title: High-throughput transcriptomics reveals common and strain-specific responses of human macrophages to infection with Mycobacterium abscessus Smooth and Rough variants.
abstract: BACKGROUND
  Mycobacterium abscessus (MAB) is an emerging pathogen causing pulmonary infections in those with inflammatory lung disorders, such as Cystic Fibrosis (CF), and is associated with the highest fatality rate among rapidly growing mycobacteria (RGM). Phenotypically, MAB manifests as either a Smooth (MAB-S) or a Rough (MAB-R) morphotype, which differ in their levels of cell wall glycopeptidolipids (GPLs) and in their pathogenicity in vivo. As one of the primary immune cells encountered by MAB, we sought to examine the early transcriptional events within macrophages, following infection with both MAB-S or MAB-R.
  
  
  RESULTS
  We sampled the transcriptomes (mRNA and miRNA) of THP-1-derived macrophages infected with both MAB-R and MAB-S at 1, 4 and 24 h post-infection (hpi) using RNA-seq. A core set of 606 genes showed consistent expression profiles in response to both morphotypes, corresponding to the early transcriptional response to MAB. The core response is type I Interferon (IFN)-driven, involving the NF-κB and MAPK signaling pathways with concomitant pro-inflammatory cytokine production, and network analysis identified STAT1, EGR1, and SRC as key hub and bottleneck genes. MAB-S elicited a more robust transcriptional response at both the mRNA and miRNA levels, which was reflected in higher cytokine levels in culture supernatants. The transcriptional profiles of macrophages infected with both morphotypes were highly correlated, however, and a direct comparison identified few genes to distinguish them. Most of the induced miRNAs have previously been associated with mycobacterial infection and overall miRNA expression patterns were similarly highly correlated between the morphotypes.
  
  
  CONCLUSIONS
  The report here details the first whole transcriptome analysis of the early macrophage response to MAB infection. The overall picture at the early stages of macrophage infection is similar to that of other mycobacteria, reflected in a core type I IFN and pro-inflammatory cytokine response. Large-scale transcriptional differences in the host response to the different MAB morphotypes are not evident in the early stages of infection, however the subset of genes with distinct expression profiles suggest potentially interesting differences in internal trafficking of MAB within macrophages.
authors.affiliation: School of Medicine & Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland. anna.aulicino@ndm.ox.ac.uk.
authors.forename: Anna
authors.initials: A
authors.lastname: Aulicino
authors.affiliation: School of Medicine & Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland. adam.dinan@ucdconnect.ie.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Dinan
authors.affiliation: School of Medicine & Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland. aleksandra.mirandacasoluengo@ucd.ie.
authors.forename: Aleksandra A
authors.initials: AA
authors.lastname: Miranda-CasoLuengo
authors.affiliation: Animal Genomics Laboratory, UCD School of Agriculture and Food Science, College of Agriculture, Food Science and Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland. john.a.browne@ucd.ie.
authors.forename: John A
authors.initials: JA
authors.lastname: Browne
authors.affiliation: Animal Genomics Laboratory, UCD School of Agriculture and Food Science, College of Agriculture, Food Science and Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland. k.rue-albrecht@imperial.ac.uk.
authors.forename: Kévin
authors.initials: K
authors.lastname: Rue-Albrecht
authors.affiliation: Animal Genomics Laboratory, UCD School of Agriculture and Food Science, College of Agriculture, Food Science and Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland. david.machugh@ucd.ie.|UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Dublin, Ireland. david.machugh@ucd.ie.
authors.forename: David E
authors.initials: DE
authors.lastname: MacHugh
authors.affiliation: School of Medicine & Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland. brendan.loftus@ucd.ie.|UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Dublin, Ireland. brendan.loftus@ucd.ie.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Loftus
mesh_terms: D002460:Cell Line; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000821:virology*; D035683:MicroRNAs / Q000235:genetics; D009161:Mycobacterium / Q000145:classification* / Q000472:pathogenicity; D009164:Mycobacterium Infections / Q000235:genetics* / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D017423:Sequence Analysis, RNA / Q000379:methods*
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger