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Early macrophage immune responses and pathogenic features of an emerging Mycobacterium wolinskyi

ABSTRACT: Mycobacterium wolinskyi is an emerging rapidly growing mycobacterial species whose pathogenic mechanisms and host response patterns remain poorly understood. In this study, a clinical M. wolinskyi strain, designated QL01, was isolated from an 11-year-old child with a facial skin infection. Whole-genome sequencing revealed multiple features associated with pathogenicity, antimicrobial resistance, and host adaptation, including antimicrobial resistance genes, putative virulence factors, genomic islands, prophages, type VII secretion systems, and mammalian cell entry operons. To investigate the early host response, mouse bone marrow-derived macrophages were infected with M. wolinskyi QL01 and subjected to RNA sequencing. Transcriptomic analysis showed broad induction of inflammatory and immunometabolic programs, with prominent enrichment of the TNF, NF-kappa B, and HIF-1 signaling pathways. These findings provide a genomic and transcriptomic framework for understanding host-pathogen interactions involving M. wolinskyi.

ORGANISM(S): Mus musculus

PROVIDER: GSE327535 | GEO | 2026/06/05

REPOSITORIES: GEO

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Project description:The immune mechanisms that control resistance vs. susceptibility to mycobacterial infection in humans were investigated by studying leprosy skin lesions, the site where the battle between the host and the pathogen is joined. Using an integrative genomics approach, we found an inverse correlation between of IFN-beta and IFN-gamma gene expression programs at the site of disease. The Type II IFN, IFN-gamma and its downstream vitamin D-dependent antimicrobial genes were preferentially expressed in the lesions from patients with the self-healing tuberculoid form of the disease and mediated antimicrobial activity against the pathogen, Mycobacterium leprae in vitro. In contrast, the Type I IFN, IFN-beta and its downstream genes, including IL-27 and IL-10, were induced in monocytes by M. leprae in vitro, and were preferentially expressed in the lesions of disseminated and progressive lepromatous form. The IFN-gamma induced macrophage antimicrobial response was inhibited by IFN-beta/IL-10, by a mechanism involving blocking the generation of bioactive 1,25-dihyroxy vitamin D as well as inhibiting induction of antimicrobial peptides cathelicidin and DEFB4. The ability of IFN-M-oM-^AM-" to inhibit the IFN-gamma induced vitamin D pathway including antimicrobial activity was reversed by neutralization of IL-10, suggesting a possible target for therapeutic intervention. Finally, a common IFN-beta and IL-10 gene signature was identified in both the skin lesions of leprosy patients and in the peripheral blood of active tuberculosis patients. Together these data suggest that the ability of IFN-beta to downregulate protective IFN-gamma responses provides one general mechanism by which some bacterial pathogens of humans evade protective host responses and contribute to pathogenesis. Peripheral blood monuclear cells derived through Ficoll-Hypaque from the blood of healthy human donors (n=4). Cells adhered to tissue culture treated 6-well plates for 2 hours in 1% Fetal Bovine Serum (FBS) RPMI and then stimulated by IL-10 (R&D Systems) 10ng/ml or media alone in 10% FBS RPMI for 24 hours at 37M-BM-0C, 5% CO2. After stimulation, cells harvested and monocytes isolated through CD14 positive selection (Miltenyi Biotec). RNA from purified monocytes extracted by Trizol and purified by Qiagen RNeasy Kit. RNA probe and microarray performed by UCLA Clinical Microarray Core using Ambion labeling kit and Affymetrix Human U133 Plus 2.0 array.

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Early macrophage immune responses and pathogenic features of an emerging Mycobacterium wolinskyi

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