Abstract
Sepsis resulting from microbial colonization of the bloodstream is a serious health concern associated with high mortality rates. The objective of this study was to define the physiologic requirements of Citrobacter freundii in the bloodstream as a model for bacteremia caused by opportunistic Gram-negative pathogens. A genetic screen in a murine host identified 177 genes that contributed significantly to fitness, the majority of which were broadly classified as having metabolic or cellular maintenance functions. Among the pathways examined, the Tat protein secretion system conferred the single largest fitness contribution during competition infections and a putative Tat-secreted protein, SufI, was also identified as a fitness factor. Additional work was focused on identifying relevant metabolic pathways for bacteria in the bloodstream environment. Mutations that eliminated the use of glucose or mannitol as carbon sources in vitro resulted in loss of fitness in the murine model and similar results were obtained upon disruption of the cysteine biosynthetic pathway. Finally, the conservation of identified fitness factors was compared within a cohort of Citrobacter bloodstream isolates and between Citrobacter and Serratia marcescens, the results of which suggest the presence of conserved strategies for bacterial survival and replication in the bloodstream environment.
Highlights
Sepsis resulting from microbial colonization of the bloodstream is a serious health concern associated with high mortality rates
Interactions between C. freundii and healthy individuals is generally considered to be non-pathogenic in nature; upon colonization of the bloodstream C. freundii is capable of causing a life-threatening infection leading to sepsis
C. freundii belongs to a relatively small group of opportunistic Gram-negative bacterial species that are encountered with frequency in healthcare settings and are capable of causing a variety of infections in individuals with diverse underlying conditions[3,5]
Summary
Sepsis resulting from microbial colonization of the bloodstream is a serious health concern associated with high mortality rates. The primary pathogenesis of sepsis is the result of a dysregulated immune response, often originating from infection, that can be followed by organ failure and death in severe cases It is well-established that pathogen-associated molecular patterns such as LPS, flagella, and peptidoglycan play a significant role in initiating the sepsis inflammatory immune response through pattern recognition receptors[22] and it is known that sepsis in model organisms can be recapitulated by exposure to these bacterial products. Together, these characteristics imply that persistence of bacteria in the bloodstream environment alone constitutes a primary driver of www.nature.com/scientificreports/. The results with C. freundii are analyzed in the context of our previous work using Serratia marcescens and a similar bacteremia model to identify common pathways of fitness in the bloodstream environment
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