Hypoxia Promotes Immune Evasion by Triggering β-Glucan Masking on the Candida albicans Cell Surface via Mitochondrial and cAMP-Protein Kinase A Signaling.
Hypoxia Promotes Immune Evasion by Triggering β-Glucan Masking on the Candida albicans Cell Surface via Mitochondrial and cAMP-Protein Kinase A Signaling.
复制标题
缺氧通过通过线粒体和cAMP蛋白激酶A信号转导在白色念珠菌细胞表面上触发β-葡聚糖掩膜来促进免疫逃避。
DOI：
10.1128/mbio.01318-18
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发表时间：
2018-11-06
期刊：
影响因子：
6.4
通讯作者：
Brown AJP
中科院分区：
文献类型：
--
作者：
Pradhan A;Avelar GM;Bain JM;Childers DS;Larcombe DE;Netea MG;Shekhova E;Munro CA;Brown GD;Erwig LP;Gow NAR;Brown AJP
动物、植物和真菌细胞所处的环境会造成氧气压力的变化。因此，许多物种进化出了一种机制，允许对这些变化进行强有力的适应。真菌病原体白色念珠菌可以在其人类宿主中的低氧(低氧)环境中定植，如下胃肠道和炎症组织，但为了定植其宿主，该真菌还必须逃避局部免疫防御。我们首次揭示了白念珠菌低氧适应和免疫逃避之间的明确联系。由于这种病原体适应低氧，它的细胞壁结构发生了变化，包括细胞表面的β-葡聚糖被掩盖，它变得更能逃避先天免疫细胞的吞噬作用。我们还定义了介导低氧诱导的β-葡聚糖屏蔽的信号机制，表明它们依赖于线粒体信号和cAMP-蛋白激酶途径。因此，低氧似乎触发了这种真菌病原体的免疫逃避。生物体必须适应氧气张力的变化，才能利用还原氧气的能量益处，同时将氧化的潜在破坏性影响降至最低。因此，所有真核生物王国中的生物都表现出对低氧(低氧水平)的强烈适应。这对寄主内低氧环境中的真菌病原体尤为重要。我们发现，在人类白色念珠菌的主要真菌病原体中，对低氧的适应包括细胞壁结构的变化和细胞表面β-葡聚糖暴露的减少，这是一种关键的病原体相关分子模式。这导致小鼠骨髓来源的巨噬细胞的吞噬功能减少，外周血单核细胞产生的IL-10、RANTES和肿瘤坏死因子-α减少，提示低氧诱导的β-葡聚糖掩蔽对白色念珠菌与宿主的相互作用有显著影响。我们发现，低氧诱导的β-葡聚糖屏蔽依赖于线粒体和cAMP-蛋白激酶A信号。β-葡聚糖暴露的减少被影响线粒体功能的突变(GOA1Δ和UPC2Δ)或减少内膜间隙过氧化氢的产生(SOD1Δ)所阻断。此外，β-葡聚糖的掩蔽通过提高线粒体活性氧物种(Aox1Δ)的突变而增强。外源性二丁酰-cAMP可抑制β-葡聚糖遮盖Δ和Upc2Δ细胞的缺陷。此外，使cAMP合成(Cyr1Δ)或PKA(tpk1Δtpk2Δ)失活的突变也阻止了掩蔽表型。我们的数据表明，白色念珠菌对低氧生态位的反应是通过线粒体cAMP-pKA信号通路诱导β-葡聚糖屏蔽，从而调节局部免疫反应和促进真菌定植。
Animal, plant, and fungal cells occupy environments that impose changes in oxygen tension. Consequently, many species have evolved mechanisms that permit robust adaptation to these changes. The fungal pathogen Candida albicans can colonize hypoxic (low oxygen) niches in its human host, such as the lower gastrointestinal tract and inflamed tissues, but to colonize its host, the fungus must also evade local immune defenses. We reveal, for the first time, a defined link between hypoxic adaptation and immune evasion in C. albicans. As this pathogen adapts to hypoxia, it undergoes changes in cell wall structure that include masking of β-glucan at its cell surface, and it becomes better able to evade phagocytosis by innate immune cells. We also define the signaling mechanisms that mediate hypoxia-induced β-glucan masking, showing that they are dependent on mitochondrial signaling and the cAMP-protein kinase pathway. Therefore, hypoxia appears to trigger immune evasion in this fungal pathogen. Organisms must adapt to changes in oxygen tension if they are to exploit the energetic benefits of reducing oxygen while minimizing the potentially damaging effects of oxidation. Consequently, organisms in all eukaryotic kingdoms display robust adaptation to hypoxia (low oxygen levels). This is particularly important for fungal pathogens that colonize hypoxic niches in the host. We show that adaptation to hypoxia in the major fungal pathogen of humans Candida albicans includes changes in cell wall structure and reduced exposure, at the cell surface, of β-glucan, a key pathogen-associated molecular pattern (PAMP). This leads to reduced phagocytosis by murine bone marrow-derived macrophages and decreased production of IL-10, RANTES, and TNF-α by peripheral blood mononuclear cells, suggesting that hypoxia-induced β-glucan masking has a significant effect upon C. albicans-host interactions. We show that hypoxia-induced β-glucan masking is dependent upon both mitochondrial and cAMP-protein kinase A (PKA) signaling. The decrease in β-glucan exposure is blocked by mutations that affect mitochondrial functionality (goa1Δ and upc2Δ) or that decrease production of hydrogen peroxide in the inner membrane space (sod1Δ). Furthermore, β-glucan masking is enhanced by mutations that elevate mitochondrial reactive oxygen species (aox1Δ). The β-glucan masking defects displayed by goa1Δ and upc2Δ cells are suppressed by exogenous dibutyryl-cAMP. Also, mutations that inactivate cAMP synthesis (cyr1Δ) or PKA (tpk1Δ tpk2Δ) block the masking phenotype. Our data suggest that C. albicans responds to hypoxic niches by inducing β-glucan masking via a mitochondrial cAMP-PKA signaling pathway, thereby modulating local immune responses and promoting fungal colonization.