Abstract
During the course of infection, pathogenic mycobacteria including Mycobacterium tuberculosis (M. tb) encounter host environments of variable oxygen tension, ranging from the hypoxic center of granulomas to the most oxygenated region in the lung cavities. Mycobacterial responses to changes of oxygen tension are critically related to infection outcomes, such as latency and reactivation. WhiB4 is an iron-sulfur containing transcription factor that is highly sensitive to oxygen exposure. In this study, we found that WhiB4 of Mycobacterium marinum (M. marinum), a pathogenic mycobacterial species that is closely related to M. tb, is required for its virulence. M. marinum ΔwhiB4 exhibited defective intracellular replication in macrophages and diminished virulence in zebrafish. Histology analysis revealed that the host had successfully controlled ΔwhiB4 bacteria, forming well-organized granulomas. RNA-seq analysis identified a large number of pe/ppe genes that were regulated by WhiB4, which provides an explanation for the essential role of WhiB4 in M. marinum virulence. Several antioxidant enzymes were also upregulated in ΔwhiB4, supporting its role in modulation of oxidative stress response. Taken together, we have provided new insight into and proposed a model to explain the physiological role of WhiB4.
Highlights
Tuberculosis, caused by Mycobacterium tuberculosis (M. tb), continues to be a major global health problem, causing 1.5 million deaths and 9.6 million new infections in 2014
WhiB4 is a member of the WhiB superfamily transcription factors that are conserved in actinomycetes, including many mycobacterial species such as M. tb and M. marinum[23,24,25,26,27,28]
We found that WhiB4 plays similar yet distinct roles in M. marinum and M. tb
Summary
Tuberculosis, caused by Mycobacterium tuberculosis (M. tb), continues to be a major global health problem, causing 1.5 million deaths and 9.6 million new infections in 2014. During the course of infection, M. tb must encounter heterogeneous host environments, including the high oxygen tension in the lung alveolus[5], the reactive oxygen and nitrogen species generated in activated macrophages[6], as well as the nutrient depleted and hypoxic center of tuberculous granulomas[7, 8]. Little is known about the reactivation of M. tb from the persistent state, and presumably access to oxygen is an important requirement Consistent with this notion, reactivation of latent TB in humans occurs most frequently in the upper lobes of the lung, the most oxygenated region of the body[9]. The ability to rapidly respond to oxygen exposure and activate DNA binding activity implies an active role of WhiB4 in mycobacterial virulence. Our study provides new insight into the biological function of WhiB4 and indicates a different role for WhiB4 in different pathogenic mycobacteria
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