Virulence Factors Identified by Cryptococcus neoformans Mutant Screen Differentially Modulate Lung Immune Responses and Brain Dissemination
Virulence Factors Identified by Cryptococcus neoformans Mutant Screen Differentially Modulate Lung Immune Responses and Brain Dissemination
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DOI：
10.1016/j.ajpath.2012.06.012
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发表时间：
2012-10-01
影响因子：
6
通讯作者：
Olszewski, Michal A.
中科院分区：
文献类型：
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作者：
He, Xiumiao;Lyons, Daniel M.;Olszewski, Michal A.
隐球菌 PIK1、RUB1 和 ENA1 基因的缺失独立地导致人脑脊液和巨噬细胞内酵母的存活缺陷。我们通过在 BALB/c 小鼠肺部感染模型中比较野生型新型隐球菌菌株 H99 与缺失菌株和补体菌株来评估这些基因的毒力潜力。受感染小鼠的存活率；肺隐球菌生长和病理学；免疫学参数；传播动力学；并检查中枢神经系统病理学。 PIK1、RUB1 和 ENA1 的缺失均不同程度地降低了新型隐球菌的肺部生长和传播率，并延长了小鼠的存活时间。此外，pik1 Delta 引起与 H99 类似的病理，但发病明显延迟； rub1 Delta 更有效地包含在肺巨噬细胞内，并进一步延迟引起中枢神经系统传播/病理；而ena1 Delta逐渐从肺部消除，不会引起病理损伤或传播到中枢神经系统。突变株毒力的减弱与肺部免疫反应的差异调节有关，包括白细胞亚群、细胞因子反应和巨噬细胞激活状态的变化。与 H99 感染相比，突变体诱导了更多的保护性 Th1 免疫反应特征，而不是 Th2，并且诱导了更经典的而不是替代性的巨噬细胞激活。免疫效应的大小与每种菌株表现出的毒力水平精确对应。因此，隐球菌 PIK1、RUB1 和 ENA1 对隐球菌毒力的贡献不同，与其调节免疫反应的能力不同相关。 （Am J Pathol 2012 年，181：1356-1364 http://dx.doi.org/10.1016/j.ajpath.2012.06.012）
Deletions of cryptococcal PIK1, RUB1, and ENA1 genes independently rendered defects in yeast survival in human CSF and within macrophages. We evaluated virulence potential of these genes by comparing wild-type Cryptococcus neoformans strain H99 with deletant and complement strains in a BALB/c mouse model of pulmonary infection. Survival of infected mice; pulmonary cryptococcal growth and pathology; immunological parameters; dissemination kinetics; and CNS pathology were examined. Deletion of each PIK1, RUB1, and ENA1 differentially reduced pulmonary growth and dissemination rates of C. neoformans and extended mice survival. Furthermore, pik1 Delta induced similar pathologies to H99, however, with significantly delayed onset; rub1 Delta was more efficiently contained within pulmonary macrophages and was further delayed in causing CNS dissemination/pathology; whereas ena1 Delta was progressively eliminated from the lungs and did not induce pathological lesions or disseminate into the CNS. The diminished virulence of mutant strains was associated with differential modulation of pulmonary immune responses, including changes in leukocyte subsets, cytokine responses, and macrophage activation status. Compared to H99 infection, mutants induced more hallmarks of a protective Th1 immune response, rather than Th2, and more classical, rather than alternative, macrophage activation. The magnitude of immunological effects precisely corresponded to the level of virulence displayed by each strain. Thus, cryptococcal PIK1, RUB1, and ENA1 differentially contribute to cryptococcal virulence, in correlation with their differential capacity to modulate immune responses. (Am J Pathol 2012, 181:1356-1364 http://dx.doi.org/10.1016/j.ajpath.2012.06.012)