How Do Fungal Infections Take Hold? Rare Disease Offers New Insights

NIAID Now | January 14, 2021

In healthy mucosal tissues (left), the immune system prevents fungal infections, with T cells (yellow and purple) playing a key protective role. In AIRE deficiency (right), aberrant T-cell responses damage the outermost layer of cells, helping fungal infections take hold.

Credit: NIAID

By studying the rare disease APECED, NIAID researchers and colleagues uncovered an unexpected immune mechanism that promotes susceptibility to fungal infections of the mucous membranes. Their findings, reported in the Jan. 15 issue of Science, suggest potential therapies for people with APECED and pave the way for work to investigate these tissue-specific immune responses in other diseases.

APECED, or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, is a genetic disease that leads to defects in the autoimmune regulator (AIRE) protein, which helps teach immune cells how to distinguish the body’s own cells and tissues from foreign invaders. The disorder can lead to a diverse range of symptoms, including chronic mucocutaneous candidiasis (CMC)—infections with the yeast fungus Candida that are limited to the mucous membranes and nails and do not spread throughout the body. 

Previously, scientists had established that defects in a type of protective immune response known as “type 17” immunity can enhance vulnerability to CMC. However, researchers led by NIAID’s Michail Lionakis, M.D., Sc.D., found that type 17 responses at mucosal tissues were intact both in people with APECED and in a mouse model of the disease, suggesting that a different mechanism promotes CMC susceptibility.

By studying mice engineered to lack AIRE, the NIAID scientists found that abnormal T-cell responses promote inflammation in mucosal tissues and disrupt the protective outermost layer of cells, facilitating Candida infections. T cells typically play a key role in protecting healthy mucosal tissues from fungal infections, but in AIRE deficiency, they exhibit enhanced “type 1” T-cell responses that instead promote infection. The researchers also observed this aberrant type 1 T-cell immunity in samples from the oral mucosa of a large cohort of APECED patients enrolled in a natural history study at the NIH Clinical Center. Specifically, they found that T cells produce excessive amounts of a key cell-signaling protein called IFN-gamma, which activates a cell-signaling process involving molecules called JAKs and STAT1, leading to damage to the barrier of cells at the surface of mucosal tissues.

Administering an antibody that blocks IFN-gamma or the drug ruxolitinib, which impedes JAK/STAT1-signaling, improved mucosal fungal infections in mice lacking AIRE. This suggests that ruxolitinib or the anti-IFN-gamma antibody emapalumab, which are both FDA-approved for other diseases, potentially could be effective for prevention or treatment of CMC in people with APECED.

The findings enhance scientific understanding of how fungal infections take hold and also will inform efforts to better understand whether type 1 immune responses contribute to CMC in other diseases, such as Down syndrome or STAT1 gain-of-function mutations.

Reference:

TJ Break, V Oikonomou, et al. Aberrant type 1 immunity drives susceptibility to mucosal fungal infections. Science DOI: 10.1126/science.aay5731 (2021).

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