Newly discovered immune pathway prevents fatal fungal infections in mice

An immune pathway has been discovered which prevents a normally harmless fungus developing into a fatal infection.

The King's College London study, published in Nature Microbiology, provides the first potential clue as to why only certain patients with weakened immune systems, including those undergoing chemotherapy or living with HIV, are at risk of life-threatening Candida albicans infections. Candida albicans is a fungus that normally lives harmlessly in areas such as the mouth and gut but can sometimes spread through the body and cause fatal disease. If the results are confirmed in humans, the results could provide a test to understand who is at risk of developing fatal fungal infections and represent a potential therapeutic target to reduce the risk of developing the disease.

Fungal infections kill more than 2.5 million people each year, with Candida albicans alone killing almost a million. However, until now we knew little about why fungi escape their natural location in mouths and gut and cause life-threatening disease in around 10% of patients who have a weakened immune system.

The scientists focused on a signal produced by the immune system to trigger symptoms to fight off infection, IL-1. Mice which were genetically modified not to produce IL-1 experienced severe disease when exposed to Candida albicans. The findings suggest that the IL-1 immune pathway is critical in preventing Candida albicans from spreading around the body and causing life-threatening disease.

They investigated this further by injecting IL-1-deficient mice with a drug that removes neutrophils, a type of white blood cell that is among the first to respond to infections and help fight threats such as bacteria and fungi. This allowed the researchers to mimic the weakened immune system seen in some immunocompromized patients. By then introducing Candida albicans to the mouths of those mice, they for the first time observed the fungus spread throughout the body and cause fatal disease, confirming that IL-1 is critical in preventing disease spreading.

While the study focused specifically on Candida albicans, the researchers say the IL-1 immune pathway may be a broader defense mechanism that helps keep fungi normally found in healthy microbiomes from spreading and causing fatal disease, and further research is needed to confirm whether this applies to other fungal species.

Understanding what causes fungi that are naturally present in our microbiomes, such as Candida albicans, to cause life-threatening disease could help spot at-risk patients earlier. The researchers suggest that, if confirmed in humans, the findings could lead to a test that identifies which immunocompromised patients have low levels of IL-1 and so are at risk of Candida albicans escaping their microbiomes and causing disease before it happens.

While drugs such as antibiotics are currently used to treat life-threatening fungal diseases, more targeted therapies are needed that tackle the root cause of infection. The researchers suggest future clinical studies in humans could test whether drugs targeting IL-1 could work as a personalized therapy for preventing life-threatening Candida albicans infection.

Most people carry Candida albicans harmlessly as part of the body's natural microbiome, but in immunocompromised patients it can spread throughout the body and become life-threatening. A major challenge has been understanding why a fungus that is normally harmless can suddenly spread beyond its natural niche and cause invasive disease. Our study identified the IL-1 family as a critical early immune defense system that helps prevent this fungus from escaping the mouth and gut and spreading to multiple organs. We hope these findings will help identify patients at greatest risk of invasive fungal disease and provide a foundation for developing new ways to strengthen protective antifungal immunity."

Dr. James S. Griffiths, Corresponding Author, Research Fellow, King's College London

Dr Lea Lortal, co-author of the study, and postdoctoral researcher in Mycology at The University of California, San Francisco (UCSF), said:

"Fungal infections are severely overlooked: they affect more than one billion people worldwide. Yet, there are still no clinically approved vaccines against any fungal pathogen, and our understanding of the immune mechanisms that protect us from fungal disease remains incomplete. What normally keeps fungi, such as Candida albicans, in check has remained a major unanswered question. In this study, we identified the IL-1 family as a key early coordinator of the immune response that helps contain Candida before it can become invasive. Understanding how these protective responses are initiated is an important step toward developing better ways to prevent and treat invasive fungal infections."