Cryptococcal Urease Promotes the Accumulation of Immature Dendritic Cells and a Non-Protective T2 Immune Response within the Lung
Cryptococcal Urease Promotes the Accumulation of Immature Dendritic Cells and a Non-Protective T2 Immune Response within the Lung
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DOI：
10.2353/ajpath.2009.080673
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发表时间：
2009-03-01
影响因子：
6
通讯作者：
Olszewski, Michal A.
中科院分区：
文献类型：
--
作者：
Osterholzer, John J.;Surana, Rishi;Olszewski, Michal A.
脲酶是新型隐球菌的主要毒力因子，可促进小鼠致命性脑膜炎/脑炎。肺部是大多数侵袭性真菌感染的主要部位，脲酶对肺部的影响尚不清楚。利用新型隐球菌产脲酶（wt 和 ure1::URE1）或脲酶缺陷（ure1）菌株 (H99) 建立的小鼠感染模型，用于表征真菌清除以及这些菌株在肺内引起的免疫反应。结果表明，感染新型隐球菌产脲酶菌株的小鼠在感染后 2 周开始，真菌负荷增加了 100 倍（与感染缺乏脲酶的微生物的小鼠相比）。产生脲酶的新型隐球菌感染与高度极化的 T2 免疫反应相关，具体表现如下：1) 肺嗜酸性粒细胞，2) 血清 IgE 水平，3) T2 细胞因子（白细胞介素 4、-13 和 -4 与干扰素-γ 的比率），4) 交替激活的巨噬细胞。此外，感染产生脲酶新型隐球菌的小鼠，肺相关淋巴结内未成熟树突状细胞的百分比和总数显着增加。总的来说，这些数据将隐球菌脲酶定义为一种肺毒力因子，可促进未成熟树突状细胞的积累和有效但非保护性的 T2 免疫反应。这些发现为微生物因素影响侵袭性真菌病相关免疫病理学的机制提供了新的见解。 (Am J Pathol 2009, 174:932-943; DOI: 10.2353/ajpath.2009.080673)
Urease, a major virulence factor for Cryptococcus neoformans, promotes lethal meningitis/encephalitis in mice. The effect of urease within the lung, the primary site of most invasive fungal infections, is unknown. An established model of murine infection that utilizes either urease-producing (wt and ure1::URE1) or urease-deficient (ure1) strains (H99) of C neoformans was used to characterize fungal clearance and the resultant immune response evoked by these strains within the lung. Results indicate that mice infected with urease-producing strains of C neoformans demonstrate a 100-fold increase in fungal burden beginning 2 weeks post-infection (as compared with mice infected with urease-deficient organisms). Infection with urease-producing C neoformans was associated with a highly polarized T2 immune response as evidenced by increases in the following: 1) pulmonary eosinophils, 2) serum IgE levels, 3) T2 cytokines (interleukin-4, -13, and -4 to interferon-gamma ratio), and 4) alternatively activated macrophages. Furthermore, the percentage and total numbers of immature dendritic cells within the lung-associated lymph nodes was markedly increased in mice infected with urease-producing C neoformans. Collectively, these data define cryptococcal urease as a pulmonary virulence factor that promotes immature dendritic cell accumulation and a potent, yet non-protective, T2 immune response. These findings provide new insights into mechanisms by which microbial factors contribute to the immunopathology associated with invasive fungal disease. (Am J Pathol 2009, 174:932-943; DOI: 10.2353/ajpath.2009.080673)