138
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Parallel bacterial evolution within multiple patients identifies candidate pathogenicity genes

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Bacterial pathogens evolve during the infection of their human hosts 1- 8 , but separating adaptive and neutral mutations remains challenging 9- 11 . Here, we identify bacterial genes under adaptive evolution by tracking recurrent patterns of mutations in the same pathogenic strain during the infection of multiple patients. We conducted a retrospective study of a Burkholderia dolosa outbreak among people with cystic fibrosis, sequencing the genomes of 112 isolates collected from 14 individuals over 16 years. We find that 17 bacterial genes acquired non-synonymous mutations in multiple individuals, which indicates parallel adaptive evolution. Mutations in these genes illuminate the genetic basis of important pathogenic phenotypes, including antibiotic resistance and bacterial membrane composition, and implicate oxygen-dependent gene regulation as paramount in lung infections. Several genes have not been previously implicated in pathogenesis, suggesting new therapeutic targets. The identification of parallel molecular evolution suggests key selection forces acting on pathogens within humans and can help predict and prepare for their future evolutionary course.

          Related collections

          Most cited references32

          • Record: found
          • Abstract: found
          • Article: not found

          The changing microbial epidemiology in cystic fibrosis.

          Infection of the airways remains the primary cause of morbidity and mortality in persons with cystic fibrosis (CF). This review describes salient features of the epidemiologies of microbial species that are involved in respiratory tract infection in CF. The apparently expanding spectrum of species causing infection in CF and recent changes in the incidences and prevalences of infection due to specific bacterial, fungal, and viral species are described. The challenges inherent in tracking and interpreting rates of infection in this patient population are discussed.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Phase and antigenic variation in bacteria.

            Phase and antigenic variation result in a heterogenic phenotype of a clonal bacterial population, in which individual cells either express the phase-variable protein(s) or not, or express one of multiple antigenic forms of the protein, respectively. This form of regulation has been identified mainly, but by no means exclusively, for a wide variety of surface structures in animal pathogens and is implicated as a virulence strategy. This review provides an overview of the many bacterial proteins and structures that are under the control of phase or antigenic variation. The context is mainly within the role of the proteins and variation for pathogenesis, which reflects the main body of literature. The occurrence of phase variation in expression of genes not readily recognizable as virulence factors is highlighted as well, to illustrate that our current knowledge is incomplete. From recent genome sequence analysis, it has become clear that phase variation may be more widespread than is currently recognized, and a brief discussion is included to show how genome sequence analysis can provide novel information, as well as its limitations. The current state of knowledge of the molecular mechanisms leading to phase variation and antigenic variation are reviewed, and the way in which these mechanisms form part of the general regulatory network of the cell is addressed. Arguments both for and against a role of phase and antigenic variation in immune evasion are presented and put into new perspective by distinguishing between a role in bacterial persistence in a host and a role in facilitating evasion of cross-immunity. Finally, examples are presented to illustrate that phase-variable gene expression should be taken into account in the development of diagnostic assays and in the interpretation of experimental results and epidemiological studies.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Tracking the in vivo evolution of multidrug resistance in Staphylococcus aureus by whole-genome sequencing.

              The spread of multidrug-resistant Staphylococcus aureus (MRSA) strains in the clinical environment has begun to pose serious limits to treatment options. Yet virtually nothing is known about how resistance traits are acquired in vivo. Here, we apply the power of whole-genome sequencing to identify steps in the evolution of multidrug resistance in isogenic S. aureus isolates recovered periodically from the bloodstream of a patient undergoing chemotherapy with vancomycin and other antibiotics. After extensive therapy, the bacterium developed resistance, and treatment failed. Sequencing the first vancomycin susceptible isolate and the last vancomycin nonsusceptible isolate identified genome wide only 35 point mutations in 31 loci. These mutations appeared in a sequential order in isolates that were recovered at intermittent times during chemotherapy in parallel with increasing levels of resistance. The vancomycin nonsusceptible isolates also showed a 100-fold decrease in susceptibility to daptomycin, although this antibiotic was not used in the therapy. One of the mutated loci associated with decreasing vancomycin susceptibility (the vraR operon) was found to also carry mutations in six additional vancomycin nonsusceptible S. aureus isolates belonging to different genetic backgrounds and recovered from different geographic sites. As costs drop, whole-genome sequencing will become a useful tool in elucidating complex pathways of in vivo evolution in bacterial pathogens.
                Bookmark

                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature Genetics
                1061-4036
                1546-1718
                15 December 2011
                13 November 2011
                01 June 2012
                : 43
                : 12
                : 1275-1280
                Affiliations
                [1 ]Department of Systems Biology, Harvard Medical School, Boston, MA, USA
                [2 ]Program for Evolutionary Dynamics, Harvard University, Cambridge, MA, USA
                [3 ]Department of Medicine, Division of Infectious Diseases, Children's Hospital Boston, Boston, MA, USA
                [4 ]Infection Prevention & Control, Children's Hospital Boston, Boston, MA, USA
                [5 ]Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
                [6 ]Department of Microbiology, University of Virginia Health System, Charlottesville, VA, USA
                [7 ]Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA
                [8 ]Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA
                [9 ]Department of Laboratory Medicine, Children's Hospital Boston, Boston, MA, USA
                [10 ]Department of Anesthesia, Division of Critical Care Medicine, Children's Hospital Boston, Boston MA, USA
                [11 ]School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA
                Author notes
                Correspondence and requests for materials regarding genotyping, phenotyping and data analysis should be sent to RK ( Roy_Kishony@ 123456hms.harvard.edu ); correspondence and requests for materials regarding clinical samples, medical information and LPS pathogenesis should be sent to AJM ( Alexander.McAdam@ 123456childrens.harvard.edu ) and GPP ( Gregory_Priebe@ 123456childrens.harvard.edu )
                [*]

                These authors contributed equally to this work.

                Article
                nihpa335194
                10.1038/ng.997
                3245322
                22081229
                48d10655-8cd3-41a1-a3a5-48c42f3407f6

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: U54 AI057159-05 || AI
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: T32 GM080177-02 || GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: R01 GM081617-05 || GM
                Categories
                Article

                Genetics
                Genetics

                Comments

                Comment on this article