通过对过氧化的适应,共同进化受furA调节的超炎症和菌根菌对氧化杀伤的耐药性
Xin Fan1, Bei Zhao2, Weishan Zhang1,2
1CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Microbiology spectrum
|June 26, 2023
概括
适应的Mycobacterium smegmatis对过氧化 (H2O2) 产生了耐药性,在小鼠中变得持久并导致致命性. 一个furA基因突变导致炎症和严重的肺损伤,突出FurA基因突变.
科学领域:
- 微生物学 微生物学
- 免疫学 免疫学 免疫学
- 遗传学 是一个遗传学.
背景情况:
- 结核菌 (Mtb) 对宿主氧化杀死机制具有很高的抵抗力.
- 了解Mtb的发病性对于制定有效的结核病控制策略至关重要.
研究的目的:
- 调查Mycobacterium smegmatis对过氧化 (H2O2) 的进化适应是否可以赋予宿主持久性.
- 确定导致Mtb耐药性和致病性的遗传因素.
主要方法:
- 通过体外进化适应,查M. smegmatis的H2O2耐药性.
- 产生一种高度耐药的菌株 (mc2114) 并在小鼠感染模型中评估其毒性.
- 全基因组测序以识别耐药菌株中的突变.
- 补充研究验证了特定突变的作用,特别是在furA基因.
主要成果:
- 与野生类型相比,调整后的菌株mc2114显示出320倍的H2O2耐药性.
- mc2114在小鼠肺部表现出类似Mtb的持久性,导致高致死率,减少NOX2/ROS/IFN-γ反应,并减少巨细胞亡.
- 全基因组测序确定了29个单核酸多态,其中一个在furA导致FurA缺乏.
- FurA 缺乏导致KatG (ROS排毒酶) 的过度表达和严重的肺炎.
- 补充野生类型furA逆转了致死率和炎症,但没有恢复NOX2,ROS,IFN-γ或巨细胞亡水平.
结论:
- FurA 缺乏,不直接参与ROS响应的限制,驱动有害的肺炎,并有助于真菌细菌的致病性.
- 菌根菌对氧化应激的耐药性涉及多个基因的复杂适应性遗传变化.
- FurA调节的肺炎是真菌菌病原发生的一个关键因素,超出了以前已知的机制.
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