Rough and smooth variants of Mycobacterium abscessus are differentially controlled by host immunity during chronic infection of adult zebrafish

Kam, Julia Y; Hortle, Elinor; Krogman, Elizabeth; Warner, Sherridan E; Wright, Kathryn; Luo, Keming; Cheng, Tina; Cholan, Pradeep Manuneedhi; Kikuchi, Kazu; Triccas, James A.; Britton, Warwick J.; Johansen, Matt D.; Kremer, Laurent; Oehlers, Stefan H.

doi:10.1038/s41467-022-28638-5

Cited by 37 publications

(30 citation statements)

References 46 publications

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“…A recent study using the established zebrafish model of Mabs pathogenesis demonstrated that growth of the inflammatory Mabs rough variant (the morphotype used in our study) results from host TNFa-driven necrotic granulomas. Restriction of virulent Mabs rough variant growth is achieved by host T regulatory cells which associate with these granulomas (43). These results parallel our immunologic findings in which a reduced percentage of T regulatory cells in IFT88 KO mice is associated with increased Mabs growth using a completely different model of Mabs infection.…”

Section: B Asupporting

confidence: 86%

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

Nava

Hahn²,

Wu³

et al. 2022

Front. Immunol.

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IntroductionHuman pulmonary infection with non-tuberculous mycobacteria (NTM) such as Mycobacterium abscessus (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.MethodsWe used a mouse strain containing a conditional floxed allele of the gene IFT88, 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, IFT88 control mice and IFT88 KO mice received different preparations of Mabs 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.ResultsMabs embedded in agarose beads persisted in the lungs of IFT88 KO mice out to approximately 8 weeks (54 days), while Mabs agarose beads in the lungs of IFT88 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 IFT88 KO mice relative to IFT88 control mice. Proinflammatory cytokines were elevated in the BAL fluid from infected IFT88 KO mice compared to infected IFT88 control mice, and histopathology showed an increased inflammatory response and greater numbers of granulomas in the lungs of infected IFT88 KO mice compared to the lungs of infected IFT88 control mice. Scanning lung morphometry did not show a significant difference comparing lung airway area and lung airway perimeter between IFT88 KO mice and IFT88 control mice.DiscussionPersistent lung infection in our model was established using Mabs embedded in agarose beads. The utility of using IFT88 mice is that a significant difference in Mabs lung CFU is observed comparing IFT88 KO mice to IFT88 control mice thus allowing for studies assessing the mechanism(s) of Mabs lung persistence. Our finding of minimal differences in lung airway area and lung airway diameter comparing IFT88 KO mice to IFT88 control mice suggests that the development of a proinflammatory lung phenotype in IFT88 KO mice contributes to Mabs lung persistence independent of bronchiectasis. The contribution of cilia to immune regulation is increasingly recognized, and our results suggest that ciliopathy associated with structural lung disease may play a role in NTM pulmonary infection via alteration of the local immunologic lung milieu.

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Section: B Asupporting

confidence: 86%

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

Nava

Hahn²,

Wu³

et al. 2022

Front. Immunol.

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“…The optical transparency of embryos has been used to visualize the formation of extracellular cords by the R variant in vivo. Using this in vivo model, some authors [ 31 , 32 ] described the ability of both variants to induce granulomas and confirmed the hypervirulence of the R morphotype related to the massive production of extracellular cords. As observed in these studies on the zebrafish infection model, M. abscessus can irreversibly switch from the smooth to the rough variant during persistent infection, resulting in granuloma rupture and bacterial cord formation [ 19 , 31 ].…”

Section: Models Of Intracellular Survivalmentioning

confidence: 82%

Updated Review on the Mechanisms of Pathogenicity in Mycobacterium abscessus, a Rapidly Growing Emerging Pathogen

