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. 2016 Nov 11;354(6313):751-757.
doi: 10.1126/science.aaf8156.

Emergence and Spread of a Human-Transmissible Multidrug-Resistant Nontuberculous Mycobacterium

Josephine M Bryant #  1   2 Dorothy M Grogono #  2   3 Daniela Rodriguez-Rincon  2 Isobel Everall  1 Karen P Brown  2   3 Pablo Moreno  4 Deepshikha Verma  5 Emily Hill  5 Judith Drijkoningen  2 Peter Gilligan  6 Charles R Esther  6 Peadar G Noone  6 Olivia Giddings  6 Scott C Bell  7   8   9 Rachel Thomson  10 Claire E Wainwright  8   11 Chris Coulter  12 Sushil Pandey  12 Michelle E Wood  7   8   9 Rebecca E Stockwell  7   8 Kay A Ramsay  7   8 Laura J Sherrard  7 Timothy J Kidd  13   14 Nassib Jabbour  15   16 Graham R Johnson  16 Luke D Knibbs  17 Lidia Morawska  16 Peter D Sly  18 Andrew Jones  19 Diana Bilton  19 Ian Laurenson  20 Michael Ruddy  21 Stephen Bourke  22 Ian Cjw Bowler  23 Stephen J Chapman  23 Andrew Clayton  24 Mairi Cullen  25 Thomas Daniels  25 Owen Dempsey  26 Miles Denton  27 Maya Desai  28 Richard J Drew  29 Frank Edenborough  30 Jason Evans  21 Jonathan Folb  31 Helen Humphrey  32 Barbara Isalska  25 Søren Jensen-Fangel  33 Bodil Jönsson  34 Andrew M Jones  25 Terese L Katzenstein  35 Troels Lillebaek  36 Gordon MacGregor  37 Sarah Mayell  29 Michael Millar  38 Deborah Modha  39 Edward F Nash  40 Christopher O'Brien  22 Deirdre O'Brien  41 Chandra Ohri  39 Caroline S Pao  38 Daniel Peckham  28 Felicity Perrin  42 Audrey Perry  22 Tania Pressler  35 Laura Prtak  31 Tavs Qvist  35 Ali Robb  22 Helen Rodgers  43 Kirsten Schaffer  41 Nadia Shafi  3 Jakko van Ingen  44 Martin Walshaw  45 Danie Watson  38 Noreen West  46 Joanna Whitehouse  40 Charles S Haworth  3 Simon R Harris  1 Diane Ordway  5 Julian Parkhill  1 R Andres Floto  2   3
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Free PMC article

Emergence and Spread of a Human-Transmissible Multidrug-Resistant Nontuberculous Mycobacterium

Josephine M Bryant et al. Science. .
Free PMC article

Abstract

Lung infections with Mycobacterium abscessus, a species of multidrug-resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF), in whom M. abscessus accelerates inflammatory lung damage, leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole-genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge.

