WhiB4 is required for the reactivation of latent infection of Mycobacterium marinum in zebrafish [zebrafish RNAseq]

ABSTRACT: Granulomas are the pathological hallmark of tuberculosis (TB). In individuals latently infected with Mycobacterium tuberculosis (M. tb), the bacteria are thought to reside within the granulomas in a nonreplicating dormant state due to the lack of oxygen and nutrients. However, a portion of these individuals will develop active TB and little is known on the bacterial mechanisms/factors involved in this process. In this study, we found that WhiB4, an oxygen sensor and a transcription factor, plays a critical role in disease progression and reactivation of Mycobacterium marinum (M. marinum) infection in zebrafish. We show that the whiB4 mutant of M. marinum caused latent infection in adult zebrafish, which is characterized by the stable bacterial loads, constant number of non-necrotized granulomas in fewer organs, and reduced immune responses compared to zebrafish infected with the wild type bacteria or the complemented strain. The mutant bacteria in zebrafish were also less responsive to antibiotic treatments. Moreover, the whiB4 mutant was defective in resuscitation from hypoxia-induced dormancy and that the DosR regulon was dysregulated in the mutant. Taken together, our results suggest that WhiB4 is a major driver of reactivation from latent infection and that WhiB4 is an attractive target for the development of novel therapeutics, which may help to prevent the reactivation of latent infection thereby reducing the incidences of active TB.

ORGANISM(S): Danio rerio

PROVIDER: GSE178186 | GEO | 2021/06/16

REPOSITORIES: GEO