2022

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In recent years, Mycobacterium abscessus has appeared as an emerging pathogen, with an increasing number of disease cases reported worldwide that mainly occur among patients with chronic lung diseases or impaired immune systems. The treatment of this pathogen represents a challenge due to the multi-drug-resistant nature of this species and its ability to evade most therapeutic approaches. However, although predisposing host factors for disease are well known, intrinsic pathogenicity mechanisms of this mycobacterium are still not elucidated. Like other mycobacteria, intracellular invasiveness and survival inside different cell lines are pathogenic factors related to the ability of M. abscessus to establish infection. Some of the molecular factors involved in this process are well-known and are present in the mycobacterial cell wall, such as trehalose-dimycolate and glycopeptidolipids. The ability to form biofilms is another pathogenic factor that is essential for the development of chronic disease and for promoting mycobacterial survival against the host immune system or different antibacterial treatments. This capability also seems to be related to glycopeptidolipids and other lipid molecules, and some studies have shown an intrinsic relationship between both pathogenic mechanisms. Antimicrobial resistance is also considered a mechanism of pathogenicity because it allows the mycobacterium to resist antimicrobial therapies and represents an advantage in polymicrobial biofilms. The recent description of hyperpathogenic strains with the potential interhuman transmission makes it necessary to increase our knowledge of pathogenic mechanisms of this species to design better therapeutic approaches to the management of these infections.

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“…The entire aerosol procedure takes approximately 1 hour to complete, of which the first 20 minutes are for Mtb aerosolization [ 10 , 14 , 15 , 17 , 26 ]. Mtb forms aggregates in liquid cultures [ 8 , 39 – 42 ] that are disrupted by adding detergents such as Tween 80 or Tyloxapol in small quantities (0.05–0.1%) [ 10 , 14 , 15 , 26 , 43 ]. Antifoam is added to Mtb cultures that destabilize foam during aerosol procedures.…”

Section: Discussionmentioning

confidence: 99%

Targeted dose delivery of Mycobacterium tuberculosis in mice using silicon antifoaming agent via aerosol exposure system

2022

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Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that forms aggregates (clumps) on solid agar plates and in liquid media. Detergents such as Tween 80/Tyloxapol are considered the gold standard to disrupt clump formation in Mtb cultures. The presence of detergent, however, may generate foam and hinder Mtb aerosolization thus requiring addition of an antifoam agent for optimal Mtb aerosol-based procedures. Aerosol inhalation can be technically challenging, in particular to achieve a reproducible inhaled target dose. In this study, the impact of an antifoam, the silicon antifoaming agent (SAF), on Mtb aerosolization and whole-body mouse aerosol infection was investigated. A comparative study using SAF in a liquid suspension containing Mycobacterium bovis BCG (M. bovis BCG) or Mtb H37Rv did not cause any adverse effect on bacterial viability. Incorporation of SAF during mycobacteria inhalation procedures revealed that aerosolized mycobacterial strains were maintained under controlled environmental conditions such as humidity, temperature, pressure, and airflow inside the aerosol chamber. In addition, environmental factors and spray factors were not affected by the presence of SAF in mycobacterial cultures during aerosolization. Spray factor was significantly less during aerosol procedures with a low-input dose of mycobacteria in comparison to high-dose, as predicted. The mycobacterial load recovered in the biosampler (AGI) was ~2–3 logs lower than nebulizer or input bacterial load. A consistent Mtb bacillary load determined in mouse lungs indicates that SAF does not affect mycobacteria aerosolization during the aerosol generation process. These data confirmed that 1) SAF prevents formation of excessive foam during aerosolization, 2) SAF had no negative impact on mycobacterial viability within aerosol droplets, 3) Mtb droplets within aerosol-generated particles are well within the range required for reaching and depositing deep into lung tissue, and 4) SAF had no negative impact on achieving a target dose in mice exposed to Mtb aerosol.

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Rough and smooth variants of Mycobacterium abscessus are differentially controlled by host immunity during chronic infection of adult zebrafish

Cited by 37 publications

References 46 publications

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

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

Updated Review on the Mechanisms of Pathogenicity in Mycobacterium abscessus, a Rapidly Growing Emerging Pathogen

Targeted dose delivery of Mycobacterium tuberculosis in mice using silicon antifoaming agent via aerosol exposure system

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