Cryptococcus neoformans infections are significant causes of morbidity and mortality among AIDS patients and the third most common invasive fungal infection in organ transplant recipients. One of the main interfaces between the fungus and the host is the fungal cell wall. The cryptococcal cell wall is unusual among human-pathogenic fungi in that the chitin is predominantly deacetylated to chitosan. Chitosan-deficient strains of C. neoformans were found to be avirulent and rapidly cleared from the murine lung. Moreover, infection with a chitosan-deficient C. neoformans strain lacking three chitin deacetylases (cda1Δcda2Δcda3Δ) was found to confer protective immunity to a subsequent challenge with a virulent wild-type counterpart. In addition to the chitin deacetylases, it was previously shown that chitin synthase 3 (Chs3) is also essential for chitin deacetylase-mediated formation of chitosan. Mice inoculated with the chs3Δ strain at a dose previously shown to induce protection with the cda1Δcda2Δcda3Δ strain die within 36 h after installation of the organism. Mortality was not dependent on viable fungi, as mice inoculated with a heat-killed preparation of the chs3Δ strain died at the same rate as mice inoculated with a live chs3Δ strain, suggesting that the rapid onset of death was host mediated, likely caused by an overexuberant immune response. Histology, cytokine profiling, and flow cytometry indicate a massive neutrophil influx in the mice inoculated with the chs3Δ strain. Mice depleted of neutrophils survived chs3Δ inoculation, indicating that death was neutrophil mediated. Altogether, these studies lead us to conclude that Chs3, along with chitosan, plays critical roles in dampening cryptococcus-induced host inflammatory responses.IMPORTANCE Cryptococcus neoformans is the most common disseminated fungal pathogen in AIDS patients, resulting in ∼200,000 deaths each year. There is a pressing need for new treatments for this infection, as current antifungal therapy is hampered by toxicity and/or the inability of the host's immune system to aid in resolution of the disease. An ideal target for new therapies is the fungal cell wall. The cryptococcal cell wall is different from the cell walls of many other pathogenic fungi in that it contains chitosan. Strains that have decreased chitosan are less pathogenic and strains that are deficient in chitosan are avirulent and can induce protective responses. In this study, we investigated the host responses to a chs3Δ strain, a chitosan-deficient strain, and found that mice inoculated with the chs3Δ strain all died within 36 h and that death was associated with an aberrant hyperinflammatory immune response driven by neutrophils, indicating that chitosan is critical in modulating the immune response to Cryptococcus.

中文翻译：

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新型隐球菌几丁质合酶3在抑制宿主炎症反应中起关键作用。

新型隐球菌感染是艾滋病患者发病和死亡的重要原因，也是器官移植受者中第三种最常见的侵袭性真菌感染。真菌和宿主之间的主要界面之一是真菌细胞壁。在人致病性真菌中，隐球菌细胞壁是不常见的，因为几丁质主要被脱乙酰化为壳聚糖。发现壳聚糖缺陷的新孢梭菌菌株无毒并且可以从鼠肺中快速清除。此外，发现缺乏三种甲壳质脱乙酰基酶（cda1Δcda2Δcda3Δ）的壳聚糖缺陷型新孢梭菌菌株的感染可赋予保护性免疫力，以应对随后的有毒野生型对应物攻击。除了几丁质脱乙酰基酶 先前已证明，几丁质合酶3（Chs3）对于几丁质脱乙酰基酶介导的壳聚糖的形成也是必不可少的。chs3Δ菌株接种的小鼠的剂量先前显示出可诱导cda1Δcda2Δcda3Δ菌株产生保护作用的剂量，在安装生物体后36小时内死亡。死亡率不依赖于活菌，因为用热灭活的chs3Δ毒株接种的小鼠死亡的速度与接种chs3Δ活菌的小鼠相同，这表明死亡的快速发作是宿主介导的，可能是由过度旺盛的免疫反应。组织学，细胞因子谱和流式细胞术表明，在接种chs3Δ菌株的小鼠中大量嗜中性粒细胞大量涌入。耗尽嗜中性粒细胞的小鼠在chs3Δ接种后存活，表明死亡是由嗜中性粒细胞介导的。共，这些研究使我们得出结论，Chs3与壳聚糖一起在抑制隐球菌诱导的宿主炎症反应中起着关键作用。重要事项新隐球菌是AIDS患者中最常见的传播性真菌病原体，每年导致约200,000例死亡。迫切需要针对这种感染的新治疗方法，因为当前的抗真菌治疗受到毒性和/或宿主免疫系统无法帮助解决疾病的困扰。真菌细胞壁是新疗法的理想靶标。隐球菌细胞壁与许多其他致病真菌的细胞壁不同，因为它含有壳聚糖。壳聚糖含量降低的菌株致病性较低，壳聚糖缺乏的菌株无毒，可以诱导保护性反应。在这个研究中，