Nontuberculous Mycobacteria in Cystic Fibrosis

Richards, Christopher J.; Olivier, Kenneth N.

doi:10.1055/s-0039-1693706

Cited by 33 publications

(28 citation statements)

References 141 publications

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“…Mabc is a subspecies of the Mabc complex that includes Mabc, M. massiliense, and M. bolletii, and has major clinical implications due to antibiotic resistance [2,3]. Mabc often causes pulmonary infection in patients with immune deficiencies, such as cystic fibrosis; however, it can also threaten immunocompetent individuals [4,5]. Mabc is divided into two morphological types, smooth and rough variants, depending on the colony phenotype [6,7].…”

Section: Introductionmentioning

confidence: 99%

Sirtuin 3 is essential for host defense against Mycobacterium abscessus infection through regulation of mitochondrial homeostasis

et al. 2020

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The global incidence of Mycobacterium abscessus (Mabc), a rapidly growing nontuberculous mycobacterial strain that causes treatment-refractory pulmonary diseases, is increasing. Despite this, the host factors that allow for protection against infection are largely unknown. In this study, we found that sirtuin 3 (SIRT3), a mitochondrial protein deacetylase, plays a critical role in host defense against Mabc infection. Mabc decreased SIRT3 and upregulated mitochondrial oxidative stress in macrophages. SIRT3 deficiency led to increased bacterial loads, histopathological, and mitochondrial damage, and pathological inflammation during Mabc infection. Administration of scavengers of mitochondrial reactive oxygen species significantly decreased the in vivo Mabc burden and excessive inflammation, and induced SIRT3 expression in infected lungs. Notably, SIRT3 agonist (resveratrol) significantly decreased Mabc growth and attenuated inflammation in mice and zebrafishes, indicating the key role for SIRT3 in metazoan host defense. Collectively, these data strongly suggest that SIRT3 is a host-directed therapeutic target against Mabc infection by controlling mitochondrial homeostasis.

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Section: Introductionmentioning

confidence: 99%

Sirtuin 3 is essential for host defense against Mycobacterium abscessus infection through regulation of mitochondrial homeostasis

et al. 2020

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“…It is estimated that 5–20% of CF patients will develop NTM infection (Richards and Olivier, 2019 ), indicating that these patients are at increased risk of infection due to genetic susceptibility. Although less frequently encountered than M. avium or M. abscessus , several studies have reported the presence of M. fortuitum in CF patients (Sermet-Gaudelus et al, 2003 ; Cândido et al, 2014 ; Martiniano et al, 2016 ; Richards and Olivier, 2019 ). Recent work has shown that CFTR is important for fine-tuning host oxidative stress and restricting intracellular growth of M. abscessus in a zebrafish model (Bernut et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

“…They have emerged in recent years as prevalent pathogens in cystic fibrosis (CF) patients, with several global CF centers reporting the isolation of NTM in the respiratory tract of CF patients (Roux et al, 2009;Skolnik et al, 2016). NTM prevalence in CF patients varies between 5 and 20%, with the Mycobacterium avium complex and the Mycobacterium abscessus complex being the most significant species (Richards and Olivier, 2019). However, less frequently isolated species in CF patients include other NTM, such as Mycobacterium gordonae, Mycobacterium kansasii or M. fortuitum (Sermet-Gaudelus et al, 2003;Cândido et al, 2014;Martiniano et al, 2016;Richards and Olivier, 2019 Wallace, 2002;Brown-Elliott and Philley, 2017;Tortoli et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…NTM prevalence in CF patients varies between 5 and 20%, with the Mycobacterium avium complex and the Mycobacterium abscessus complex being the most significant species (Richards and Olivier, 2019). However, less frequently isolated species in CF patients include other NTM, such as Mycobacterium gordonae, Mycobacterium kansasii or M. fortuitum (Sermet-Gaudelus et al, 2003;Cândido et al, 2014;Martiniano et al, 2016;Richards and Olivier, 2019 Wallace, 2002;Brown-Elliott and Philley, 2017;Tortoli et al, 2017). M. fortuitum is a rapid-growing and frequently identified NTM species, causing localized skin and soft tissue infections (Wallace et al, 1983).…”

Section: Introductionmentioning

confidence: 99%

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CFTR Depletion Confers Hypersusceptibility to Mycobacterium fortuitum in a Zebrafish Model

Johansen

Kremer

2020

Front. Cell. Infect. Microbiol.

