Curbing Candida: The Cells That Keep Fungal Infections at Bay

AHA Publisher — Thu, 14 Jul 2022 07:00:19 +0000

Weizmann Institute of Science via Newswise – 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 may, on occasion, prove fatal. In a study published today in Nature Immunology, a Weizmann Institute of Science research team headed by Prof. Jakub Abramson uncovered a previously unknown defense mechanism employed by the immune system in fighting Candida infections. Candida is present at low levels in the bodies of most healthy people, forming part of the microbiome – a diverse spectrum of microbes that reside peacefully in our gut and on our skin. Under normal circumstances, Candida is held in check by the immune system, but it can occasionally grow excessively, invading the lining of the mouth, the vagina, the skin or other parts of the body. In severe cases, it can spread to the bloodstream and from there to the kidneys. Such life-threating infections may occur when a person’s immune system has been weakened, for example, by AIDS or by immunosuppressive drugs such as cancer chemotherapy or steroids. Antibiotics, which wipe out many of the beneficial bacteria within our microbiome, can also unleash local or invasive Candida eruptions by providing this yeast with an unfair advantage vis-à-vis other microorganisms. That’s why, for instance, women sometimes develop a vaginal yeast infection after taking antibiotics. Until now, the immune cells that got most of the credit for defending the body against Candida were the small, round lymphocytes of the T cell type, called TH17. These cells were also the ones to take the blame when this defense failed. In the new study, postdoctoral fellow Dr. Jan Dobeš, working together with colleagues in Abramson’s lab in Weizmann’s Immunology and Regenerative Biology Department, discovered that a powerful commando unit of TH17 cells capable of fighting 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, that express a gene called the autoimmune regulator, or Aire The two groups of cells belong to the two different arms of the immune system, which, like foot patrols and specialized units, join forces against a common enemy. The Aire-ILC3s – part of the more ancient, innate arm – spring into action almost immediately upon encountering a threat – in this case, a Candida infection. The TH17s belong to the immune system’s more recent, adaptive arm, which takes several days or even weeks to respond, but which launches a much more targeted and potent attack than the innate one. The scientists found that as soon as Candida starts infecting tissues, the Aire-ILC3s engulf the yeast whole, chop them up and display some of the yeast pieces on their surfaces. That’s how these bits are presented to the TH17s, a few of which are generally on call in the lymph nodes, ready for an infection alert. This kind of presentation instructs the specialized T cells to start dividing rapidly, soaring in number from a few lone commandos to several hundred or even thousands of Candida-specific fighters, 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. Abramson became intrigued by Candida because it commonly leads to severe, chronic infections in people with a rare autoimmune syndrome caused by defects in the Aire gene. Abramson’s lab had conducted extensive studies of this gene, helping to clarify its role in preventing autoimmune disorders. That research, as well as studies by other scientists, had shown that Aire-expressing cells in the thymus instruct developing T cells to refrain from attacking the body’s own tissues. When Aire is defective, T cells fail to receive proper instructions, consequently causing 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 outside the thymus, Aire is also expressed 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 group lacked it in the ILC3s in the lymph nodes. The first group developed autoimmunity but was able to successfully fight off Candida. In contrast, those in the second group, the ones lacking Aire in ILC3s, did not suffer from autoimmunity, but were unable to generate numerous Candida-specific TH17s. Consequently, they failed to effectively eliminate Candida infections. In other words, without Aire-expressing ILC3s, the specialized T cells needed for fighting Candida were not produced in sufficient numbers. “We found an entirely new role for Aire, one that it plays in the lymph nodes – turning on a mechanism that increases the numbers of Candida-fighting T cells,” Dobeš explains. These findings open up new directions of research that in the future may help develop new treatments for severe Candida, and possibly for other fungal infections. The newly discovered mechanism might, for example, help produce large numbers of Candida-fighting T cells to be used in cell therapy. And if scientists one day identify the signals by which Aire-ILC3s boost T cell proliferation, these signals themselves might provide 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 Immunology and Regenerative Biology Department; Dr. Liat Stoler-Barak and Prof. Ziv Shulman of the Systems Immunology Department; Katarína Kováčová, Helena Böhmová and Evgeny Valter of Charles University, Prague; Bergithe E. Oftedal and Prof. 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. To read the original article click here.

