Candida auris Cell Wall Mannosylation Contributes to Neutrophil Evasion through Pathways Divergent from Candida albicans and Candida glabrata.
Candida auris Cell Wall Mannosylation Contributes to Neutrophil Evasion through Pathways Divergent from Candida albicans and Candida glabrata.
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DOI：
10.1128/msphere.00406-21
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发表时间：
2021-06-30
期刊：
影响因子：
4.8
通讯作者：
Nett JE
中科院分区：
文献类型：
--
作者：
Horton MV;Johnson CJ;Zarnowski R;Andes BD;Schoen TJ;Kernien JF;Lowman D;Kruppa MD;Ma Z;Williams DL;Huttenlocher A;Nett JE
耳念珠菌是最近出现的一种真菌病原体，在世界各地的卫生保健机构中引起侵袭性感染。死亡率接近60%，医院传播对公共卫生构成威胁。与其他念珠菌相比，金黄色葡萄球菌避免触发中性粒细胞的抗真菌活性，中性粒细胞是应对许多侵袭性真菌感染（包括念珠菌病）的先天免疫细胞。然而，支撑这种免疫逃避的机制在很大程度上是未知的。在这里，我们在斑马鱼感染模型中表明，金黄色葡萄球菌细胞壁甘露糖基化有助于中性粒细胞的体外逃避。甘露糖基化途径（PMR1和VAN1）的遗传破坏减少了外细胞壁甘露糖，揭示了免疫刺激成分，并促进中性粒细胞参与、吞噬和杀伤。在检查了其他念珠菌（白色念珠菌和光滑念珠菌）的这些途径后，我们没有发现对中性粒细胞相互作用的影响。这些研究表明，耳念珠菌甘露糖基化是如何通过不同于其他常见念珠菌的途径促进中性粒细胞逃避的。这些发现揭示了这种新兴病原体的先天免疫逃避。新出现的真菌病原体耳念珠菌对全球公共卫生构成威胁。对于这种经常耐药的病原体，治疗选择往往有限，而且侵袭性疾病的死亡率很高。先前的研究表明，中性粒细胞（抗真菌宿主防御的关键白细胞）不能有效地识别和杀死金黄色葡萄球菌。在这里，我们展示了金黄色葡萄球菌的外细胞壁如何促进免疫逃避。这种甘露聚糖多糖层的破坏使金黄色葡萄球菌易受中性粒细胞体外杀伤和斑马鱼侵袭性念珠菌病模型的影响。这些甘露糖基化途径对中性粒细胞逃避的作用似乎与其他常见念珠菌不同。
Candida auris, a recently emergent fungal pathogen, has caused invasive infections in health care settings worldwide. Mortality rates approach 60% and hospital spread poses a public health threat. Compared to other Candida spp., C. auris avoids triggering the antifungal activity of neutrophils, innate immune cells that are critical for responding to many invasive fungal infections, including candidiasis. However, the mechanism underpinning this immune evasion has been largely unknown. Here, we show that C. auris cell wall mannosylation contributes to the evasion of neutrophils ex vivo and in a zebrafish infection model. Genetic disruption of mannosylation pathways (PMR1 and VAN1) diminishes the outer cell wall mannan, unmasks immunostimulatory components, and promotes neutrophil engagement, phagocytosis, and killing. Upon examination of these pathways in other Candida spp. (Candida albicans and Candida glabrata), we did not find an impact on neutrophil interactions. These studies show how C. auris mannosylation contributes to neutrophil evasion though pathways distinct from other common Candida spp. The findings shed light on innate immune evasion for this emerging pathogen. IMPORTANCE The emerging fungal pathogen Candida auris presents a global public health threat. Therapeutic options are often limited for this frequently drug-resistant pathogen, and mortality rates for invasive disease are high. Previous study has demonstrated that neutrophils, leukocytes critical for the antifungal host defense, do not efficiently recognize and kill C. auris. Here, we show how the outer cell wall of C. auris promotes immune evasion. Disruption of this mannan polysaccharide layer renders C. auris susceptible to neutrophil killing ex vivo and in a zebrafish model of invasive candidiasis. The role of these mannosylation pathways for neutrophil evasion appears divergent from other common Candida species.