Furuuchi, K. | bioRxiv Science

bioRxiv2026

Clinical isolates of Mycobacterium avium complex reveal an M. intracellulare-associated IL-17/neutrophilic pulmonary immune program in a murine disease model

Mycobacterium avium complex (MAC) is the leading cause of nontuberculous mycobacterial pulmonary disease (NTM-PD) and mainly comprises M. avium (MAV) and M. intracellulare (MI). Host-pathogen interactions may contribute to the heterogeneous clinical course of MAC pulmonary disease (MAC-PD); however, species- or isolate-associated differences in virulence and host immune responses induced by MAC strains remain poorly understood. Here, we established a panel of MAC clinical isolates exhibiting persistent pulmonary infection in mice and performed transcriptomic analyses to evaluate pulmonary immune responses. Although MAC infections induced broadly shared inflammatory responses, MI infection elicited a robust IL-17/neutrophilic inflammatory signature, whereas MAV infection showed relative enrichment of IFN-{gamma}/cytotoxicity-associated responses, indicating differences in the balance of their immune gene expression programs. The MI-associated IL-17/neutrophilic program remained evident at the isolate level and after adjustment for pulmonary growth phenotype. RT-qPCR and flow cytometric analyses using the representative isolate pair FKJ-1 (MI) and FKJ-8 (MAV) further supported the differential induction of these immune signatures in infected lungs. To define the cellular basis of these immune programs, we performed single-cell RNA sequencing on lungs infected with FKJ-1 and FKJ-8. Infection with the representative MI isolate was associated with increased Il17a-expressing CD4+ T cells and {gamma}{delta} T cells, neutrophilic inflammation, and the expansion of inflammatory macrophages. Taken together, these findings demonstrate that within a selected panel of persistent MAC clinical isolates, MI infection is associated with a robust IL-17/neutrophilic pulmonary immune program, providing a preclinical framework for dissecting species- and isolate-associated host-pathogen interactions in MAC-PD.

immunology↗

bioRxiv2025

Strain-dependent disease progression and necrotizing granuloma formation induced by virulent Mycobacterium avium complex strains in a murine model

Mycobacterium avium complex (MAC) is the leading cause of non-tuberculous mycobacterial pulmonary disease (NTM-PD), a chronic infection with a heterogeneous clinical course. Although murine models of MAC-PD have been developed, reproducing the key features of progressive human disease, including diverse pathological features and therapeutic sensitivities, remains challenging. In this study, we evaluated five clinical MAC strains, including a newly identified highly virulent isolate, NBRC112750, in immunocompetent BALB/c mice. Among these, FKJ-1 and NBRC112750 induced progressive pulmonary infection with increasing bacterial burdens and extensive lung involvement by 25 weeks post-infection. Notably, both strains led to the formation of necrotizing granulomas resembling those observed in M. tuberculosis-infected C3HeB/FeJ mice. These lesions featured neutrophilic infiltration, foamy macrophages, and collagen encapsulation. Using FKJ-1 strain, we also established an inhalation infection model, in which low-dose exposure reproduced necrotizing granulomas. Despite in vitro drug susceptibility, FKJ-1 infection exhibited poor response to standard therapy, highlighting strain-dependent variability in treatment efficacy. These findings establish a murine model that reflects both key pathological and therapeutic aspects of MAC-PD and provides a valuable platform for investigating MAC pathogenesis and evaluating novel therapies.

microbiology↗