Non-typhoidal Salmonella enterica subspecies I, serovar typhimurium is a growing and evolving threat, both in Sub-Saharan Africa, where it is now a leading cause of invasive, bacteremic infections, and also in the United States, where it has been responsible for numerous food-related outbreaks, where it has expanded its contamination profile historically into poultry, and recently has apparently been able to colonize (or at least survive robustly) on peanuts and tomatoes. In both cases, it appears likely that selection pressures are driving evolution of S. typhimurium to acquire and/or lose biological capabilities to take advantage of new routes of transmission. Less is known about what elements in the genome of S. typhimurium have been altered to enable these adaptations, or what impact that may have on the human immune response. We will use high-throughput in-vitro phenotyping to characterize strains causing diarrheal vs. non-diarrheal disease from Sub-Saharan Africa. To better understand the genetic traits behind adaptation in S. typhimurium we will use next-generation whole genome to fully characterize all allelic differences in core genome elements, and to inventory missing genes, and define the presence of novel genes in many strains from NTS in Africa, and from varying foodborne sources in the USA. Correlated genetic elements will be functionally verified by allelic replacement and in some cases demonstrated by animal model virulence tests. For functionally verified genetic markers, simplified assays will be developed (PCR, Allele-specific PCR or locus-specific DNA sequencing), which can then be implemented in the field to assess their prevalence and clinical significance.

Public Health Relevance

Salmonella Enterica serovar typhimurium is a widespread and rapidly evolving pathogen that is now a leading cause of fatal diarrheal and bacteremic disease in Africa, and also a major cause of foodborne Illness in western countries. This project aims to identify genetic elements that correlate clinical and phenotypic data with observed genetic elements that can be used as markers for epidemiologic study, and as potential therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI090882-05
Application #
8707324
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
Singletary, Larissa A; Karlinsey, Joyce E; Libby, Stephen J et al. (2016) Loss of Multicellular Behavior in Epidemic African Nontyphoidal Salmonella enterica Serovar Typhimurium ST313 Strain D23580. MBio 7:e02265
Hayden, Hillary S; Matamouros, Susana; Hager, Kyle R et al. (2016) Genomic Analysis of Salmonella enterica Serovar Typhimurium Characterizes Strain Diversity for Recent U.S. Salmonellosis Cases and Identifies Mutations Linked to Loss of Fitness under Nitrosative and Oxidative Stress. MBio 7:e00154
LaRock, Doris L; Chaudhary, Anu; Miller, Samuel I (2015) Salmonellae interactions with host processes. Nat Rev Microbiol 13:191-205
Pavlinac, Patricia B; Tickell, Kirkby D; Walson, Judd L (2015) Management of diarrhea in HIV-affected infants and children. Expert Rev Anti Infect Ther 13:5-8
Akullian, Adam; Ng'eno, Eric; Matheson, Alastair I et al. (2015) Environmental Transmission of Typhoid Fever in an Urban Slum. PLoS Negl Trop Dis 9:e0004212
Roxby, Alison C; Unger, Jennifer A; Slyker, Jennifer A et al. (2014) A lifecycle approach to HIV prevention in African women and children. Curr HIV/AIDS Rep 11:119-27
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
Stewart, Mary K; Cookson, Brad T (2014) Mutually repressing repressor functions and multi-layered cellular heterogeneity regulate the bistable Salmonella fliC census. Mol Microbiol 94:1272-84
Miller, Claire B; Pierlé, Sebastian Aguilar; Brayton, Kelly A et al. (2014) Transcriptional Profiling of a Cross-Protective Salmonella enterica serovar Typhimurium UK-1 dam Mutant Identifies a Set of Genes More Transcriptionally Active Compared to Wild-Type, and Stably Transcribed across Biologically Relevant Microenvironments. Pathogens 3:417-436
Stewart, Mary K; Cookson, Brad T (2012) Non-genetic diversity shapes infectious capacity and host resistance. Trends Microbiol 20:461-6

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