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Reprogramming of Immune System Cures Child with Often-Fatal Fungal Infection

AHA Publisher — Wed, 17 Jun 2020 07:00:54 +0000

University of California, Los Angeles (UCLA), Health Sciences via Newswise – In the June 11 issue of the New England Journal of Medicine, a team of UCLA physicians and scientists describes the first case of immune modulation being used to cure a severe and often fatal fungal infection. The team “retuned” a 4-year-old’s immune system so that it could fight off disseminated coccidioidomycosis. The case, originally reported by UCLA in 2019, could pave the way for a new treatment for the infection, which affects hundreds of Americans each year, primarily in the Southwest, and kills approximately 40% of the people who contract it. The technique described in the study could also suggest a new paradigm for treating other severe fungal infections, bacterial infections such as tuberculosis, and severe viral infections such as influenza and COVID-19. “Immune modulation isn’t currently part of the strategy with any of these severe infections,” said Dr. Manish Butte, the report’s senior author, who holds the E. Richard Stiehm Endowed Chair in Pediatric Allergy, Immunology and Rheumatology at the David Geffen School of Medicine at UCLA. “Our case suggests that rather than hoping to get the upper hand with more and more antibiotics or antifungals, we can have some success by combining these established approaches with the new idea of programming the patient’s immune response to better fight the infection.” Each year, more than 100,000 people are infected with Coccidioides fungi, which reside in the soils of California, Arizona and West Texas. Most people who are infected are asymptomatic, and about 20,000 experience the minor respiratory illness commonly known as Valley fever. The vast majority of people with Valley fever respond well to antifungal medications, but approximately 1% of the infections progress to disseminated coccidioidomycosis, in which the infection spreads rapidly throughout the body, leading to bone and tissue damage, and in many cases death. “Historically, severe infections have been seen as ‘bad luck,’” Butte said. “Doctors haven’t looked at how we can harness the immune systems of these patients to fight the infection.” According to a 2019 study in the International Journal of Environmental Research and Public Health, California spends between $700 million and $900 million a year in direct and indirect costs related to the care of people infected by the cocci fungus, including more than $300 million to care for the approximately 200 people with disseminated coccidioidomycosis. The boy who was treated by Butte and his team had previously been treated with high doses of multiple antifungal medicines, but by the time he arrived at UCLA, he could barely walk or talk and required a feeding tube to eat. When UCLA physicians homed in on the patient’s immune system, they concluded that his T cells — the white blood cells that play a key role in the body’s immune response — were failing to properly recognize the invading fungus. The T cells were responding as though the infection was a parasitic infection rather than a fungal one. That prompted the team to supplement the boy’s antifungal medications with an immune stimulator called interferon-gamma. And Dr. Maria Garcia-Lloret, a pediatric allergist and immunologist, suggested adding yet another medication, dupilumab, which was developed as a medication for allergic diseases and had never before been used to treat infections. Dupilumab is a prescription drug that has not been approved by the FDA as a treatment for disseminated coccidioidomycosis. The combination of immune modulators restored the proper programming to the patient’s T cells — and the boy’s infection went away in a month. The UCLA research team cites that the immunomodulatory approach has the potential to enhance the ability of patients to clear other types of fungal, bacterial, and viral infections that are not responding to established therapies. In partnership with the Bakersfield, California-based Valley Fever Institute and the drugs’ manufacturers — Horizon Therapeutics, Regeneron Pharmaceuticals and Sanofi Genzyme — the UCLA researchers are planning to test the two drugs on other people with disseminated coccidioidomycosis. They also plan to study the approach for treating other types of severe infections. To read the original article click here.

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Curbing Candida: The Cells That Keep Fungal Infections at Bay

Reprogramming of Immune System Cures Child with Often-Fatal Fungal Infection