The proposed work will explore the genetic basis for real-world variability in the behavior of human pathogens during infections of individual humans and whole populations. The focus will be on two gramnegative pathogens, Burkholderia pseudomallei and Shigella dysenteriae, both of which cause infectious diseases associated with substantial mortality in humans. B. pseudomallei is an opportunistic pathogen that causes melioidosis, a disease largely found in Southeast Asia and Northern Australia;it has been classified as a select agent because of its perceived potential as a biowarfare agent. S. dysenteriae causes dysentery epidemics, predominantly in developing countries, which cause substantial mortality, particular in children. The basic hypothesis behind the proposed work is that genetic changes occurring during individual B. pseudomallei infections or during S. dysenteriae epidemics will reveal the selective pressures operating on these species as a result of host defenses, treatment, and?in the case of S. dysenteriae?the dynamic changes in the characteristics of the host population within which the epidemic is spreading. A better understanding of the molecular basis for these genetic effects may suggest new approaches to the clinical and public-health management of the diseases. The project has a major technical component since, although new-generation-sequencing technology is opening up the opportunity for studies of the type proposed, key aspects of the technology remain underdeveloped. We place particular emphasis on improvements in the rapidity with which new base-pair-accurate, finished genome sequences can be produced for the index strains of particular infections or epidemics. These reference sequences play a key in role in the experimental and computational methods used to detect the genetic changes that occur during infections and epidemics.

Public Health Relevance

The proposed work is relevant to the clinical and public-health management of bacterial disease in two ways: (1) Improved knowledge of genetic responses of bacteria to treatment, host defenses, and public-health interventions may suggest improved disease management (e.g., pharmacological means of avoiding or circumventing antibiotic resistance);(2) Rapid, comprehensive tracking of pathogen genotypes during disease outbreaks would support epidemiological and/or forensic investigation of epidemics and provide public reassurance that health officials have a clear picture of what is happening.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZAI1-DDS-M)
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University of Washington
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West, T Eoin; Myers, Nicolle D; Chantratita, Narisara et al. (2014) NLRC4 and TLR5 each contribute to host defense in respiratory melioidosis. PLoS Negl Trop Dis 8:e3178
Hagar, Jon A; Miao, Edward A (2014) Detection of cytosolic bacteria by inflammatory caspases. Curr Opin Microbiol 17:61-6
Majerczyk, Charlotte D; Brittnacher, Mitchell J; Jacobs, Michael A et al. (2014) Cross-species comparison of the Burkholderia pseudomallei, Burkholderia thailandensis, and Burkholderia mallei quorum-sensing regulons. J Bacteriol 196:3862-71
Loomis, Wendy P; Johnson, Matthew L; Brasfield, Alicia et al. (2014) Temporal and anatomical host resistance to chronic Salmonella infection is quantitatively dictated by Nramp1 and influenced by host genetic background. PLoS One 9:e111763
Martínez, Luary C; Vadyvaloo, Viveka (2014) Mechanisms of post-transcriptional gene regulation in bacterial biofilms. Front Cell Infect Microbiol 4:38
Myers, Nicolle D; Chantratita, Narisara; Berrington, William R et al. (2014) The role of NOD2 in murine and human melioidosis. J Immunol 192:300-7
Correia, Bruno E; Bates, John T; Loomis, Rebecca J et al. (2014) Proof of principle for epitope-focused vaccine design. Nature 507:201-6
Majerczyk, Charlotte; Brittnacher, Mitchell; Jacobs, Michael et al. (2014) Global analysis of the Burkholderia thailandensis quorum sensing-controlled regulon. J Bacteriol 196:1412-24
Pruneda, Jonathan N; Smith, F Donelson; Daurie, Angela et al. (2014) E2~Ub conjugates regulate the kinase activity of Shigella effector OspG during pathogenesis. EMBO J 33:437-49
Sureka, Kamakshi; Choi, Philip H; Precit, Mimi et al. (2014) The cyclic dinucleotide c-di-AMP is an allosteric regulator of metabolic enzyme function. Cell 158:1389-401

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