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STUDY HYPOTHESES 1. There are ecological niches that are nodes for dissemination of ST, SE, and AMR and can be modeled using source-sink ecological approaches. 2. There are ecological and epidemiological determinants that are associated with genetics and fitness of ST, SE, and AMR that impact effective local and wider dissemination. <P>STUDY OBJECTIVES 1. Develop empirically grounded eco-evolutionary mathematical models that describe the dynamics and dissemination of ST and SE across local and global scales. 2. Validate and adjust the assumptions and results of the dissemination model using banked and characterized isolates of ST, SE and AMR from the United States, and United Kingdom. 3. Prospectively collect ST and SE isolates with a clearly defined geographical, demographical, ecological and epidemiological context to further evaluate the validity of the dissemination model and develop robust estimates of dissemination rates. <P>Expected Outputs from Objective 1: Completion of Objective 1 will result in: 1. A flexible, empirical vetted quantitative modeling scaffold that quantitates the dynamics and dissemination of ST, SE, and AMR over local and regional scales. 2. A process-based bioinformatic framework that draws explicit connections between observable data and population processes thereby allowing inference of processes and rates that are difficult to measure directly. 3. A modeling framework that can be modified to explore the impacts of potential intervention strategies. <br/>Expected Outputs from Objective 2: The completion of Objective 2 will result in: 1. The coordination and annotation of 5 separately collected and curated ST and SE datasets, 2. Coordinated characterization of select ST and SE (and AMR traits) from human, retail, environment, and animal samples, 3. Refinement of initial source-sink dissemination model and testing of basic hypotheses used in model development. <br/>Expected Outputs from Objective 3: The completion of Objective 3 will result in: 1. The selection and characterization of four comparative study sites in Washington and Uganda, 2. Isolation and characterization of ST and SE from human, retail, environment, and animal samples that will broadly represent the gene pool and putative dissemination pathways from the study sites, 3. Collection of relevant public and animal health ST and SE isolates from clinical cases which represent the gene pool 4.Characterization of AMR phenotypes and genotypes of ST and SE isolates, 5. Refined source-sink dissemination models for ST, SE and associated AMR.
Non-Technical Summary:<br/>
There are two globally important serovars of the bacterium Salmonella enterica: S. Enteritidis (SE) and S. Typhimurium (ST). Both are associated with human and animal infections found in the environment, and carry multidrug resistance traits (AMR). It is believed these two serovars are not adapted to specific niches. It is believed that AMR traits observed in these serovars may have separate transmission dynamics. There are examples in the literature that support these beliefs but there is an emerging literature that describes geographic differences in disease manifestation and other data suggest barriers to wide dissemination yet support robust local dissemination. In developed countries there are host factors that could explain these different manifestations but there are data that suggest that there exist geographical, ecological, and epidemiological factors that result in Salmonella niche evolution and result in either barriers to dissemination or promote rapid dissemination. This area at the intersection of ecological and evolutionary modeling has great potential to describe and explain transmission dynamics of public and animal health infectious disease but is largely unexplored. The proposed model organisms ST, SE and associated AMR have similar global distributions, are significant pathogens but have contrasting niche distributions and different population structures as measured by both overall genetic variability and the carriage of transmissible genetic elements associated with antibiotic resistance. The ecological models we develop to describe dissemination dynamics of these serovars will be robustly tested because of these similarities and differences and because we will have both historical and systematically collected isolates to evaluate our hypotheses. This proposal will focus on two contrasting human ecosystems in Washington and allow us to rigorously test our models.
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Approach:<br/>
OBJ 1: Develop empirically grounded eco-evolutionary mathematical models that describe the dynamics and dissemination of Salmonella Typhimurium and Enteritidis across local scales. Our overall strategy for achieving this objective is to develop a progression of mathematical models that increase in complexity as we compare predictions of initial, more basic model versions to data. Because this approach would add complexity only when simpler models fail to explain data adequately, only factors that significantly impact prediction of disease spread will be considered in detail. We also propose to develop models for dissemination of three independent systems with varying population complexity, ST, SE, and associated AMR.
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OBJ 2: Evaluating Databases. The assumptions for the dissemination models for ST, SE, and associated AMR are initially tested using isolate sets collected by five sites. These databases together comprise more than 10,000 isolates of ST and SE, respectively. In addition, subsets of these isolates are further categorized by subtyping methods and many isolates are characterized by resistance phenotypes. It is important to note that these different datasets are independently managed and organized. The assembled database will be summarized and these data shared with collaborators. It is expected that this will take approximately 6 months to complete.
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OBJ 3: Prospectively collect ST and SE isolates with a clearly defined geographic, demographic, ecological, and epidemiological context to further evaluate the validity of the dissemination model and develop robust estimates of dissemination rates. Study Sites: Two study sites are included in the research project: urban Washington (Seattle), and rural Washington (Yakima River Valley). These sites are relevant to the basic study hypotheses. Urban Seattle has a strong manufacturing and technology economy. It has a mobile, international population and access to a diverse food supply with global, national, and local sourcing. The rural Washington site has a strong agriculture economy based on crops, fruits, and animals. Its population is locally rooted but also has access to a diverse food supply with global, national, and local sourcing. These will allow us to compare and contrast demographic, ecological, and epidemiological characteristics and their influence on dissemination dynamics. Sampling emphasis will be on human, food, animal and environmental sources with the primary goal to define common and unique dissemination pathways at each of the sampling sites and use these data to test the parameters of our ecological models for ST, SE, and associated AMR dissemination.