Recent progress towards understanding genetic variation in the Mycobacterium abscessus complex
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)
- et al.
An unusual acid-fast infection of the knee with subcutaneous, abscess-like lesions of the gluteal region; report of a case with a study of the organism, Mycobacterium abscessus, n. sp
J Invest Dermatol
(1953) - et al.
Mycobacterium abscessus: a new player in the mycobacterial field
Trends Microbiol
(2010) - et al.
Chronic Mycobacterium abscessus infection and lung function decline in cystic fibrosis
J Cyst Fibros
(2010) - et al.
Whole-genome sequencing to identify transmission of Mycobacterium abscessus between patients with cystic fibrosis: a retrospective cohort study
Lancet
(2013) - et al.
Phylogenomics of Brazilian epidemic isolates of Mycobacterium abscessus subsp. bolletii reveals relationships of global outbreak strains
Infect Genet Evol
(2013) - et al.
Further isolation of Mycobacterium abscessus subsp. abscessus and subsp. bolletii in different regions of Japan and susceptibility of these isolates to antimicrobial agents
Int J Antimicrob Agents
(2013) - et al.
Clinical relevance of Mycobacterium chelonae-abscessus group isolation in 95 patients
J Infect
(2009) - et al.
Mce2 operon mutant strain of Mycobacterium tuberculosis is attenuated in C57BL/6 mice
Tuberculosis (Edinb)
(2010) - et al.
Extrapulmonary infections caused by a dominant strain of Mycobacterium massiliense (Mycobacterium abscessus subspecies bolletii)
Clin Microbiol Infect
(2013) - et al.
Drosophila melanogaster model for Mycobacterium abscessus infection
Microbes Infect
(2013)
Pathogenesis of Mycobacterium spp. in zebrafish (Danio rerio) from research facilities
Comp Biochem Physiol C Toxicol Pharmacol
High virulent clinical isolates of Mycobacterium abscessus from patients with the upper lobe fibrocavitary form of pulmonary disease
Microb Pathog
An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases
Am J Respir Crit Care Med
Outbreak of Mycobacterium abscessus wound infections among “lipotourists” from the United States who underwent abdominoplasty in the Dominican Republic
Clin Infect Dis
Ocular infections caused by non-tuberculous mycobacteria: update on epidemiology and management
Clin Experiment Ophthalmol
Mycobacterium abscessus Bacteremia After Receipt of Intravenous Infusate of Cytokine-Induced Killer Cell Therapy for Body Beautification and Health Boosting
Clin Infect Dis
Multicenter study of prevalence of nontuberculous mycobacteria in patients with cystic fibrosis in france
J Clin Microbiol
Antimicrobial susceptibility testing, drug resistance mechanisms, and therapy of infections with nontuberculous mycobacteria
Clin Microbiol Rev
Respiratory outbreak of Mycobacterium abscessus subspecies massiliense in a lung transplant and cystic fibrosis center
Am J Respir Crit Care Med
Occurrence of nontuberculous mycobacterial pulmonary infection in an endemic area of tuberculosis
PloS Negl Trop Dis
Clinical features of pulmonary disease caused by rapidly growing mycobacteria
Am Rev Respir Dis
Mycobacterium abscessus: a new antibiotic nightmare
J Antimicrob Chemother
Epidemiology of infection by nontuberculous mycobacteria
Clin Micro Review
Molecular fingerprinting of Mycobacterium abscessus strains in a cohort of pediatric cystic fibrosis patients
J Clin Microbiol
Isolation of NTM from household water and shower aerosols in patients with NTM Pulmonary disease
J Clin Microbiol
Mycobacterium abscessus isolated from municipal water – a potential source of human infection
BMC Infect Dis
Adherence and biofilm formation of Mycobacterium avium, Mycobacterium intracellulare and Mycobacterium abscessus to household plumbing materials
J Appl Microbiol
Construction of Mycobacterium abscessus defined glycopeptidolipid mutants: comparison of genetic tools
Appl Environ Microbiol
Non mycobacterial virulence genes in the genome of the emerging pathogen. Mycobacterium abscessus.
PLoS One
Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence
Nature
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
New rapid scheme for distinguishing the subspecies of the Mycobacterium abscessus group and identification of Mycobacterium massiliense with inducible clarithromycin resistance
J Clin Microbiol
Cohort study of molecular identification and typing of Mycobacterium abscessus, Mycobacterium massiliense, and Mycobacterium bolletii.
J Clin Microbiol
Multilocus sequence analysis and rpoB sequencing of Mycobacterium abscessus (sensu lato) strains
J Clin Microbiol
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
Amoebal coculture of ”Mycobacterium massiliense“ sp. nov. from the sputum of a patient with hemoptoic pneumonia
J Clin Microbiol
Rapid identification of mycobacteria to the species level by polymerase chain reaction and restriction enzyme analysis
J Clin Microbiol
Proportions of Mycobacterium massiliense and Mycobacterium bolletii strains among Korean Mycobacterium chelonae-Mycobacterium abscessus group isolates
J Clin Microbiol
Inaccuracy of single-target sequencing for discriminating species of the Mycobacterium abscessus group
J Clin Microbiol
Mycobacterium massiliense is differentiated from Mycobacterium abscessus and Mycobacterium bolletii by erythromycin ribosome methyltransferase gene (erm) and clarithromycin susceptibility patterns
Microbiol Immunol
Assessment of Clarithromycin Susceptibility in Strains Belonging to the Mycobacterium abscessus Group by erm(41) and rrl Sequencing
Antimicrob Agents Chemother
Genetic basis for clarithromycin resistance among isolates of Mycobacterium chelonae and Mycobacterium abscessus.
Antimicrob Agents Chemother
Susceptibility testing of mycobacteria, nocardia, and other aerobic actinomycetes: approved standard
NCCLS
A novel gene, erm(41), confers inducible macrolide resistance to clinical isolates of Mycobacterium abscessus but is absent from Mycobacterium chelonae.
Antimicrob Agents Chemother
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Mycobacterium abscessus ESX-3 plays an important role in host inflammatory and pathological responses during infection
2017, Microbes and InfectionCitation 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.
Rapid prediction of inducible clarithromycin resistance in Mycobacterium abscessus
2015, Molecular and Cellular ProbesMolecular mechanisms of clarithromycin resistance in Mycobacterium abscessus complex clinical isolates from Venezuela
2015, Journal of Global Antimicrobial ResistanceCitation 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].