Figures

Figure 1
Figure 1. Global phylogeny of clinical isolates of M. abscessus.
Maximum likelihood phylogenetic tree of clinical isolates of M. abscessus collected with relevant local and/or national Ethical Board approval from 517 patients (using one isolate per patient), obtained from UK CF clinics and their associated regional reference laboratories, CF Centres in the US (UNC Chapel Hill), the Republic of Ireland (Dublin), mainland Europe (Denmark, Sweden, The Netherlands), and Australia (Queensland), supplemented by published genomes from US, France, Brazil, Malaysia, China, and South Korea (listed in Table S1).
Figure 2
Figure 2. Transcontinental spread of dominant circulating clones.
(A). Hierarchical branch density analysis of phylogenetic trees for each subspecies of M. abscessus identifies multiple clusters of closely related isolates predominantly within the M. a. abscessus and M. a. massiliense subspecies (numbered, and spectrally coloured red to blue, from most densely clustered to least; black indicating no significant clustering). (B). Analysis of M. abscessus clusters found in two or more CF centers showing (top) numbers of patients infected with each cluster (grey bars) or unclustered isolates (green) and median branch length (SNPs) of different patients’ isolates within each cluster (blue circles); (bottom) numbers of potential recent transmission events with < 20 SNPs (red) or 20 - 38 SNPs (yellow) difference between isolates from different patients. (C) Global distribution of clustered M. abscessus isolates showing M. a. abscessus Cluster 1 (red) and Cluster 2 (green), M. a. massiliense Cluster 1 (blue), other clustered isolates (grouped together for clarity; white) and unclustered isolates (black) with numbers of patients (n) sampled per location. (D) Genetic differences between isolates (measured by pairwise SNP distance) from different patients attending the same CF center, different CF centers within the same country, or CF centers in different countries (boxes indicate median and interquartile range; p values obtained from Mann Whitney Rank Sum tests). To exclude multiple highly distant comparisons, for each isolate only the smallest pairwise distance with an isolate from another patient is included. Colour coding indicates whether there were < 20 SNPs difference (red), 20-38 SNPs difference (yellow), or >38 SNPs difference (grey) between isolates from different patients.
Figure 3
Figure 3. Dating the emergence of dominant circulating clones.
(A). Dating the emergence of the M. a. massiliense Cluster 1 (responsible for the Papworth and Seattle CF center outbreaks), using Bayesian analysis, with geographical annotation of isolates within the cluster. (B). Predicted evolution of subclones (identified through minority variant linkage; see Supplementary Methods [23]) within a single patient with CF (Patient 2 from Ref. 19) chronically infected with the dominant circulating clone Massiliense Cluster 1 (representative of a total of 11 patients studied). (i) Analysis revealed successive acquisition of non-synonymous polymorphisms (NS) by the most common recent ancestral clone (MRCA; white) in potential virulence genes (UBiA, MAB_0173; Crp/Fnr, MAB_0416c; mmpS, MAB_0477; PhoR, MAB_0674) and then transmission of a single subclone to another patient from the same CF center (Patient 28 from Ref. 19). (ii) Frequency of each subclone within longitudinal sputum isolates analysed during the course of Patient 2’s infection and the subsequent transmission of a subclone to Patient 28. We observed considerable heterogeneity in the detected repertoire of subclones within each sputum sample (vertical rectangles coloured to illustrate the proportion of detected subclones coded as for (i) in each sputum sample), reflecting either temporal fluctuations in dominant sub-lineages or variable sampling of geographical diversity of subclones within the lung (as previously described for P. aeruginosa [37]). Previously determined opportunities for hospital-based cross-infection between the two patients (using social network and epidemiologic analysis [17]), are shown in grey vertical bars.
Figure 4
Figure 4. Comparison of clinical outcomes and functional phenotyping of clustered and unclustered M. abscessus isolates.
(A, B). Relationship of phylogeny with clinical metadata. Phylogenetic tree of M. abscessus isolates (one isolate per patient) with dominant circulating clones M. a. abscessus 1 (Absc 1), abscessus 2 (Absc 2), and M. a. massiliense (Mass 1) highlighted (grey). For each isolate, clinical data (where available) was used to determine whether (column 1) the infected patient fulfilled the ATS/IDSA criteria for NTM pulmonary disease, namely the presence of two or more culture-positive sputum samples with NTM-associated symptoms and radiological changes [1] (yes: blue; no: orange); whether (column 2) isolates have acquired amikacin resistance (through 16S rRNA mutations; red), macrolide resistance (through 23S rRNA mutations; yellow), or both (orange- B only); and whether (column 3) patients culture converted (green) or remained chronically infected (red) with M. abscessus. (C, D). In vitro phenotyping of representative isolates of clustered (blue) and unclustered (green) M. a. abscessus and clustered (red) and unclustered (yellow) M. a. massiliense comparing phagocytosis by (C) and intracellular survival (normalised for uptake) within (D) differentiated THP1 cells. Data points represent averages of at least three independent replicates. (E, F) Using SCID mice, infection with clustered M. a. abscessus (blue) and M. a. massiliense (red) led to (E) greater intracellular survival within (i) bone marrow-derived macrophages in vitro and (ii) higher bacterial burdens in lung and spleen after in vivo inoculation with 1 x 107 bacilli per animal with (F) worse granulomatous lung inflammation (arrowheads), than unclustered controls (M. a. abscessus green; M. a. massiliense yellow), scale bar x 4. CFU data is shown as mean ± sem; * p < 0.05; ** p < 0.005 (two-tailed unpaired Student’s t-test).

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