COVID-19. Sepsis. Hemophagocytic lymphohistiocytosis. What do all these life-threatening diseases have in common? They can all lead to an overactivation of the immune system and the release of large amounts of small chemical messengers called cytokines.

Cytokines are important for the normal function of the immune system to kill invading bacteria and viruses and protect against infection. But when lots of cytokines are made, this protective function can get out of control, and a “cytokine storm” occurs. When this happens, instead of helping protect the body, the cytokines start to damage tissues and organs. And in COVID-19, and several other diseases, this cytokine storm can be fatal.

When cytokines go bad

Throughout the COVID-19 pandemic, researchers have been trying to understand when cytokines are good and when they become bad during the infection. Early during infection, cytokines are likely important to stop the virus from spreading, but later in the disease the cytokine response seems to get out of hand for some reason.

Work in the Immunology Department lab of Thirumala-Devi Kanneganti, PhD, recently provided some important answers as to why this happens. Rajendra Karki, PhD, and Bhesh Raj Sharma, PhD, of Kanneganti’s lab were the first authors on the study. The findings appeared in the journal Cell.

The researchers showed that two specific cytokines, tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma), work together to cause inflammatory cell death. During inflammatory cell death, cells spew out their contents instead of neatly packaging them away, as cells would do during non-inflammatory types of death. Neighboring cells see the unexpected debris as a sign of danger, and they can respond by secreting more cytokines, allowing the cytokine storm to build.

Calming the cytokine storm

The scientists used this new-found understanding of the cause for the cytokine storm to find ways to stop it. For example, they looked at models that lacked molecules they found to be needed for inflammatory cell death and discovered that these could survive being given TNF-alpha and IFN-gamma, while normal models died rapidly.

Also, drugs that stop TNF-alpha and IFN-gamma from functioning are already FDA approved and used to treat inflammatory diseases. Kanneganti and her colleagues used similar drugs to stop TNF-alpha and IFN-gamma in mice. This treatment saved mice from dying during infection with SARS-CoV-2, the virus responsible for COVID-19. It also kept mice alive during sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock.

There are still limited treatment options for COVID-19, and learning more about how to calm the immune system and stop the cytokine storm is an exciting step forward with immediate and clear clinical implications. And the life-saving potential of understanding the cytokine storm could also be extended to sepsis, hemophagocytic lymphohistiocytosis, and other highly fatal diseases and syndromes associated with cytokine storm.