Infectious diseases continue to endanger global health with over 25% of world deaths attributed to communicable diseases. The ongoing trend towards globalization, coupled with the emergence of novel pathogens that are associated with an increased incidence and severity of disease, further exacerbates the risk of rapidly disseminating and potentially fatal infections. Salmonella species are endemically present throughout food and water supplies and pose a significant challenge to human and animal health as well as the livestock industry. Here we describe the potential role of the host in the emergence of new pathogenic strains, and its influence on the efficacy of antibiotics during infection. Analysis of a collection of Salmonella enterica human and animal isolates revealed that serovar Typhimurium human clinical isolates differed from animal isolates in both their maintenance of the Salmonella virulence plasmid (required for systemic virulence) and their ability to cause disease in mice, suggesting that Salmonella may experience specific host/niche selective pressures that result in human salmonellosis clinical isolates that are distinct from those of animal origin. Further characterization of Salmonella clinical isolates identified intraspecies variation in the ability to undergo pronounced increases in virulence during the infective process leading to the identification of hypervirulent Salmonella strains which are among the most virulent of the species. Adoption of the hypervirulent phenotype was rapid (and rapidly reversible) resulting in enhanced killing of both naïve and vaccinated animals and was associated with increased cytotoxin production, host colonization and cytocidal activity. The mechanistic basis appears to be associated with altered virulence regulatory networks and metabolism coupled with the induction of an altered host immune cytokine response. To examine the influence of in vivo conditions on bacterial antibiotic resistance, salmonellae grown under conditions representative of the intracellular environment were challenged with clinically relevant antibiotics. Such conditions markedly altered the efficacy of trimethoprim resulting in high a level of bacterial resistance relative to that exhibited on laboratory medium. Molecular characterization of the diverse and dynamic survival strategies employed by salmonellae may lead to better approaches to the identification, prevention and treatment of emerging bacterial pathogens.
|Advisor:||Mahan, Michael J.|
|Commitee:||Hayes, Christopher S., Low, David A., Samuel, Charles E.|
|School:||University of California, Santa Barbara|
|Department:||Molecular, Cellular & Developmental Biology|
|School Location:||United States -- California|
|Source:||DAI-B 73/08(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Microbiology|
|Keywords:||Host adaptation, Host passage, Hypervirulence, Hypervirulent, Pathogenesis, Salmonella|
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