Elsevier

Tuberculosis

Volume 93, Supplement, 1 December 2013, Pages S15-S20
Tuberculosis

Recent progress towards understanding genetic variation in the Mycobacterium abscessus complex

https://doi.org/10.1016/S1472-9792(13)70005-2Get rights and content

Abstract

Mycobacterium abscessus is an emerging cause of respiratory disease and soft tissue infections. Whole genome sequencing and other molecular approaches are enhancing our understanding of outbreaks, antibiotic resistance mechanisms, and virulence properties, and of the phylogeny of the M. abscessus complex. Infection models are providing further insights into factors such as colony phenotype that impact host-pathogen interactions. This paper reviews recent developments in our understanding of genetic variation in M. abscessus and the potential relevance for disease and treatment.

Introduction

Mycobacterium abscessus was first isolated from a knee abscess,1 and is now increasingly identified as a cause of skin, ocular, and other soft tissue infections associated with injury, cosmetic or medical procedures.2, 3, 4, 5 However, it is arguably of greatest concern as an emerging respiratory pathogen, particularly in cystic fibrosis (CF) patients.6, 7, 8 Risk factors for M. abscessus respiratory disease include CF, bronchiectasis, tuberculosis or other mycobacterial respiratory disease,2, 6, 9, 10, 11, 12 and symptoms include cough and fatigue, with cavitation occurring in about 15% of cases.2, 13 M. abscessus is the leading of cause of respiratory disease cases due to rapidly-growing mycobacteria (RGM).13

Recently described as an “antibiotic nightmare”,14 M. abscessus is naturally resistant to most antibiotics in clinical use, including first-line antitubercular drugs.2 Unlike M. tuberculosis, respiratory infection with M. abscessus is believed to occur from environmental sources,15 with only limited evidence suggesting patient-to-patient transmission.10, 11, 16 Isolation from water, a high level of resistance to chlorine, and the ability of M. abscessus to form biofilms in household plumbing materials are consistent with recent studies pointing to municipal water systems as a key source of infection, especially with respiratory disease.17, 18, 19

Genetic studies on M. abscessus have lagged far behind those on M. tuberculosis and the organism can be difficult to mutate,20 hindering our understanding of the relevance of strain differences and the genetic factors that may influence disease type and progression, antibiotic resistance, environmental distribution, and other properties. Indeed, the first full genome sequence of an M. abscessus strain21 was published over 10 years after the sequence of M. tuberculosis H37Rv.22 Much remains to be learned regarding genotypic diversity in M. abscessus and its clinical significance. This review highlights some of the recent progress towards understanding the genetic differences, and the relevance of these differences, in the M. abscessus complex.

Section snippets

The M. abscessus complex

M. abscessus is a complex of subspecies, but these subspecies are less well-defined than in the M. tuberculosis complex, and the nomenclature is undergoing revisions.23, 24 Three subspecies of M. abscessus have been described in the literature, based on differentiation by PCR and multilocus sequencing of housekeeping genes: M. abscessus subsp. abscessus (M. abscessus sensu stricto), M. abscessus subsp. bolletii (M. bolletii), and M. abscessus subsp. massiliense (M. massiliense).23, 24, 25, 26

Macrolide susceptibility

The macrolides clarithromycin and azithromycin are important therapeutic agents for the treatment of M. abscessus respiratory infections.2 Mutational resistance to these macrolides results from point mutations at positions 2058 or 2059 in the 23S rRNA gene, and is detected as growth in three days in the presence of clarithromycin.35, 36 Mutational resistance to macrolides has been detected in all three subspecies of the complex,34, 37 and the type strain M. bolletii BD (see Table 1) was

Genomic analyses

M. abscessus strain ATCC19977 (CIP 104536T) was designated the type strain for M. abscessus45 before separation of the complex into subspecies. It is now the type strain for M. abscessus sensu stricto, and became the first strain of the M. abscessus complex to have a fully sequenced genome.21, 46 Prior to completion of the full genome sequence of 5.1 Mb, the most extensive sequence data available for ATCC19977 was of a 25.2 kb region that is missing from some strains47 and that corresponds to

Strain differentiation

For many years, PFGE has been the standard method for differentiating strains within the M. abscessus complex.25, 51, 63 Recently, faster molecular typing methods have been introduced, including methods based on variable number tandem repeats (VNTR).16, 64, 65 The various typing methods and the advent of rapid whole-genome sequencing have aided in assessing outbreaks and monitoring chronic infections.11, 16, 66, 67 Recent studies demonstrating the clonality of M. massiliense isolates in groups

Infection models

Like M. tuberculosis, M. abscessus is an intracellular pathogen, and macrophages and mice are the standard models for studying the organism.70, 71 However, Drosophila melanogaster is also being explored,72 and as for other pathogenic mycobacteria, amoebae may also prove to be a useful model.73, 74 One of the earliest studies on M. abscessus reported that strains had differing capacities to cause fatal infections, kidney lesions, and a neurological condition known as spinning disease in mice

Conclusions

M. abscessus is an emerging pathogen of increasing concern to the medical community. Fortunately, however, the organism is also of growing interest to the scientific community. New research is providing insights into the genetic differences between subspecies and strains, and into the factors influencing antibiotic resistance and host-pathogen interactions. Much remains to be learned about the M. abscessus complex, but the recent availability of multiple genome sequences will be of tremendous

Competing interests

None declared.

