Chen Zhenkang, Hu Yangbo, Cumming Bridgette M, Lu Pei, Feng Lipeng, Deng Jiaoyu, Steyn Adrie J C, Chen Shiyun
Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 10086, China.
Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
Cell Rep. 2016 Aug 30;16(9):2512-24. doi: 10.1016/j.celrep.2016.07.080. Epub 2016 Aug 18.
During the course of infection, Mycobacterium tuberculosis (Mtb) is exposed to diverse redox stresses that trigger metabolic and physiological changes. How these stressors are sensed and relayed to the Mtb transcriptional apparatus remains unclear. Here, we provide evidence that WhiB6 differentially regulates the ESX-1 and DosR regulons through its Fe-S cluster. When challenged with NO, WhiB6 continually activates expression of the DosR regulons but regulates ESX-1 expression through initial activation followed by gradual inhibition. Comparative transcriptomic analysis of the holo- and reduced apo-WhiB6 complemented strains confirms these results and also reveals that WhiB6 controls aerobic and anaerobic metabolism, cell division, and virulence. Using the Mycobacterium marinum zebrafish infection model, we find that holo- and apo-WhiB6 modulate levels of mycobacterial infection, granuloma formation, and dissemination. These findings provide fresh insight into the role of WhiB6 in mycobacterial infection, dissemination, and disease development.
在感染过程中，结核分枝杆菌（Mtb）会面临多种氧化还原应激，这些应激会引发代谢和生理变化。目前尚不清楚这些应激源是如何被感知并传递给Mtb转录装置的。在此，我们提供证据表明，WhiB6通过其铁硫簇对ESX-1和DosR调控子进行差异调节。当受到一氧化氮（NO）刺激时，WhiB6持续激活DosR调控子的表达，但通过先激活后逐渐抑制来调节ESX-1的表达。对全蛋白和还原脱辅基WhiB6互补菌株的比较转录组分析证实了这些结果，并且还揭示了WhiB6控制有氧和无氧代谢、细胞分裂及毒力。使用海分枝杆菌斑马鱼感染模型，我们发现全蛋白和脱辅基WhiB6调节分枝杆菌感染水平、肉芽肿形成及扩散。这些发现为WhiB6在分枝杆菌感染、扩散及疾病发展中的作用提供了新的见解。
