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19 May 2020

Immunological scarring: new research reveals why your immune system can shut down

Researchers have identified a molecular “switch” that triggers a powerful chain of events in response to severe bacterial or viral infections that could change how we manage patients in intensive care, including those with COVID-19.

Studying mice and humans, the scientists discovered that after recovering from a severe infection their lungs bore an “immunological scar”, which impacted the immune system’s ability to respond to new threats. Specifically, they found that cells that form the immune system’s frontline defence – macrophages - were paralysed by the initial infection.

Macrophages play a crucial role in the immune system, gobbling bacteria they encounter or raising an internal “alarm”. When the alarm has been raised, immune cells rush in like emergency services to the site and slay the infection. After recovery, the state of alarm subsides and the immune system returns to its resting state. After a severe infection, however, macrophages are unable to mount an effective attack against new infections, leaving the body immunosuppressed and vulnerable to secondary infections that cause fatal pneumonia.

The new study, published today in Nature Immunology, was co-led by University of Melbourne Professor Jose Villadangos at the Peter Doherty Institute for Infection and Immunity (Doherty Institute – a joint venture between the University of Melbourne and The Royal Melbourne Hospital) and Dr Antoine Roquilly, a scientist and intensive care specialist based at the University Hospital in Nantes, France. It not only described the paralysis of the macrophages following an infection, but also identified a molecular control switch responsible for paralysis induction, called ‘Sirp-alpha’. They found that if the Sirp-alpha switch is turned off it can restore the macrophages to their full capacity.

The study builds upon the scientists’ previous work on dendritic cells – the macrophages’ partner in this frontline work – and their understanding that the current hospital practice of treating severely ill patients with antibiotics may not be addressing the root cause of immunosuppression, and in fact, may be contributing to another major problem: the emergence of antibiotic-resistant bacteria.

“As humans, we have not evolved to survive the level of infection that requires to keep a patient in an intensive care unit (ICU); modern medicine is the only reason we survive,” said Professor Jose Villadangos.

“Treating patients with general antibiotics is a common practice in the ICU. This helps thwart hospital-acquired infections, but comes at a cost; it encourages the emergence of multi-resistant strains of bacteria that can be dangerous, not just for the ICU patients but also for the general population.

“We believe an alternative approach is to recharge the immune system to take it out of its paralysed state, or to prevent paralysis in the first place, so that patients will be able to protect themselves against secondary infections without resorting to antibiotics. Turning off the newly-described switch may be such an approach.”

Dr Antoine Roquilly said: “The main cause of death in COVID-19 patients is a “cytokine storm”, an out-of-control immune response. Engaging SIRP-alpha or other switches that turn off the immune response may prevent the storm from occurring and improve the survival of these patients”.

The new findings encourage investigation of treatments to turn on the immunosuppressive switch in COVID-19 patients.

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