Transcriptome Remodeling of Acinetobacter baumannii during Infection and Treatment

Meredith S Wright,Michael R Jacobs,Robert A Bonomo,Mark D Adams,Paul Keim

doi:10.1128/mbio.02193-16

Meredith S Wright, Michael R Jacobs + Show 3 more

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https://doi.org/10.1128/mbio.02193-16

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Abstract

ABSTRACTAcinetobacter baumannii is 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-resistant A. baumannii isolates 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 the pmrAB and adeRS two-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.

Highlights

Acinetobacter baumannii is an increasingly common multidrug-resistant pathogen in health care settings
Genetic variation arises during host infection, and new mutations are often enriched in genes encoding transcriptional regulators, iron acquisition systems, and surface-associated structures
By using high-resolution genomic analysis of longitudinal series of Acinetobacter baumannii isolates, we recently found that newly arising nonsynonymous nucleotide substitutions and insertion sequence events were enriched in certain functional classes of genes, including two-component regulatory systems (TCRS) and other transcriptional regulators, iron acquisition and other transporters, and genes coding for surface-associated proteins like capsule and pilus genes [11]

Summary

Introduction

Acinetobacter baumannii is an increasingly common multidrug-resistant pathogen in health care settings. By using high-resolution genomic analysis of longitudinal series of Acinetobacter baumannii isolates, we recently found that newly arising nonsynonymous nucleotide substitutions and insertion sequence events were enriched in certain functional classes of genes, including two-component regulatory systems (TCRS) and other transcriptional regulators, iron acquisition and other transporters, and genes coding for surface-associated proteins like capsule and pilus genes [11]. Transcriptional studies involving A. baumannii responses to iron or zinc limitation, antibiotic exposure, planktonic or biofilm conditions, and growth phase differences highlighted transcriptional changes in genes coding for type 1 pili (csu genes), biofilm formation, quorum sensing, and iron acquisition [18,19,20,21] Most of these studies used the ATCC 17978 strain as a model. The transcriptional responses of clinical isolates with well-defined genetic variation remain largely unexplored

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