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Common fungi, often present in the gut, teach the immune system how to respond to their more dangerous relatives, according to new research by scientists. Breakdowns in this process can leave people susceptible to deadly fungal infections.
The study, published Feb. 5 in Cell, reveals a new twist in the complex relationship between humans and their associated microbes, and points the way toward novel therapies that could help combat a rising tide of drug-resistant pathogens.
The new discovery stemmed from work on inflammatory bowel disease, which often causes patients to carry larger than normal populations of fungi in their guts. These patients often develop strong antibody responses against mannan, a molecule common to a wide range of fungal species. The researchers also noticed that healthy controls in these studies also had some level of anti-fungal antibodies. The team developed a platform that allowed them to determine which gut fungi are targeted by antibodies in the blood of individual patients. They detected a strong response against the yeast Candida albicans.
Colonizing the animals' guts with Candida albicans caused them to develop antibodies against the fungus in their bloodstreams, even though they didn't develop blood-borne fungal infections. Instead, the animals' immune cells. appeared to transport fungal antigens to the spleen, stimulating the production of circulating antibodies in the bloodstream."Those fungi just educate that immune response.
The results suggest that normal intestinal fungi such as Candida albicans may function as a kind of intestinal vaccine against fungal infection in healthy people, by inducing the production of bloodborne antibodies that can target multiple species of potentially pathogenic fungi. When those fungi do enter the bloodstream, the antibodies bind them and target them for destruction by cells of the Immune system. In patients with suppressed immunity, the anti-fungal antibodies may decline, leaving them vulnerable to fungal infection. New therapies that involve either stimulating the production of anti-fungal antibodies, or injecting such purified antibodies directly into patients' bloodstreams, could potentially help combat these increasingly common infections.
In patients with suppressed immune systems, such as organ transplant recipients and some cancer patients, fungi in the gut can invade the bloodstream and cause life-threatening infections. Researchers mimicked this process by treating mice with immunosuppressive drugs. When a Candida species colonizes the gut of these mice, the fungus moves into the bloodstream, causing a fatal infection. Treating the mice with purified anti-fungal antibodies from donor animals protected the immunosuppressed mice from these infections. The same strategy worked against infection with either Candida albicans or the emerging pathogenic yeast Candida auris, which has become a major cause of fungal disease in immunosuppressed patients and the elderly in recent years.
The team also looked at serum from patients with mutations in a gene called CARD9. This mutation affects a critical adapter protein in the immune system, leaving the affected individuals susceptible to severe fungal infections. The team found that the serum of these patients lacked the anti-fungal antibodies normally seen in serum of patients without this mutation. Experiments in mice confirmed an essential and specific role for CARD9 in priming the production of anti-fungal antibodies.
Itai Doron et al. Human gut mycobiota tune immunity via CARD9-dependent induction of anti-fungal IgG antibodies, Cell (2021). DOI: 10.1016/j.cell.2021.01.016