Associate Professor Immunology College of Medicine, Qatar University Doha, Qatar
Introduction/Rationale: Pathogenic mycobacteria use specialized secretion systems to subvert host defenses and establish infection. ESX-1 and ESX-5 are major virulence determinants that shape immune responses and promote intracellular survival. Mycobacterium marinum, a close relative of M. tuberculosis, is a convenient model for these systems, yet how ESX systems reprogram bacterial and host transcription during infection remains poorly defined.
Methods: To investigate ESX-dependent host–pathogen interactions, dual RNA sequencing was performed on human THP-1 and murine RAW macrophages infected with wild-type Mmar E11 and its ESX-1 and ESX-5 knockout mutants. Comparative transcriptomic analyses identified differentially expressed bacterial and host genes. Functional enrichment, pathway analysis, and protein–protein interaction networks were used to determine the impact of ESX disruption on virulence and immune responses.
Results: Using dual RNA-seq of THP-1 and RAW264.7 macrophages infected with Mycobacterium marinum E11 and isogenic ESX-1/ESX-5 mutants, we define reproducible, host- and strain-specific transcriptomes. Murine macrophages show a broader transcriptional response than human cells; ESX-1 drives pro-inflammatory, phagosomal-rupture signatures, whereas ESX-5 loss attenuates the virulence program but unexpectedly amplifies early innate IFN/TNF signaling. These results indicate that ESX-1 and ESX-5 orchestrate distinct virulence networks that reprogram host immune pathways in a species-dependent manner, revealing secretion-system strategies for intracellular adaptation and immune modulation.
Conclusion: ESX-1 and ESX-5 coordinate M. marinum virulence and sculpt species-specific host immune responses. Disrupting either system weakens bacterial virulence and alters macrophage inflammatory signaling, confirming their central role in host–pathogen interactions and defining molecular signatures of ESX-dependent pathogenesis and host adaptation
