Mice with lung airway ciliopathy develop persistent Mycobacterium abscessus lung infection and have a proinflammatory lung phenotype associated with decreased T regulatory cells

• Published in: Frontiers in immunology 2022-11, Vol.13, p.1017540-1017540
• Main Authors: Nava, Audrey, Hahn, Andrew C, Wu, Terry H, Byrd, Thomas F
• Format: Article
• Language: English
• Subjects: Adult; Animals; Bronchiectasis; CD4+FoxP3; CD4+IL17; cilia; Cytokines; Humans; IFT88; Immunology; Lung; Lung Diseases; Mice; Mycobacterium abscessus - genetics; Mycobacterium Infections, Nontuberculous - genetics; Nontuberculous Mycobacteria; Thorax
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.1017540

Human pulmonary infection with non-tuberculous mycobacteria (NTM) such as (Mabs) occurs in seemingly immunocompetent patients with underlying structural lung disease such as bronchiectasis in which normal ciliary function is perturbed. In addition to alterations in mucociliary clearance, the local immunologic milieu may be altered in patients with structural lung disease, but the nature of these changes and how they relate to NTM persistence remain unclear. We used a mouse strain containing a conditional floxed allele of the gene , which encodes for the protein Polaris. Deletion of this gene in adult mice reportedly leads to loss of cilia on lung airway epithelium and to the development of bronchiectasis. In a series of experiments, control mice and KO mice received different preparations of lung inocula with lung CFU assessed out to approximately 8 weeks post-infection. In addition, cytokine levels in bronchoalveolar lavage (BAL) fluid, lung T cell subset analysis, and lung histopathology and morphometry were performed at various time points. embedded in agarose beads persisted in the lungs of KO mice out to approximately 8 weeks (54 days), while agarose beads in the lungs of control mice was cleared from the lungs of all mice at this time point. T cells subset analysis showed a decrease in the percentage of CD4 FoxP3 T cells in the total lymphocyte population in the lungs of KO mice relative to control mice. Proinflammatory cytokines were elevated in the BAL fluid from infected KO mice compared to infected control mice, and histopathology showed an increased inflammatory response and greater numbers of granulomas in the lungs of infected KO mice compared to the lungs of infected control mice. Scanning lung morphometry did not show a significant difference comparing lung airway area and lung airway perimeter between KO mice and control mice. Persistent lung infection in our model was established using embedded in agarose beads. The utility of using mice is that a significant difference in lung CFU is observed comparing KO mice to control mice thus allowing for studies assessing the mechanism(s) of lung persistence. Our finding of minimal differences in lung airway area and lung airway diameter comparing KO mice to control mice suggests that the development of a proinflammatory lung phenotype in KO mice contributes to lung persistence independent of bronchiectasis. The contribution of cilia to immune regulation is increasingly recognized, and our results s