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

• 成果类型: Article
• 署名作者: Pradhan, Arnab; Nev, Olga A.; Leaves, Ian; Nev, Oleg A.; Ma, Qinxi; Milne, Gillian; Patterson, Grace; Netea, Mihai G.; Erwig, Lars P.; Farrer, Rhys A.; Brown, Gordon D.; van den Berg, Hugo A.; Gow, Neil A. R.; Brown, Alistair J. P.
• 署名单位: UK Research & Innovation (UKRI); Medical Research Council UK (MRC); University of Exeter; University of Aberdeen; University of Exeter; Radboud University Nijmegen; Radboud University Nijmegen; University of Bonn; Cancer Research UK; University of Warwick
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14771
• DOI: 10.1073/pnas.2423864122
• 发表日期: 2025-06-17
• 关键词: candida-albicans; cell-wall; RECOGNITION; morphogenesis; SEPARATION; receptor; GROWTH

摘要

Fungal pathogens infect billions and kill millions of people each year. Many of these pathogens have evolved strategies to evade our antifungal immune defenses. Candida albicans, for example, masks the proinflammatory pathogen-associated molecular pattern (PAMP) beta-1,3-glucan, in response to specific host signals such as lactate. In C. albicans, most beta-1,3-glucan lies in the inner cell wall shielded, by the outer mannan layer, from recognition by certain immune cells such as macrophages. beta-1,3-glucan that becomes exposed at the cell surface can be shaved off by secreted enzymes. By integrating mathematical modeling with experimentation, we show that the dynamics of this shaving, together with the dynamics of beta-1,3-glucan exposure during growth, can account for a range of beta-1,3-glucan masking phenotypes. The mathematical model accurately simulates the dynamics of beta- 1,3-glucan exposure during growth and predicts levels of beta-1,3-glucan shaving under a variety of conditions, revealing how subtle differences in growth contribute to observed variabilities in lactate-induced beta-1,3-glucan masking. For example, clinical isolates previously thought to display minimal lactate-induced masking are shown to mask robustly. Using a range of C. albicans mutants, we confirm the importance of Gpr1/Gpa2-protein kinase A signaling for lactate-induced beta-1,3-glucan shaving and define the contributions of the Xog1 and Eng1 glucanases to this shaving. Furthermore, examination of a shielding-defective C. albicans mnn2x6 mutant confirms that both beta-1,3-glucan shaving and shielding contribute to the dynamism of beta-1,3-glucan masking at the fungal cell surface. Dynamism in PAMP masking is likely to be relevant to other fungal pathogens of humans. Significance Pathogenic fungi impose a heavy burden upon human health. Many, particularly opportunistic fungal pathogens such as Candida albicans, have evolved strategies to evade our immune defenses. These include masking of pathogen-associated molecular patterns (PAMPs) whose recognition triggers antifungal immunity. C. albicans masks the proinflammatory PAMP, beta-1,3-glucan from recognition by macrophages, thereby turning this fungus into a moving target for immune cells. Combining experimentation with mathematical modeling to explore the dynamics of this phenotype, we show that beta-1,3-glucan exposure during growth, combined with beta-1,3-glucan shaving, underlie this PAMP masking. We define how different host-related signals impact beta-1,3-glucan exposure by influencing growth and shaving, providing insights that are relevant to immune evasion by other fungal pathogens.