Acknowledgments

The author thanks Richard J. Wallace Jr. and Barbara Brown-Elliott for helpful discussions, and the Dept. of Microbiology and the Amon G. Carter Foundation for their support.

References (88)

  • V Watral et al.

    Pathogenesis of Mycobacterium spp. in zebrafish (Danio rerio) from research facilities

    Comp Biochem Physiol C Toxicol Pharmacol

    (2007)
  • H Sohn et al.

    High virulent clinical isolates of Mycobacterium abscessus from patients with the upper lobe fibrocavitary form of pulmonary disease

    Microb Pathog

    (2009)
  • DE Griffith et al.

    An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases

    Am J Respir Crit Care Med

    (2007)
  • EY Furuya et al.

    Outbreak of Mycobacterium abscessus wound infections among “lipotourists” from the United States who underwent abdominoplasty in the Dominican Republic

    Clin Infect Dis

    (2008)
  • DO Girgis et al.

    Ocular infections caused by non-tuberculous mycobacteria: update on epidemiology and management

    Clin Experiment Ophthalmol

    (2012)
  • R Liu et al.

    Mycobacterium abscessus Bacteremia After Receipt of Intravenous Infusate of Cytokine-Induced Killer Cell Therapy for Body Beautification and Health Boosting

    Clin Infect Dis

    (2013)
  • AL Roux et al.

    Multicenter study of prevalence of nontuberculous mycobacteria in patients with cystic fibrosis in france

    J Clin Microbiol

    (2009)
  • BA Brown-Elliott et al.

    Antimicrobial susceptibility testing, drug resistance mechanisms, and therapy of infections with nontuberculous mycobacteria

    Clin Microbiol Rev

    (2012)
  • ML Aitken et al.

    Respiratory outbreak of Mycobacterium abscessus subspecies massiliense in a lung transplant and cystic fibrosis center

    Am J Respir Crit Care Med

    (2012)
  • AR da Costa et al.

    Occurrence of nontuberculous mycobacterial pulmonary infection in an endemic area of tuberculosis

    PloS Negl Trop Dis

    (2013)
  • DE Griffith et al.

    Clinical features of pulmonary disease caused by rapidly growing mycobacteria

    Am Rev Respir Dis

    (1993)
  • R Nessar et al.

    Mycobacterium abscessus: a new antibiotic nightmare

    J Antimicrob Chemother

    (2012)
  • JO Falkinham

    Epidemiology of infection by nontuberculous mycobacteria

    Clin Micro Review

    (1996)
  • KA Harris et al.

    Molecular fingerprinting of Mycobacterium abscessus strains in a cohort of pediatric cystic fibrosis patients

    J Clin Microbiol

    (2012)
  • R Thomson et al.

    Isolation of NTM from household water and shower aerosols in patients with NTM Pulmonary disease

    J Clin Microbiol

    (2013)
  • R Thomson et al.

    Mycobacterium abscessus isolated from municipal water – a potential source of human infection

    BMC Infect Dis

    (2013)
  • SN Mullis et al.

    Adherence and biofilm formation of Mycobacterium avium, Mycobacterium intracellulare and Mycobacterium abscessus to household plumbing materials

    J Appl Microbiol

    (2013)
  • H Medjahed et al.

    Construction of Mycobacterium abscessus defined glycopeptidolipid mutants: comparison of genetic tools

    Appl Environ Microbiol

    (2009)
  • F Ripoll et al.

    Non mycobacterial virulence genes in the genome of the emerging pathogen. Mycobacterium abscessus.

    PLoS One

    (2009)
  • ST Cole et al.

    Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence

    Nature

    (1998)
  • SC Leao et al.

    Characterization of mycobacteria from a major Brazilian outbreak suggests that revision of the taxonomic status of members of the Mycobacterium chelonae-M. abscessus group is needed

    J Clin Microbiol

    (2009)
  • SJ Shallom et al.

