Functional characterization of the Mycobacterium abscessus genome coupled with condition specific transcriptomics reveals conserved molecular strategies for host adaptation and persistence

Miranda-CasoLuengo, Aleksandra A.; Staunton, Patrick M.; Dinan, Adam M.; Lohan, Amanda J.; Loftus, Brendan J.

Functional characterization of the Mycobacterium abscessus genome coupled with condition specific transcriptomics reveals conserved molecular strategies for host adaptation and persistence

dc.contributor.author	Miranda-CasoLuengo, Aleksandra A.
dc.contributor.author	Staunton, Patrick M.
dc.contributor.author	Dinan, Adam M.
dc.contributor.author	Lohan, Amanda J.
dc.contributor.author	Loftus, Brendan J.
dc.contributor.funder	Science Foundation Ireland
dc.contributor.funder	Wellcome Trust
dc.date.accessioned	2017-06-21T11:01:24Z
dc.date.available	2017-06-21T11:01:24Z
dc.date.issued	2016-08-05
dc.description.abstract	Background: Mycobacterium abscessus subsp. abscessus (MAB) is a highly drug resistant mycobacterium and the most common respiratory pathogen among the rapidly growing non-tuberculous mycobacteria. MAB is also one of the most deadly of the emerging cystic fibrosis (CF) pathogens requiring prolonged treatment with multiple antibiotics. In addition to its “mycobacterial” virulence genes, the genome of MAB harbours a large accessory genome, presumably acquired via lateral gene transfer including homologs shared with the CF pathogens Pseudomonas aeruginosa and Burkholderia cepacia. While multiple genome sequences are available there is little functional genomics data available for this important pathogen. Results: We report here the first multi-omics approach to characterize the primary transcriptome, coding potential and potential regulatory regions of the MAB genome utilizing differential RNA sequencing (dRNA-seq), RNA-seq, Ribosome profiling and LC-MS proteomics. In addition we attempt to address the genomes contribution to the molecular systems that underlie MAB’s adaptation and persistence in the human host through an examination of MABs transcriptional response to a number of clinically relevant conditions. These include hypoxia, exposure to sub-inhibitory concentrations of antibiotics and growth in an artificial sputum designed to mimic the conditions within the cystic fibrosis lung. Conclusions: Our integrated map provides the first comprehensive view of the primary transcriptome of MAB and evidence for the translation of over one hundred new short open reading frames (sORFs). Our map will act as a resource for ongoing functional genomics characterization of MAB and our transcriptome data from clinically relevant stresses informs our understanding of MAB’s adaptation to life in the CF lung. MAB’s adaptation to growth in artificial CF sputum highlights shared metabolic strategies with other CF pathogens including P. aeruginosa and mirrors the transcriptional responses that lead to persistence in mycobacteria. These strategies include an increased reliance on amino acid metabolism, and fatty acid catabolism and highlights the relevance of the glyoxylate shunt to growth in the CF lung. Our data suggests that, similar to what is seen in chronically persisting P. aeruginosa, progression towards a biofilm mode of growth would play a more prominent role in a longer-term MAB infection. Finally, MAB’s transcriptional response to antibiotics highlights the role of antibiotic modifications enzymes, active transport and the evolutionarily conserved WhiB7 driven antibiotic resistance regulon.	en
dc.description.sponsorship	Science Foundation Ireland (grants 05/RP1/B908; 05/RP1/908/EC07); Wellcome Trust (grant no. 099817/Z/12/Z).	en
dc.description.status	Peer reviewed	en
dc.description.version	Published Version	en
dc.format.mimetype	application/pdf	en
dc.identifier.articleid	553
dc.identifier.citation	Miranda-CasoLuengo, A. A., Staunton, P. M., Dinan, A. M., Lohan, A. J. and Loftus, B. J. (2016) 'Functional characterization of the Mycobacterium abscessus genome coupled with condition specific transcriptomics reveals conserved molecular strategies for host adaptation and persistence', BMC Genomics, 17, 553 (12pp). doi:10.1186/s12864-016-2868-y	en
dc.identifier.doi	10.1186/s12864-016-2868-y
dc.identifier.endpage	12
dc.identifier.issn	1471-2164
dc.identifier.journaltitle	BMC Genomics	en
dc.identifier.startpage	1
dc.identifier.uri	https://hdl.handle.net/10468/4121
dc.identifier.volume	17
dc.language.iso	en	en
dc.publisher	BioMed Central	en
dc.relation.uri	https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-016-2868-y
dc.rights	© 2016, the Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.	en
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/	en
dc.subject	Integrated map	en
dc.subject	Mycobacterium abscessus	en
dc.subject	WhiB7	en
dc.subject	Antibiotic	en
dc.subject	Cystic fibrosis	en
dc.title	Functional characterization of the Mycobacterium abscessus genome coupled with condition specific transcriptomics reveals conserved molecular strategies for host adaptation and persistence	en
dc.type	Article (peer-reviewed)	en