| Autor: |
Shey-Njila O; Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA., Hikal AF; 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., Gupta T; Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA., Sakamoto K; Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA., Yahyaoui Azami H; Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA., Watford WT; Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA., Quinn FD; Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA., Karls RK; Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA. |
| Abstrakt: |
Copper is required for aerobic respiration by Mycobacterium tuberculosis 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 M. tuberculosis , aids in response to nutritional immunity. In vitro, the induced expression of ctpB 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 ctpB resulted in hypervirulence in the DBA/2 mouse infection model. As ctpB 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 M. tuberculosis toolkit to counter host nutritional immunity and underscores the importance of elucidating copper-uptake mechanisms in pathogenic mycobacteria. |