    New rapid scheme for distinguishing the subspecies of the Mycobacterium abscessus group and identification of Mycobacterium massiliense with inducible clarithromycin resistance

    J Clin Microbiol

    (2013)
  • AM Zelazny et al.

    Cohort study of molecular identification and typing of Mycobacterium abscessus, Mycobacterium massiliense, and Mycobacterium bolletii.

    J Clin Microbiol

    (2009)
  • E Macheras et al.

    Multilocus sequence analysis and rpoB sequencing of Mycobacterium abscessus (sensu lato) strains

    J Clin Microbiol

    (2011)
  • T Adékambi et al.

    rpoB gene sequence-based characterization of emerging non-tuberculous mycobacteria with descriptions of Mycobacterium bolletii sp. nov., Mycobacterium phocaicum sp. nov. and Mycobacterium aubagnense sp. nov

    Int J Syst Evol Microbiol

    (2006)
  • T Adékambi et al.

    Amoebal coculture of ”Mycobacterium massiliense“ sp. nov. from the sputum of a patient with hemoptoic pneumonia

    J Clin Microbiol

    (2004)
  • A Telenti et al.

    Rapid identification of mycobacteria to the species level by polymerase chain reaction and restriction enzyme analysis

    J Clin Microbiol

    (1993)
  • HY Kim et al.

    Proportions of Mycobacterium massiliense and Mycobacterium bolletii strains among Korean Mycobacterium chelonae-Mycobacterium abscessus group isolates

    J Clin Microbiol

    (2008)
  • E Macheras et al.

    Inaccuracy of single-target sequencing for discriminating species of the Mycobacterium abscessus group

    J Clin Microbiol

    (2009)
  • HY Kim et al.

    Mycobacterium massiliense is differentiated from Mycobacterium abscessus and Mycobacterium bolletii by erythromycin ribosome methyltransferase gene (erm) and clarithromycin susceptibility patterns

    Microbiol Immunol

    (2010)
  • S Bastian et al.

    Assessment of Clarithromycin Susceptibility in Strains Belonging to the Mycobacterium abscessus Group by erm(41) and rrl Sequencing

    Antimicrob Agents Chemother

    (2011)
  • RJ Wallace et al.

    Genetic basis for clarithromycin resistance among isolates of Mycobacterium chelonae and Mycobacterium abscessus.

    Antimicrob Agents Chemother

    (1996)
  • GL Woods et al.

    Susceptibility testing of mycobacteria, nocardia, and other aerobic actinomycetes: approved standard

    NCCLS

    (2003)
  • KA Nash et al.

    A novel gene, erm(41), confers inducible macrolide resistance to clinical isolates of Mycobacterium abscessus but is absent from Mycobacterium chelonae.

    Antimicrob Agents Chemother

    (2009)
  • Cited by (28)

    • Three cases of otitis media caused by Mycobacterium abscessus subsp. abscessus: Importance of medical treatment and efficacy of surgery

      2021, Journal of Infection and Chemotherapy
      Citation Excerpt :

      In addition, multiple processes are required to identify the species of NTM. In particular, for identifying the subspecies of MAbC, it is essential using multiplex PCR or housekeeping gene sequencing in addition to species identification by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) [8–11]. Though we initially identified MAbC by DNA–DNA hybridization, MALDI-TOF MS is currently used for bacterial identification mainly [11].

    • Mycobacterium abscessus ESX-3 plays an important role in host inflammatory and pathological responses during infection

      2017, Microbes and Infection
      Citation Excerpt :

      Activation of innate immune signaling leads to the production of proinflammatory cytokines, including tumor necrosis factor TNF-α, interleukin (IL)-6, IL-1β, and IL-12 [8,10]. The development of molecular genetic approaches, such as whole-genome sequencing, has markedly enhanced our understanding of various properties of Mab [11]. The identification and immunological characterization of essential Mab genes contributes to the development of novel protective and therapeutic strategies against Mab infection.

    • Molecular mechanisms of clarithromycin resistance in Mycobacterium abscessus complex clinical isolates from Venezuela

      2015, Journal of Global Antimicrobial Resistance
      Citation Excerpt :

      In this strain collection, M. abscessus was the most prevalent species; 80% of these strains were isolated from SSTIs, whilst 50% of the M. massiliense and M. bolletii strains were obtained from respiratory infection specimens. Previous studies indicate that the distribution of species appears to vary by geographic region and although the basis for these geographic differences is unknown, regions with a high incidence of respiratory infections due to M. massiliense (e.g. Korea) should have higher response rates to macrolide-based treatment [2,23–25]. It has been reported that the mechanism of resistance to macrolides by the erm(41) gene in the M. abscessus group is specifically associated with a single nucleotide polymorphism at position 28 (T or C) [2,9,12].

    View all citing articles on Scopus
    View full text