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
Medical Research Council Centre for Medical Mycology at the University of Exeter, Department of Biosciences, Faculty of Health and Life Sciences, Exeter EX4 4QD, United Kingdom.
Software Consultant, Belgrade, Serbia.
Proc Natl Acad Sci U S A. 2025 Jun 17;122(24):e2423864122. doi: 10.1073/pnas.2423864122. Epub 2025 Jun 9.
Fungal pathogens infect billions and kill millions of people each year. Many of these pathogens have evolved strategies to evade our antifungal immune defenses. for example, masks the proinflammatory pathogen-associated molecular pattern (PAMP) β-1,3-glucan, in response to specific host signals such as lactate. In , most β-1,3-glucan lies in the inner cell wall shielded, by the outer mannan layer, from recognition by certain immune cells such as macrophages. β-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 β-1,3-glucan exposure during growth, can account for a range of β-1,3-glucan masking phenotypes. The mathematical model accurately simulates the dynamics of β-1,3-glucan exposure during growth and predicts levels of β-1,3-glucan shaving under a variety of conditions, revealing how subtle differences in growth contribute to observed variabilities in lactate-induced β-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 mutants, we confirm the importance of Gpr1/Gpa2-protein kinase A signaling for lactate-induced β-1,3-glucan shaving and define the contributions of the Xog1 and Eng1 glucanases to this shaving. Furthermore, examination of a shielding-defective x6 mutant confirms that both β-1,3-glucan shaving and shielding contribute to the dynamism of β-1,3-glucan masking at the fungal cell surface. Dynamism in PAMP masking is likely to be relevant to other fungal pathogens of humans.
真菌病原体每年感染数十亿人并导致数百万人死亡。许多这类病原体已经进化出逃避我们抗真菌免疫防御的策略。例如，响应特定的宿主信号（如乳酸），掩盖促炎的病原体相关分子模式（PAMP）β-1,3-葡聚糖。在[具体情况未提及]中，大多数β-1,3-葡聚糖位于内层细胞壁，被外层甘露聚糖层屏蔽，从而避免被某些免疫细胞（如巨噬细胞）识别。在细胞表面暴露的β-1,3-葡聚糖可被分泌的酶去除。通过将数学建模与实验相结合，我们表明这种去除的动力学，以及生长过程中β-1,3-葡聚糖暴露的动力学，可以解释一系列β-1,3-葡聚糖掩盖表型。该数学模型准确模拟了生长过程中β-1,3-葡聚糖暴露的动力学，并预测了在各种条件下β-1,3-葡聚糖去除的水平，揭示了生长中的细微差异如何导致乳酸诱导的β-1,3-葡聚糖掩盖中观察到的变异性。例如，先前认为表现出最小乳酸诱导掩盖的临床分离株被证明具有强大的掩盖能力。使用一系列[未明确的]突变体，我们证实了Gpr1/Gpa2-蛋白激酶A信号传导对于乳酸诱导的β-1,3-葡聚糖去除的重要性，并确定了Xog1和Eng1葡聚糖酶对这种去除的贡献。此外，对一个屏蔽缺陷的x6突变体的研究证实，β-1,3-葡聚糖的去除和屏蔽都有助于真菌细胞表面β-1,3-葡聚糖掩盖的动态变化。PAMP掩盖的动态变化可能与人类的其他真菌病原体有关。
