title: Transcriptome Remodeling ofAcinetobacter baumanniiduring Infection and Treatment.
abstract: Acinetobacter baumanniiis an increasingly common multidrug-resistant pathogen in health care settings. Although the genetic basis of antibiotic resistance mechanisms has been extensively studied, much less is known about how genetic variation contributes to other aspects of successful infections. Genetic changes that occur during host infection and treatment have the potential to remodel gene expression patterns related to resistance and pathogenesis. Longitudinal sets of multidrug-resistantA. baumanniiisolates from eight patients were analyzed by RNA sequencing (RNA-seq) to identify differentially expressed genes and link them to genetic changes contributing to transcriptional variation at both within-patient and population levels. The number of differentially expressed genes among isolates from the same patient ranged from 26 (patient 588) to 145 (patient 475). Multiple patients had isolates with differential gene expression patterns related to mutations in thepmrABandadeRStwo-component regulatory system genes, as well as significant differences in genes related to antibiotic resistance, iron acquisition, amino acid metabolism, and surface-associated proteins. Population level analysis revealed 39 genetic regions with clade-specific differentially expressed genes, for which 19, 8, and 3 of these could be explained by insertion sequence mobilization, recombination-driven sequence variation, and intergenic mutations, respectively. Multiple types of mutations that arise during infection can significantly remodel the expression of genes that are known to be important in pathogenesis.IMPORTANCEHealth care-associated multidrug-resistantAcinetobacter baumanniican cause persistent infections in patients, but bacterial cells must overcome host defenses and antibiotic therapies to do so. Genetic variation arises during host infection, and new mutations are often enriched in genes encoding transcriptional regulators, iron acquisition systems, and surface-associated structures. In this study, genetic variation was shown to result in transcriptome remodeling at the level of individual patients and across phylogenetic groups. Differentially expressed genes include those related to capsule modification, iron acquisition, type I pili, and antibiotic resistance. Population level transcriptional variation reflects genome dynamics over longer evolutionary time periods, and convergent transcriptional changes support the adaptive significance of these regions. Transcriptional changes can be attributed to multiple types of genomic change, but insertion sequence mobilization had a predominant effect. The transcriptional effects of mutations that arise during infection highlight the rapid adaptation ofA. baumanniiduring host exposure.
authors.affiliation: The J. Craig Venter Institute, La Jolla, California, USA.
authors.forename: Meredith S
authors.initials: MS
authors.lastname: Wright
authors.affiliation: Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.|Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jacobs
authors.affiliation: Departments of Pharmacology, Molecular Biology, and Microbiology and Center for Proteomics, Case Western Reserve University, Cleveland, Ohio, USA.|Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Bonomo
authors.affiliation: The J. Craig Venter Institute, La Jolla, California, USA mark.adams@jax.org.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Adams
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy* / Q000382:microbiology*; D040981:Acinetobacter baumannii / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D024901:Drug Resistance, Multiple, Bacterial; D020869:Gene Expression Profiling; D006801:Humans; D008137:Longitudinal Studies; D017423:Sequence Analysis, RNA