Controlling Candida: Cells That Keep Yeast Infections At Away

Of all the fungi that live in the human body, the most infamous is probably the yeast Candida. This distant cousin of baker’s yeast is notorious for causing various types of thrush that can be a major nuisance, but it can also lead to an invasive infection that can sometimes be fatal. In a study published today in Nature Immunology, a research team from the Weizmann Institute of Science led by Prof. Jakub Abramson discovered a previously unknown defense mechanism used by the immune system to fight Candida infections.

(lr) Prof. dr. Jakub Abramson, Osher Ben-Nun, Dr. Yael Goldfarb, Tal Givony and Amit Binyamin

Candida is present in low concentrations in the bodies of most healthy people and is part of the microbiome – a diverse spectrum of microbes that live peacefully in our gut and on our skin. Under normal circumstances, Candida is kept in check by the immune system, but it can occasionally overgrow and invade the lining of the mouth, vagina, skin or other parts of the body. In severe cases, it can spread to the bloodstream and from there to the kidneys. Such life-threatening infections can occur when a person’s immune system is weakened, for example by AIDS or by immunosuppressants such as cancer chemotherapy or steroids. Antibiotics, which wipe out many of the beneficial bacteria in our microbiome, can also unleash local or invasive Candida outbreaks by giving this yeast an unfair advantage over other microorganisms. That is why, for example, women sometimes get a vaginal yeast infection after taking antibiotics.

Until now, the immune cells that got the most credit for defending the body against Candida were the small, round, T-cell-type lymphocytes called T.huh17. These cells were also the ones who took the blame when this defense failed.

In the new study, postdoctoral fellow Dr. Jan Dobeš, in collaboration with colleagues in Abramson’s lab in Weizmann’s Department of Immunology and Regenerative Biology, developed a powerful command unit from Thuh17 cells that can fight Candida cannot be generated without crucial early support from an entirely different contingent: a subset of rare lymphoid cells known as type-3 innate lymphoid cells, or ILC3, which express a gene that the autoimmune regulator is called, or Aire

The two groups of cells belong to two different branches of the immune system, which, like foot patrols and specialized units, join forces against a common enemy. The Aire-ILC3s – part of the older, congenital arm – spring into action almost immediately when they encounter a threat – in this case a Candida infection. the Thuh17s belong to the more recent, adaptive arm of the immune system, taking several days or even weeks to respond, but launching a much more focused and powerful attack than the innate.

dr. Jan Dobes

The scientists found that once Candida begins to infect tissues, the Aire-ILC3s gobble up the yeast in its entirety, mince them and reveal some of the yeast bits on their surface. Thus, these bits are added to the T . presentedhuh17’s, a few of which are generally available in the lymph nodes, ready for infection warning. This kind of presentation instructs the specialized T cells to begin dividing rapidly, increasing in number from a few lone commandos to several hundred or even thousands of Candida-specific combatants, capable of destroying the yeast at the sites of infection.

“We have identified a previously unrecognized immune system weapon that is indispensable for orchestrating an effective response against the fungal infection,” Abramson says.

An Aire-ILC3 cell (grey) captures and swallows a Candida cell (red)

Abramson became intrigued by Candida because it often leads to serious, chronic infections in people with a rare autoimmune syndrome caused by defects in the Aire gene. Abramson’s lab had conducted extensive studies on this gene, illustrating its role in preventing autoimmune diseases. That research, as well as studies by other scientists, had shown that cells that express Aire in the thymus instruct the developing T cells not to attack the body’s own tissues. When Aire is defective, T cells do not receive proper instructions, triggering widespread autoimmunity that wreaks havoc in multiple body organs. But one puzzle remained: Why would Aire-deficient patients suffering from a devastating autoimmune syndrome also develop chronic Candida infections?

While trying to complete the Aire puzzle, Dobeš and colleagues found that Aire is also expressed outside the thymus in a small subset of ILC3s in the lymph nodes. The researchers then genetically engineered two groups of mice: one lacked Aire in the thymus and the other lacked it in the ILC3s in the lymph nodes. The first group developed autoimmunity, but was able to successfully fight Candida. In contrast, those in the second group, those without Aire in ILC3s, had no autoimmunity, but were unable to produce numerous Candida-specific Thuh17s. Consequently, they failed to effectively eliminate Candida infections. In other words, without Aire-expressing ILC3s, the specialized T cells necessary to fight Candida were not produced in sufficient numbers.

“We found an entirely new role for Aire, a role it plays in the lymph nodes — by triggering a mechanism that increases the number of Candida-fighting T cells,” explains Dobeš.

An Aire-ILC3 cell (green)

These findings open up new avenues of research that could help develop new treatments for severe Candida and possibly other fungal infections in the future. For example, the newly discovered mechanism could help produce large numbers of Candida-fighting T cells for use in cell therapy. And if scientists one day identify the signals through which Aire-ILC3s stimulate T cell proliferation, these signals themselves could form the basis for new therapies.

Study participants also included Osher Ben-Nun, Amit Binyamin, Dr. Yael Goldfarb, Dr. Noam Kadouri, Yael Gruper, Tal Givony, and Itay Zalayat of Weizmann’s Department of Immunology and Regenerative Biology; dr. Liat Stoler-Barak and Prof. Ziv Shulman of the Department of Systems Immunology; Katarína Kováčová, Helena Böhmová and Evgeny Valter from Charles University, Prague; Bergithe E. Oftedal and Prof. dr. Eystein S. Husebye of the University of Bergen, Norway; and dr. Dominik Filipp of the Institute of Molecular Genetics of the Czech Academy of Sciences, Prague.

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