NEW YORK—Common fungi, which are often present in the gut, can teach the immune system how to respond to their more dangerous relatives, according to new research from scientists at Weill Cornell Medicine. But breakdowns in this process can leave people susceptible to deadly fungal infections.
A study, published in Cell, has revealed a new piece of the complex relationship between humans and their associated microbes. The research points the way toward novel therapies that may be able to help combat drug-resistant fungal infections.
This discovery stemmed from work on inflammatory bowel disease, which often causes patients to carry larger than average 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. Dr. Iliyan Iliev, associate professor of immunology in medicine in the Division of Gastroenterology and Hepatology at Weill Cornell Medicine, noticed that healthy controls in these studies also had some level of anti-fungal antibodies.
“There was no actual evidence for fungal infections in the healthy individuals that we examined, so we started thinking about the possible function of those antibodies,” noted Iliev, who is senior author on the study, and a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease.
The team developed a platform 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. Iliev and Itai Doron, a Weill Cornell Medicine Graduate School of Medical Sciences doctoral candidate as well as lead author of the study, experimented in mouse models and found that colonizing the animals’ guts with Candida albicans caused them to develop antibodies against the fungus in their bloodstreams — even though the models 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,” Iliev added.
In patients with suppressed immune systems, like organ transplant recipients and cancer patients, fungi in the gut can invade the bloodstream and cause life-threatening infections. Iliev and his colleagues mimicked this process by treating mice with immunosuppressive drugs. When a Candida species colonized the gut of these mice, the fungus moved into the bloodstream, causing a fatal infection.
The researchers treated the mice with purified anti-fungal antibodies from donor animals, and this technique protected the immunosuppressed mice from Candida infections. The same strategy worked against infection with either Candida albicans or Candida auris, which has become a major cause of fungal disease in immunosuppressed patients and the elderly in recent years.
The Weill Cornell team collaborated with researchers at INSERM in Paris, and looked at serum from patients with mutations in a gene called CARD9, which affects a critical adapter protein in the immune system — leaving the affected individuals susceptible to severe fungal infections. Iliev’s team found that the serum of these patients lacked the anti-fungal antibodies normally seen in the serum of patients who lack this mutation. Mouse model experiments confirmed an essential and specific role for CARD9 in priming the production of anti-fungal antibodies.
The results suggest that normal intestinal fungi like Candida albicans may function as a type of intestinal vaccine against fungal infection in healthy people, by inducing the production of blood-borne 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 infections.
“Many fungal infections in immunosuppressed patients and elderly patients are happening by translocation of pathogenic Candida species from the gastrointestinal tract, and the survival rates upon systemic spreading are alarmingly low,” stated Iliev.
New therapies that involve either stimulating the production of anti-fungal antibodies, or injecting purified antibodies directly into patients’ bloodstreams, have the potential to help combat these increasingly common infections. If this approach works, it will be an important development against the threat of deadly fungal infections.