A new view of immune responses to fungal diseases

2021

Challenge

Investigating genetic variations that affect a person’s susceptibility to infection can reveal immune system pathways that control infection and offer insight into potential treatments. For instance, mutations in the AIRE gene lead to a condition called Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy (APECED). Patients with APECED experience chronic infections of their mucus membranes by the yeast Candida albicans, which is typically harmless in healthy people. Previous studies have attempted to understand the mechanisms behind this disease by extrapolating from insights into other conditions rather than by directly studying the underlying mechanisms behind the yeast infections in APECED patients.

Advance

IRP researchers led by Michail Lionakis, M.D., Sc.D., assembled the world’s largest cohort of APECED patients in order to dissect and characterize the fundamental mechanisms underlying fungal infections of the mucus membranes. Previously, researchers believed APECED caused the immune system to block an immune response involving T cells called the Th17 pathway, resulting in increased susceptibility to fungal infections. However, Dr. Lionakis and his research team found that the Th17 immune response in mucous membranes worked properly in both mice without the AIRE gene and in APECED patients. Instead, they discovered, T cells present in the mouth’s mucous membranes were producing high levels of interferon-γ (IFN-γ), which is important in combatting viral infections but damaging when levels are too high. This excessive INF-γ disrupts the ‘mucosal barrier’ that helps keep infectious organisms and toxins outside the body, leading to an increased vulnerability to fungal infections. Furthermore, the scientists found that blocking IFN-γ or the cascade of molecular events that excess INF-γ triggers markedly improved mucosal fungal disease in mice with fungal infections.

Impact

This work upended decades of conviction regarding the role of T cells in general, and Th17 cells in particular, in fungal infections of the mucous membranes. The unexpected findings identified excess IFN-γ as a cause of increased susceptibility to fungal infections at mucosal barrier sites, a discovery that may lead to new therapeutic approaches to treating APECED and similar conditions.

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