The proposed studies are directed at understanding how single nucleotide polymorphisms, insertion/deletions, or other mutational changes contribute to the emergence of S. enterica serovars adapted to warm-blooded hosts (including domesticated animals) and which cause typhoid or non-typhoid infections in humans.
Our aim i s to examine every gene shared by specific pathogenic lineages of S. enterica as being a potential target for positive selection for mutations of a pathoadaptive nature. To do this, we will employ comparative genetic analyses of Salmonella isolates adapted to cold- and warm-blooded hosts and, among the latter, those causing systemic, non-systemic and asymptomatic infections. We expect to use 30-40 fully sequenced genomes for the analysis and about the same or a larger number of strain pairs will be resequenced by mutation tiling microarrays. Genetic polymorphisms will be analyzed for a footprint of positive selection. Using additional isolates, we will investigate association of the mutational changes with strains from specific habitats or types of infection caused. The pathoadaptive nature of mutations in some of the genetic loci will be examined experimentally, using both in vitro and in vivo models. As a result, we plan to obtain (i) a map of S. enterica genes targeted for mutations that contribute to the host adaptation and virulence of S. enterica;(ii) a list of naturally-occurring mutations in these genes that likely affect the gene/protein function in a pathoadaptive manner, and (iii) a comprehensive phylogenetic history and dynamics model of the evolution of virulence in Salmonella. Narrative. We propose to dissect molecular basis of evolution of virulence of Salmonella strains that cause human infections. We will determine genetic changes that contribute to emergence of Salmonella that are infecting warm-blooded animals and cause typhoid or non-typhoid disease in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084318-04
Application #
8120334
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Eckstrand, Irene A
Project Start
2008-09-01
Project End
2014-08-31
Budget Start
2011-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2011
Total Cost
$528,554
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Chattopadhyay, Sujay; Taub, Fred; Paul, Sandip et al. (2013) Microbial variome database: point mutations, adaptive or not, in bacterial core genomes. Mol Biol Evol 30:1465-70
Kisiela, Dagmara I; Chattopadhyay, Sujay; Tchesnokova, Veronika et al. (2013) Evolutionary analysis points to divergent physiological roles of type 1 fimbriae in Salmonella and Escherichia coli. MBio 4:
Irvahn, Jan; Chattopadhyay, Sujay; Sokurenko, Evgeni V et al. (2013) rbrothers: R Package for Bayesian Multiple Change-Point Recombination Detection. Evol Bioinform Online 9:235-8
Zeiner, Sarah A; Dwyer, Brett E; Clegg, Steven (2013) FimY does not interfere with FimZ-FimW interaction during type 1 fimbria production by Salmonella enterica serovar Typhimurium. Infect Immun 81:4453-60
Chattopadhyay, Sujay; Paul, Sandip; Dykhuizen, Daniel E et al. (2013) Tracking recent adaptive evolution in microbial species using TimeZone. Nat Protoc 8:652-65
Paul, Sandip; Million-Weaver, Samuel; Chattopadhyay, Sujay et al. (2013) Accelerated gene evolution through replication-transcription conflicts. Nature 495:512-5
Kisiela, Dagmara I; Chattopadhyay, Sujay; Libby, Stephen J et al. (2012) Evolution of Salmonella enterica virulence via point mutations in the fimbrial adhesin. PLoS Pathog 8:e1002733
Zeiner, Sarah A; Dwyer, Brett E; Clegg, Steven (2012) FimA, FimF, and FimH are necessary for assembly of type 1 fimbriae on Salmonella enterica serovar Typhimurium. Infect Immun 80:3289-96
Dwyer, Brett E; Newton, Karly L; Kisiela, Dagmara et al. (2011) Single nucleotide polypmorphisms of fimH associated with adherence and biofilm formation by serovars of Salmonella enterica. Microbiology 157:3162-71
Kisiela, Dagmara I; Kramer, Jeremy J; Tchesnokova, Veronika et al. (2011) Allosteric catch bond properties of the FimH adhesin from Salmonella enterica serovar Typhimurium. J Biol Chem 286:38136-47

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