Cytokines weaken TB immune response

 Researchers have discovered how anti-viral cytokines can reduce the immunological response to tuberculosis.

The study was published in the journal, 'Cellular Immunology.'

A new collaboration study between Trinity's School of Medicine and the Trinity College Institute of Neuroscience (TCIN) is decreasing the research gap on the activities of type 1 interferon, a critical immune system protein whose actions are still unknown.

Type one interferons are cytokines that destroy viruses such as COVID-19. Cytokines are tiny proteins that play an important role in regulating the proliferation and function of other immune and blood cells. They alert the immune system to start working when they are released.

Although cytokines perform a good, protective role, many individuals suffer from disorders that are exacerbated by chronic production of type 1 interferons. These include patients suffering from the auto-immune disease systemic lupus erythematosus (SLE) and those with persistent TB.

Dr Gina Leisching, Senior Research Fellow, Clinical Medicine, School of Medicine has led the group to study the influence of type 1 interferons on the immune system, using an animal model. This study demonstrates that type 1 interferon treatment induces an inflammatory state characterized by the increased production of white cells, and inflammatory intermediate metabolites as well as immune cell metabolic rewiring - which interferes with the ability of macrophages to fight bacteria.

Specifically, the group have identified type one interferons as impairing the metabolic response to Mycobacterium tuberculosis, the bacteria that causes TB.

Dr Leisching said, "This work has provided new evidence that chronic type I interferons blunt the immune response and explains why patients with diseases that are driven by these immune proteins are prone to infections. We now have new targets to test to see if we can reverse this poor response by either boosting immune cell function or limiting the effects of type I interferons. We are now working with immune cells from SLE patients to gain more insight into whether these effects are observed in all immune cells or only a select few."

These findings now identify type 1 interferons as a potential target for the development of host directed therapies in patients who suffer from excess production of this cytokine.

This approach is already used in treating SLE - an autoimmune disease in which the immune system attacks its own tissues, causing widespread inflammation and tissue damage in the affected organs - but might now be looked at in pre-clinical models of tuberculosis. The field of TB needs new adjuvant therapies that support the host, especially as antibiotics are rendered redundant by the increasing development of resistance in the Mycobacterium tuberculosis bacteria (XDR TB).

Anjali Yennemadi, PhD candidate, Clinical Medicine, School of Medicine, said, "We are very excited by these findings as they help to close a gap in the literature by showing what a significant effect type I interferons have on altering immune cell metabolism. This is particularly interesting to us as we are now working with SLE patients to understand why they are more susceptible to infections, including TB. Going forward, with the use of more advanced experimental and computational techniques, we hope to uncover potential diagnostic and/or therapeutic targets specific to chronic production of type I interferons in SLE and TB."