New research from Talal Chatila, MD, of the Division of Immunology at Boston Children's Hospital and colleagues provides some insights, particularly regarding the mechanisms involved in severe lung inflammation in COVID-19. The study, published in Immunity, also provides some therapeutic suggestions to quiet the runaway immune response.

"We wanted to answer why this runaway inflammation happens despite mechanisms that normally would put the brakes on the immune system response", says Chatila. "Something needed to shift gears to allow the immune response to become so active that it spills over to inflict tissue damage that winds up killing people. Once the underlying mechanisms for such a misfiring are identified, then we could start to think about how to intervene therapeutically".

Notch4 notched up T-cell responses

Chatila and his colleagues studied the immune response of 120 adults from the U.S., Italy, and Turkey with lung inflammation from COVID-19. The results identified excess levels of Notch4 protein receptor found on regulatory T-cells (Tregs) as a key instigating mechanism of the runaway inflammation. Tregs normally regulate or suppress other immune system components. But in severe COVID-19 lung inflammation, the team observed an overabundance of the Notch4 receptor on Tregs. While Notch4 production may normally increase in lung inflammatory conditions or infections, such as asthma or COVID-19, when over-expressed it can switch Tregs from a normal tissue repair program to one permissive for tissue inflammation.

"In patients with severe COVID this pathway seems to be hyperactivated", says Chatila. "And it is associated with disease severity and increased risk of death". Chatila and colleagues previously described a similar finding in asthma where they found that Notch4 caused severe lung inflammation in asthma.

Treatment stopped the storm

"In lung injury from COVID-19, Notch4 derails amphiregulin production by suppressing the activity of interleukin-18", says Chatila. "We showed we could reset the immune response either by inhibiting Notch4 using an antibody directed at it or by providing amphiregulin, suggesting that the Notch4-amphiregulin nexus could be a putative target of therapy in COVID-19". Currently, no anti-Notch4 antibodies or amphiregulin therapies are available for human use, though Chatila's team is working on developing them.

Next step: Focus on pediatric COVID-19

As more patients-adults and even some children appear to linger with symptoms of COVID-19 long past an active infection, Chatila's focus has shifted to studying the immune responses in pediatric COVID-19 as well as the severe post-COVID-19 syndrome in children, known as MIS-C. "We want to know if there are other molecular switches like Notch 4 that enable these different complications of COVID-19 to take place and that involve other tissues, like the brain and heart", he says. "And I expect that longer-term complications of COVID, such as MIS-C or long COVID-19 in adults, may entail their own set of immune regulatory problems".