TNF-α-Producing Cryptococcus neoformans Exerts Protective Effects on Host Defenses in Murine Pulmonary Cryptococcosis
TNF-α-Producing Cryptococcus neoformans Exerts Protective Effects on Host Defenses in Murine Pulmonary Cryptococcosis
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产生 TNF-α 的新型隐球菌对小鼠肺隐球菌病的宿主防御具有保护作用
DOI：
10.3389/fimmu.2019.01725
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发表时间：
2019-07-26
影响因子：
7.3
通讯作者：
Olszewski, Michal A.
中科院分区：
文献类型：
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作者：
Fa, Zhenzong;Xu, Jintao;Olszewski, Michal A.
肿瘤坏死因子α（TNF-α）在控制隐球菌感染中发挥着关键作用，其不足会促进隐球菌的持续存在。为了探索补充 TNF-α 作为宿主抗隐球菌反应增强剂的治疗潜力，我们设计了表达鼠 TNF-α 的新型隐球菌菌株。使用肺隐球菌病的小鼠模型，我们证明与野生型菌株感染的小鼠相比，产生 TNF-α 的新型隐球菌菌株增强了宿主反应的保护性要素，包括优先 T 细胞积累和改善 Th1/Th2 细胞因子平衡，减少肺嗜酸性粒细胞增多以及在感染适应阶段肺巨噬细胞的替代激活。此外，新型隐球菌表达的 TNF-α 增强了巨噬细胞的体外杀菌活性。最后，与野生型菌株感染的小鼠相比，感染产生 TNF-α 的新型隐球菌菌株的小鼠显示出改善的真菌控制和显着延长的存活期，但不能诱导不育免疫。综上所述，我们的结果支持工程改造的新型隐球菌菌株的 TNF-α 表达虽然不足以驱动完整的免疫保护，但在原发性隐球菌感染期间强烈增强了保护反应。
Tumor necrosis factor alpha (TNF-alpha) plays a critical role in the control of cryptococcal infection, and its insufficiency promotes cryptococcal persistence. To explore the therapeutic potential of TNF-alpha supplementation as a booster of host anti-cryptococcal responses, we engineered a C. neoformans strain expressing murine TNF-alpha. Using a murine model of pulmonary cryptococcosis, we demonstrated that TNF-alpha-producing C. neoformans strain enhances protective elements of host response including preferential T-cell accumulation and improved Th1/Th2 cytokine balance, diminished pulmonary eosinophilia and alternative activation of lung macrophages at the adaptive phase of infection compared to wild type strain-infected mice. Furthermore, TNF-alpha expression by C. neoformans enhanced the fungicidal activity of macrophages in vitro. Finally, mice infected with the TNF-alpha-producing C. neoformans strain showed improved fungal control and considerably prolonged survival compared to wild type strain-infected mice, but could not induce sterilizing immunity. Taken together, our results support that TNF-alpha expression by an engineered C. neoformans strain while insufficient to drive complete immune protection, strongly enhanced protective responses during primary cryptococcal infection.