Figures
- FIGURE 1
Interactions between nontuberculous mycobacteria (NTM), the microbiome and the host inflammatory response. Upon presentation to the host cell, NTM along with resident lung microbiota induce complex inflammatory interactions that propagate NTM infection and disease. Initial stimulation by the innate immune response is composed mainly of neutrophils, macrophages, dendritic and natural killer cells. Activation is mediated by recognition of mycobacterial and microbial pathogen-associated molecular patterns (PAMPs) through Toll-like receptors (TLRs) and Nod-like receptors (NLRs). Phagocytosis and pathogenesis ensues with stimulation of the cellular-mediated immune response (T-cells and B-cells) through complex cytokine interactions, primarily interferon-γ (IFN-γ), interleukin (IL)-2, IL-12 and tumour necrosis factor-α (TNF-α). Various other cytokine and chemoattract ligands have been implicated in pathogenesis as listed. The role of the microbiome within this inflammatory cascade is complex and intricate within all of the aforementioned pathways. Created with BioRender.com. CCL: chemokine (C-C motif) ligand; MIP: macrophage inflammatory protein.
- FIGURE 2
Potential mechanistic pathways between nontuberculous mycobacteria (NTM) and the host lung microbiome. The complex interplay between healthy state and dysbiosis is influenced by microbial factors (species present in the microbiome, presence of virulence genes and acquisition of genes by horizontal gene transfer) and host factors (innate and adaptive immune system, external pressure selection such as by antimicrobials). This dynamic ecological niche plays a critical role in the transition between acquisition to infection and finally infection of organisms, such as NTM. Created with BioRender.com.
Tables
- TABLE 1
American Thoracic Society/Infectious Diseases Society of America criteria for diagnosing NTM pulmonary disease [19]
Clinical criteria Respiratory or constitutional symptoms and appropriate exclusion of other diagnosis and: Radiological criteria Reticular, interstitial or nodular infiltrate or cavitation on chest radiography, or high-resolution computed tomography scan that shows multifocal bronchiectasis with multiple small nodules, and: Microbiological criteria Positive cultures from at least one bronchial wash or lavage, or positive sputum from at least two separate expectorated sputum samples; or transbronchial or other lung biopsy with microbiological histopathological features (granulomatous inflammation or acid-fast bacilli) and positive culture for NTM, or biopsy showing microbacterial histopathological features and one sputum sample or bronchial washing/lavage that is culture-positive for NTM. NTM: nontuberculous mycobacteria.
- TABLE 2
Summary of current studies examining the lung microbiome in individuals with NTM disease#
Year Patient type Patient characteristics Patients n Sample type Predominant taxa by OTU Yamasaki et al. [50] 2015 NTM-positive bronchiectasis Stable, met ATS criteria for NTM disease¶ and without history of antimicrobial treatment. 27 BAL Prevotella, Streptococcus, Pseudomonas, Neisseria, Fusobacterium, Propionibacterium, Veillonella, Haemophilus, Granulicatella, Curvibacter, Lactobacillus NTM-negative bronchiectasis As above but did not meet ATS criteria for NTM disease. 25 BAL Haemophilus, Staphylococcus, Pseudomonas, Streptococcus, Prevotella, Trabulsiella, Granulicatella, Neisseria, Fusobacterium, Propionibacterium Sulaiman et al. [49] 2018 NTM-positive bronchiectasis Stable, non-HIV, non-CF bronchiectasis. Inclusion criteria included CT imaging abnormalities and symptoms consistent with bronchiectasis. Exclusion criteria included patients with recent antimicrobial or corticosteroid therapy in the last month and recent history of smoking in the last year. Met ATS criteria for NTM disease¶. 61 Oral wash and induced sputum Actinomyces, Actinomycetaceae, Streptophyta, Cyanobacteria, Streptophyta, Bifidobacteriales, Bifidobacteriaceae, Bifidobacterium, Rhodobacterales, Rhodobacteraceae, Bacillus BAL+ Mycobacterium, Ralstonia, Clavibacter, Oxalobacteraceae, Enterobacter, Comamonas, Hyphomonadaceae, Xenococcaceae, Paracoccus, Lactobacillales NTM-negative bronchiectasis As above but did not meet ATS criteria for NTM disease. 45 Oral wash and induced sputum Proteobacteria, Gammaproteobacteria, Pasteurellales, Pasteurellalaceae, Pseudomonadales, Pseudomonadaceae, Pseudomonas, Actinobacillus, Weeksellaceae, Comamonadaceae BAL+ Porphyromonas, Mannheimia, Kaistobacter, Selenomonas, Dialister Philley et al. [51] 2019 NTM-positive and breast cancer Stable, patients met ATS criteria for NTM disease¶. 15 Expectorated sputum ± sera-derived extracellular vesicles§ Haemophilus, Streptococcus, Neisseria, Veilonella, Rothia, Fusobacterium, Leptotrichia, Prevotella, Bacteroides, Escherichia/Shigella, Streptococcus, Alistipes, Cloacibacterium, Faecalibacterium, Lachnoclostridium, Staphylococcus, Neisseria, Fusicatenibacter, Fusobacterium, Lachnospira, Tepidimonus NTM-negative Stable, healthy controls. 5 Expectorated sputum Haemophilus, Streptococcus, Neisseria, Veillonella, Rothia, Fusobacterium, Leptotrichia, Prevotella NTM: nontuberculous mycobacteria; OTU: operational taxonomic unit; ATS: American Thoracic Society; BAL: bronchoalveolar lavage; CF: cystic fibrosis; CT: computed tomography. #: the studies presented here focus on non-CF conditions; ¶: as defined by the ATS/Infectious Diseases Society of America 2007 criteria [4]; +: a subset of 20 patients underwent BAL sampling, with eight patients identified as NTM-positive and 12 as NTM-negative; §: sera-derived extracellular vesicles were examined in a subset of four patients from the NTM-breast cancer group.
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- Abstract
- Abstract
- Introduction
- Nontuberculous mycobacteria
- The respiratory microbiome and the landscape of microbial players
- The respiratory microbiome and NTM: who is involved?
- Pathogenesis of the mycobacteriome
- Effect of NTM antibiotic treatment on the microbiome
- Future directions and challenges
- Footnotes
- References
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