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Protein kinase A signaling regulates immune evasion by shaving and concealing fungal β-1,3-glucan

Summary

Candida albicans is a fungus that causes infections in humans. The fungus has developed a clever way to hide from our immune system by covering up a molecule on its surface called β-1,3-glucan that normally triggers immune responses. This study shows that the fungus masks this molecule through a combination of growing and dividing to create new surfaces, and then using enzymes to trim away exposed molecules. The research reveals that a specific cell signaling pathway controlled by lactate (a chemical found in our bodies) activates this masking behavior, helping the fungus evade immune recognition.

Background

Candida albicans is an opportunistic fungal pathogen that has evolved strategies to evade human immune defenses by masking the proinflammatory pathogen-associated molecular pattern (PAMP) β-1,3-glucan. This masking involves both shielding of the glucan by an outer mannan layer and enzymatic shaving of exposed glucan at the cell surface.

Objective

To investigate how protein kinase A signaling regulates β-1,3-glucan masking in C. albicans by combining mathematical modeling with experimentation to understand the dynamics of glucan exposure and shaving in response to host signals like lactate.

Results

The mathematical model revealed that β-1,3-glucan masking results from combined effects of growth rate and enzymatic shaving dynamics. Lactate induced approximately threefold increase in shaving through Gpr1/Gpa2-PKA signaling pathway. Clinical isolates previously thought to show minimal lactate-induced masking were found to mask robustly when analyzed dynamically. The glucanases Eng1 and Xog1 contribute to but are not essential for shaving, and masking depends on both shaving and mannan shielding mechanisms.

Conclusion

Integration of mathematical modeling with experimentation demonstrates that the dynamics of β-1,3-glucan masking in C. albicans depend on both cell growth-related exposure and enzymatic shaving regulated by PKA signaling. These findings provide insights into immune evasion mechanisms and suggest this approach is applicable to understanding PAMP masking in other fungal pathogens.
  • Published in:Proceedings of the National Academy of Sciences of the United States of America,
  • Study Type:Experimental Research,
  • Source: 10.1073/pnas.2423864122, PMID: 40489619
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