extent, guided by an article he just published in the journal Molecular Medicine with Kevin Tracey, professor of neurosurgery and molecular medicine.
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Confirmed number of infected and dead in the world
* In the list of confirmed numbers of infected and dead per 100,000 inhabitants, all countries with a population of less than 100,000 are removed. The reason is that smaller countries make it difficult to see other differences in the world. Sweden’s figure is from the Public Health Authority. International figures are from Johns Hopkins University, CSSE. The map is updated daily.
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