Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
Department of Bacteriology, Immunology and Mycology, College of Veterinary Medicine, Benha University, Toukh 13736, Egypt.
Int J Mol Sci. 2022 May 20;23(10):5713. doi: 10.3390/ijms23105713.
Copper is required for aerobic respiration by and its human host, but this essential element is toxic in abundance. Copper nutritional immunity refers to host processes that modulate levels of free copper to alternately starve and intoxicate invading microbes. Bacteria engulfed by macrophages are initially contained within copper-limited phagosomes, which fuse with ATP7A vesicles that pump in toxic levels of copper. In this report, we examine how CtpB, a P-type ATPase in , aids in response to nutritional immunity. In vitro, the induced expression of in copper-replete medium inhibited mycobacterial growth, while deletion of the gene impaired growth only in copper-starved medium and within copper-limited host cells, suggesting a role for CtpB in copper acquisition or export to the copper-dependent respiration supercomplex. Unexpectedly, the absence of resulted in hypervirulence in the DBA/2 mouse infection model. As null strains exhibit diminished growth only in copper-starved conditions, reduced copper transport may have enabled the mutant to acquire a "Goldilocks" amount of the metal during transit through copper-intoxicating environments within this model system. This work reveals CtpB as a component of the toolkit to counter host nutritional immunity and underscores the importance of elucidating copper-uptake mechanisms in pathogenic mycobacteria.
铜是 和其人类宿主进行需氧呼吸所必需的，但这种必需元素在大量存在时是有毒的。铜的营养免疫是指宿主调节游离铜水平的过程，以使入侵的微生物时而饥饿、时而中毒。被巨噬细胞吞噬的细菌最初被包含在铜有限的吞噬体中，这些吞噬体与 ATP7A 囊泡融合，将有毒水平的铜泵入其中。在本报告中，我们研究了 中的 CtpB 如何辅助营养免疫反应。在体外，铜充足培养基中诱导表达 的表达抑制了分枝杆菌的生长，而该基因的缺失仅在铜饥饿培养基中和铜有限的宿主细胞中损害了生长，表明 CtpB 在铜获取或向铜依赖性呼吸超级复合物的外排中发挥作用。出乎意料的是， 在 DBA/2 小鼠感染模型中缺乏 会导致高毒力。由于 缺失株仅在铜饥饿条件下表现出生长减弱，因此减少铜转运可能使突变体在通过该模型系统中铜中毒环境的运输过程中获得“恰到好处”的金属量。这项工作揭示了 CtpB 是 对抗宿主营养免疫的工具包的一个组成部分，并强调了阐明致病性分枝杆菌中铜摄取机制的重要性。
