Severe cases of Covid-19 have been known to lead to a mysterious condition whereby the body’s immune system goes haywire and starts attacking healthy cells, rather than just those that are infected.
This prolonged state of self-sabotage is known as a ‘cytokine storm’ and can be fatal, but researchers have struggled to understand how it works and how to treat it.
Now new research has looked at the progression of a coronavirus infection in mice and found the cytokine storm is a vicious cycle, which leads to the overproduction of two signalling proteins called tumour necrosis factor (TNF)-alpha and interferon (INF)-gamma.
They work together to cause the serious condition which can lead to inflammation, organ damage and eventual death.
But the study on mice found using pre-existing antibodies designed to combat these proteins is an effective way of preventing death in severe cases of Covid-19.
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Researchers have found two proteins made by the immune system which cause the cytokine storm which can be fatal. They also found pre-existing antibodies for them can reduce the risk of death from Covid-19 (stock)
New research looked at the course of a coronavirus infection in mice and found the cytokine storm is a vicious cycle which leads to the overproduction of two signaling proteins, called tumor necrosis factor (TNF)-alpha and interferon (INF)-gamma
‘Understanding the pathways and mechanism driving this inflammation is critical to develop effective treatment strategies,’ co-author of the study Thirumala-Devi Kanneganti of St. Jude’s department of immunology in Tennessee said.
‘This research provides that understanding. We also identified the specific cytokines that activate inflammatory cell death pathways and have considerable potential for treatment of COVID-19 and other highly fatal diseases, including sepsis.’
Cytokines are small signalling proteins which are pumped out by the cells of the immune system to tell other cells what to do.
They are vital in the immune response as they can restrict the spread of the virus, but some also trigger inflammation.
Inflammation is a natural part of the immune response and sees white blood cells flock to the site of infection to fight it off.
However, inflammation is also to blame for some autoimmune disorders, such as arthritis, where the body causes inflammation despite there being no cause.
This graphic released by the researchers shows how infection with the coronavirus (top left) leads to the initial immune response which churns out cytokines (top right). TNF-alpha and IFN-gamma lead to uncontrolled cell death, triggering inflammation and more cytokines, which creates a vicious circle and results in organ failure and death
Early in the pandemic, evidence of overactive cytokine production was spotted, and scientists coined the term ‘cytokine storm’ to describe the condition.
It leads to severe inflammation in the respiratory system as well as lung damage, organ failure and death in severe Covid-19 patients, but how it works has been a mystery until now.
Dr Kanneganti focused on the cytokines most frequently seen in Covid-19 patients, and conducted controlled experiments on mice.
They revealed no single cytokine caused the condition seen in Covid-19 patients.
Researchers then began combining the cytokines and tried 28 different concoctions, with only one pairing triggered the lethal response.
TNF-alpha and INF-gamma were together found to cause a process dubbed PANoptosis, which triggers three pathways that kill cells.
These are called pyroptosis, apoptosis and necroptosis, and all function in slightly different ways, but all are specific mechanisms which are designed to kill cells.
As they go around slaughtering cells, the idea is they destroy infected cells, stopping the virus reaching healthy, uninfected areas.
But the presence of the two elevated cytokines leads to too many cells being targeted and killed, and the buildup of dead cells fuels inflammation.
This, in turn, releases more of the cytokines, creating a vicious cycle.
In mice that were not infected with the coronavirus, the researchers gave them a cocktail of both TNF-alpha and IFN-gamma and found it caused damage similar to what is seen in cases of Covid-19.
By mapping these pathways, the researchers now know which can be targeted by drugs in order to treat the condition.
Antibodies which target and neutralise these two cytokines already exist and are used in the treatment of other inflammatory diseases.
Researchers gave them to mice infected with the SARS-CoV-2 coronavirus and found the animals were less likely to die.
‘The findings link inflammatory cell death induced by TNF-alpha and IFN-gamma to COVID-19,’ Dr Kanneganti said.
‘The results also suggest that therapies that target this cytokine combination are candidates for rapid clinical trials for treatment of not only COVID-19, but several other often fatal disorders associated with cytokine storm.’