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The Mycobacterium fortuitum complex comprises several closely related species, causing pulmonary and extra-pulmonary infections. However, there is very limited knowledge about the disease pathogenesis involved in M. fortuitum infections, particularly due to the lack of suitable animal models. Using the zebrafish model, we show that embryos are susceptible to M. fortuitum infection in a dose-dependent manner. Furthermore, zebrafish embryos form granulomas from as early as 2 days post-infection, recapitulating critical aspects of mycobacterial pathogenesis observed in other pathogenic species. The formation of extracellular cords in infected embryos highlights a previously unknown pathogenic feature of M. fortuitum. The formation of large corded structures occurs also during in vitro growth, suggesting that this is not a host-adapted stress mechanism deployed during infection. Moreover, transient macrophage depletion led to rapid embryo death with increased extracellular cords, indicating that macrophages are essential determinants of M. fortuitum infection control. Importantly, morpholino depletion of the cystic fibrosis transmembrane conductance regulator (cftr) significantly increased embryo death, bacterial burden, bacterial cords and abscesses. There was a noticeable decrease in the number of cftr-deficient infected embryos with granulomas as compared to infected controls, suggesting that loss of CFTR leads to impaired host immune responses and confers hypersusceptiblity to M. fortuitum infection. Overall, these findings highlight the application of the zebrafish embryo to study M. fortuitum and emphasizes previously unexplored aspects of disease pathogenesis of this significant mycobacterial species.

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“…Here we explore the interaction of Ag85 with Fn at the single molecule level. We concentrate on M. abscessus, an emerging, human-transmissible, multidrug-resistant pathogen causing severe lung infections in cystic fibrosis patients, often resulting in poor treatment outcomes [27,28]. Like other nontuberculous mycobacteria, M. abscessus presents as two different morphological forms, i.e., a smooth (S) morphotype characterized by smooth, dome-shaped, mucoid colonies and homogenously dispersed liquid cultures, and a rough (R) morphotype characterized by rough, dry, wrinkled colonies and highly aggregated liquid cultures [29].…”

Section: Introductionmentioning

confidence: 99%

Mechanical Forces between Mycobacterial Antigen 85 Complex and Fibronectin

Viljoen

Alsteens

Dufrêne

2020

Cells

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Adhesion to extracellular matrix proteins is an important first step in host invasion, employed by many bacterial pathogens. In mycobacteria, the secreted Ag85 complex proteins, involved in the synthesis of the cell envelope, are known to bind to fibronectin (Fn) through molecular forces that are currently unknown. In this study, single-molecule force spectroscopy is used to study the strength, kinetics and thermodynamics of the Ag85-Fn interaction, focusing on the multidrug-resistant Mycobacterium abscessus species. Single Ag85 proteins bind Fn with a strength of~75 pN under moderate tensile loading, which compares well with the forces reported for other Fn-binding proteins. The binding specificity is demonstrated by using free Ag85 and Fn peptides with active binding sequences. The Ag85-Fn rupture force increases with mechanical stress (i.e., loading rate) according to the Friddle-Noy-de Yoreo theory. From this model, we extract thermodynamic parameters that are in good agreement with previous affinity determinations by surface plasmon resonance. Strong bonds (up to~500 pN) are observed under high tensile loading, which may favor strong mycobacterial attachment in the lung where cells are exposed to high shear stress or during hematogenous spread which leads to a disseminated infection. Our results provide new insight into the pleiotropic functions of an important mycobacterial virulence factor that acts as a stress-sensitive adhesin.

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Nontuberculous Mycobacteria in Cystic Fibrosis

Cited by 33 publications

References 141 publications

Sirtuin 3 is essential for host defense against Mycobacterium abscessus infection through regulation of mitochondrial homeostasis

Sirtuin 3 is essential for host defense against Mycobacterium abscessus infection through regulation of mitochondrial homeostasis

CFTR Depletion Confers Hypersusceptibility to Mycobacterium fortuitum in a Zebrafish Model

Mechanical Forces between Mycobacterial Antigen 85 Complex and Fibronectin

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