This staining image of kidney tissue affected by candidiasis shows the fungus Candida albicans and infiltrating immune cells.
Image Credit: Biswas Laboratory
Scientific Frontline: Extended "At a Glance" Summary: Immune Reprogramming to Treat Candidiasis
The Core Concept: Systemic candidiasis is a severe, opportunistic fungal infection caused by Candida albicans. Recent research demonstrates that reprogramming the metabolic pathways of a host's immune cells offers a viable strategy to clear the infection, circumventing the need for traditional antifungal medications.
Key Distinction/Mechanism: Rather than targeting the fungus directly with antifungal drugs—which increasingly face resistance—this approach strengthens the host's natural defenses. Because Candida albicans aggressively consumes extracellular glucose, local immune cells (neutrophils) are typically starved and rendered ineffective. However, activating the glycogen phosphorylase liver form (PYGL) enzyme allows these neutrophils to mobilize internal glycogen stores, ensuring their survival and ability to destroy the fungus in a nutrient-deprived environment.
Major Frameworks/Components:
- Neutrophils: The primary effector immune cells responsible for mounting a rapid defense and clearing fungal invaders.
- PYGL Enzyme: An enzyme that breaks down intracellular glycogen, providing a crucial alternative energy source for immune cells operating in hostile, glucose-depleted environments.
- Beta-2 Adrenergic Receptor Agonists: Clinically approved medications (such as Albuterol, typically used for asthma) that successfully activate the PYGL enzyme and upregulate antifungal immune functions in models.
- Metabolic Competition: The fundamental biological conflict where host immune cells and invading pathogens compete for limited localized nutrients.
Branch of Science: Immunology, Microbiology, and Immunometabolism.
Future Application: This discovery introduces the potential to repurpose existing, clinically approved beta-2 adrenergic receptor agonists to reprogram immune function in patients suffering from drug-resistant systemic candidiasis and potentially other invasive fungal infections.
Why It Matters: Systemic candidiasis is becoming increasingly prevalent due to rising rates of immunosuppression, prolonged antibiotic use, and antifungal drug resistance. Identifying a previously unrecognized metabolic pathway to enhance natural immune function bypasses current pharmacological roadblocks, offering a highly needed alternative for combating severe, life-threatening fungal infections.
Systemic candidiasis is an opportunistic fungal infection that has been difficult to treat effectively. Research published in a paper in the April edition of Cell Host & Microbe suggests that immune metabolic reprogramming could be a new strategy to fight the infection rather than developing another specific antifungal medication.
The fungus Candida albicans causes infections that range from superficial on the skin and nails to invasive into organs and the bloodstream. In recent decades, systemic candidiasis has increased due to more patients with immunosuppression from disease or treatments, prolonged antibiotic exposure and certain conditions such as kidney disease. Management of systemic candidiasis has become more difficult because of antifungal drug resistance, limited early diagnostic tools and absence of approved fungal vaccines.
According to Partha Biswas, DVM, PhD, lead author of the paper and a professor in the Department of Microbiology and Immunology in the Renaissance School of Medicine (RSOM) at Stony Brook University, these challenges have become roadblocks to treating systemic candidiasis and illustrate the need for new and different therapeutic strategies.
This staining image of kidney tissue affected by candidiasis shows the fungus Candida albicans and infiltrating immune cells. Credit: Biswas Laboratory
Dr. Biswas and his coinvestigators used a murine model of candidiasis to look at neutrophils, which are the primary effector cells responsible for rapid fungal clearance during candidiasis. However, this natural antifungal activity depends largely on extracellular glucose, which becomes scarce in this infection process because C. albicans competes for the nutrient. What usually occurs is that metabolic competition within the host is a hostile environment that limits neutrophil survival and function, especially when underlying metabolic impairments (disease) are present.
The research team demonstrated in the model that neutrophils overcome glucose deprivation by activating the glycogen phosphorylase liver form (PYGL) enzyme. This enzyme mobilizes intracellular glycogen stores that fuel antifungal activity.
They further found that by a neutrophil-specific deletion of PYGL in the model, the mice had an increased susceptibility to candidiasis. But then, by using a clinically approved PYGL activator, beta 2 adrenergic receptor agonist, the host defense against candidiasis was greatly improved by way of increased antifungal functions. Additionally, by using neutrophils from the peripheral blood of healthy volunteers, the authors demonstrated that human neutrophils similarly upregulate PYGL function to control fungal infections.
Beta 2 adrenergic receptor agonists, such as Albuterol, are currently used to treat asthma and other respiratory conditions, as they relax muscles in the airways to improve breathing.
“Our results uncover a previously unrecognizable metabolic pathway that has the potential to be therapeutically targeted against candidiasis,” explained Dr. Biswas. “If we are able to identify and use the PYGL enzyme to essentially reprogram neutrophil function in people against C. albicans that cause infection, this could significantly change the course of future treatments against candidiasis and perhaps other invasive fungal infections.”
Funding: The research is supported in part by numerous grants from federal agencies, including three National Institutes of Health (NIH) grants to Dr. Biswas, and another NIH grant and a Department of Defense (DOD) grant to a co-author, Charles K. Vorkas, MD, of Stony Brook Medicine.
Published in journal: Cell Host & Microbe
Authors: Wonseok Choi, De-dong Li, Colin T. McLaughlin, Doureradjou Peroumal, Kiyoshi P. Shiomitsu, Gillian A. Moschetta, Hossein Rahimi, Shuxia Wang, Kiaan Biswas, Danielle Xie, Charles K. Vorkas, and Partha S. Biswas
Source/Credit: Stony Brook University
Reference Number: imgy040326_01
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