The antagonistic transcription factors, EspM and EspN, regulate the ESX-1 secretion system in M. marinum

• Published in: mBio Vol. 15; no. 4; p. e0335723
• Main Authors: Nicholson, Kathleen R, Cronin, Rachel M, Prest, Rebecca J, Menon, Aruna R, Yang, Yuwei, Jennisch, Madeleine K, Champion, Matthew M, Tobin, David M, Champion, Patricia A
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 10.04.2024
• Subjects: Animals; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; ESX-1; Microbial Pathogenesis; Mycobacterium; Mycobacterium marinum - metabolism; Mycobacterium tuberculosis - metabolism; regulation; Research Article; transcription; Transcription Factors - genetics; Transcription Factors - metabolism; Tuberculosis - microbiology; type VII secretion; Type VII Secretion Systems - genetics; Type VII Secretion Systems - metabolism; Zebrafish; Mycobacterium; regulation; transcription; type VII secretion; ESX-1
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mbio.03357-23

Bacterial pathogens use protein secretion systems to transport virulence factors and regulate gene expression. Among pathogenic mycobacteria, including and , the ESAT-6 system 1 (ESX-1) secretion is crucial for host interaction. Secretion of protein substrates by the ESX-1 secretion system disrupts phagosomes, allowing mycobacteria cytoplasmic access during macrophage infections. Deletion or mutation of the ESX-1 system attenuates mycobacterial pathogens. Pathogenic mycobacteria respond to the presence or absence of the ESX-1 system in the cytoplasmic membrane by altering transcription. Under laboratory conditions, the EspM repressor and WhiB6 activator control transcription of specific ESX-1-responsive genes, including the ESX-1 substrate genes. However, deleting the or gene does not phenocopy the deletion of the ESX-1 substrate genes during macrophage infection by . In this study, we identified EspN, a critical transcription factor whose activity is masked by the EspM repressor under laboratory conditions. In the absence of EspM, EspN activates transcription of and ESX-1 genes during both laboratory growth and macrophage infection. EspN is also independently required for growth within and cytolysis of macrophages, similar to the ESX-1 genes, and for disease burden in a zebrafish larval model of infection. These findings suggest that EspN and EspM coordinate to counterbalance the regulation of the ESX-1 system and support mycobacterial pathogenesis.IMPORTANCEPathogenic mycobacteria, which are responsible for tuberculosis and other long-term diseases, use the ESX-1 system to transport proteins that control the host response to infection and promote bacterial survival. In this study, we identify an undescribed transcription factor that controls the expression of ESX-1 genes and is required for both macrophage and animal infection. However, this transcription factor is not the primary regulator of ESX-1 genes under standard laboratory conditions. These findings identify a critical transcription factor that likely controls expression of a major virulence pathway during infection, but whose effect is not detectable with standard laboratory strains and growth conditions.