Calming a cytokine storm

Inducing a gene-regulating protein called Nrf2 could be worth investigating as a means of suppressing the hyperactive immune response that causes severe illness and death in some people infected with the SARS-CoV-2 virus.

“The main factor causing COVID-19 mortality is not the virus itself, but the body’s excessive immune response to infection,” explains virologist turned cell biologist, Roman A. Zinovkin, of Lomonosov Moscow State University.

Much of Zinovkin’s current research is related to the anti-inflammatory functions of ‘nuclear factor erythroid 2-related factor 2’ (Nrf2) in some human immune cells. He and his colleague Oleg A. Grebenchikov, of the Russian Academy of Medical Sciences, suggest there is a strong rationale for trialling the use of Nrf2 inducers to prevent the development of some of the more severe manifestations of COVID-19 disease.

Nrf2 is a transcription factor that regulates the activation of some genes. When reactive oxygen species accumulate in cells during oxidative stress, Nrf2 moves into the cell nucleus to activate target genes that trigger an anti-oxidant response. Nrf2 also has a host of anti-inflammatory roles, including the inhibition of specific immune-related molecules.

Interestingly, research suggests that Nrf2 activity decreases with age, and in people with high blood sugar, while female mice have higher Nrf2 activity than males – factors that have been associated with a higher risk of developing severe COVID-19 symptoms.

In their study, reported in the journal Biochemistry (Moscow), Zinovkin and Grebenchikov suggest that inducing Nrf2 could be a way to prevent or treat the so-called cytokine storm and release of reactive oxygen species that occur in severe cases of COVID-19 infection. This response damages airway cells, impairing gas exchange in the lungs, and can also lead to clot formation and multiple organ failure.

Drugs that induce Nrf2 have already been approved for use in chronic diseases, such as multiple sclerosis and psoriasis. Clinical trials are also underway to test their use in chronic obstructive pulmonary disease, asthma, arthritis and some cancers.

However, as Zinovkin points out: “They haven’t been used to treat acute inflammatory conditions.”

Nrf2 inducers could provide an alternative to currently available treatments, such as corticosteroids, which can cause secondary bacterial pneumonia, and drugs that can only target specific chemokines.

Along with others, Zinovkin and Grebenchikov are now conducting clinical trials to test Nrf2 inducers for preventing and treating the cytokine storm associated with severe cases of COVID-19 disease. They are also investigating the anti-inflammatory mechanisms of Nrf2 inducers in cellular models of viral infection.