Coordinate regulation of virulence and metabolic genes by the transcription factor HbhR in Mycobacterium marinum

Summary The heparin‐binding hemagglutinin (HBHA) is a multifunctional protein involved in adherence of Mycobacterium tuberculosis to non‐phagocytic cells and in the formation of intracytosolic lipid inclusions. We demonstrate that the expression of hbhA is regulated by a transcriptional repressor, named HbhR, in Mycobacterium marinum. The hbhR gene, located upstream of hbhA, was identified by screening a transposon insertion library and detailed analysis of a mutant overproducing HBHA. HbhR was found to repress both hbhA and hbhR transcription by binding to the promoter regions of both genes. Complementation restored production of HBHA. RNA‐seq analyses comparing the mutant and parental strains uncovered 27 genes, including hbhA, that were repressed and 20 genes activated by HbhR. Among the former, the entire locus of genes coding for a type‐VII secretion system, including esxA, esxB and pe‐ppe paralogs, as well as the gene coding for PspA, present in intracellular lipid vesicles, was identified, as was katG, a gene involved in the sensitivity to isoniazid. The latter category contains genes that play a role in diverse functions, such as metabolism and resistance to oxidative conditions. Thus, HbhR appears to be a master regulator, linking the transcriptional regulation of virulence, metabolic and antibiotic sensitivity genes in M. marinum. This study describes a transcriptional repressor, HbhR, involved in the regulation of the orthologous gene of HBHA in Mycobacterium marinum. This virulence factor has been described in Mycobacterium tuberculosis to promote the dissemination of the bacilli and to participate in the intracytoplasmic lipid droplets formation. In parallel, HbhR positively or negatively regulates paralogs of genes from the ESX‐1 locus and a number of metabolic genes that are likely important during the mycobacterial life cycle in the host.