Mycobacterium avium, a slow-growing nontuberculous mycobacterium (NTM), is the main cause of life-threatening NTM infections, which are globally on the rise. Unlike Mycobacterium tuberculosis and Mycobacterium marinum, M. avium lacks ESX-1, a subtype of Type VII secretion system (T7SS) and a key virulence determinant. The absence of ESX-1 in M. avium raises questions about its alternative intracellular survival strategies. To investigate M. avium pathogenesis, we exploited our recently established infection model in zebrafish larvae, enabling live imaging of early host-pathogen interactions. Macrophage depletion significantly increased M. avium burden and larval mortality, while neutrophil depletion had no major effect, emphasizing macrophages as key defenders against M. avium. In support, imaging of tnfa activation showed that macrophages polarized to a proinflammatory phenotype. However, like M. marinum, M. avium exploits chemokine receptor Cxcr3.2 signaling in macrophages for its expansion in granuloma-like clusters. Both M. avium and M. marinum preferentially infected macrophages, but M. avium-induced granuloma-like clusters were more compact and exhibited less cell death. Supporting this, lytic cell death pathways were enriched in M. marinum but not M. avium transcriptome signatures. Consequently, we investigated pyroptosis, an important form of inflammation-induced lytic cell death. We found that knockdown of critical mediators of pyroptosis, namely inflammatory caspase a (caspa) and gasdermin Eb (gsdmeb), produced opposing effects on the two mycobacterial pathogens, indicating a host-protective role during M. avium infection, while exacerbating M. marinum growth. These findings highlight the interaction with host cell death signaling as a determining factor for the pathogenic potential of mycobacterial species.
Hu et al. (Thu,) studied this question.