Abstract
As both a commensal and a major cause of healthcare-associated infections in humans, Enterococcus faecalis is a remarkably adaptable organism. We investigated how E. faecalis adapts in a mammalian host as a pathogen by characterizing changes in the transcriptome during infection in a rabbit model of subdermal abscess formation using transcriptional microarrays. The microarray experiments detected 222 and 291 differentially regulated genes in E. faecalis OG1RF at two and eight hours after subdermal chamber inoculation, respectively. The profile of significantly regulated genes at two hours post-inoculation included genes involved in stress response, metabolism, nutrient acquisition, and cell surface components, suggesting genome-wide adaptation to growth in an altered environment. At eight hours post-inoculation, 88% of the differentially expressed genes were down-regulated and matched a transcriptional profile consistent with a (p)ppGpp-mediated stringent response. Subsequent subdermal abscess infections with E. faecalis mutants lacking the (p)ppGpp synthetase/hydrolase RSH, the small synthetase RelQ, or both enzymes, suggest that intracellular (p)ppGpp levels, but not stringent response activation, influence persistence in the model. The ability of cells to synthesize (p)ppGpp was also found to be important for growth in human serum and whole blood. The data presented in this report provide the first genome-wide insights on E. faecalis in vivo gene expression and regulation measured by transcriptional profiling during infection in a mammalian host and show that (p)ppGpp levels affect viability of E. faecalis in multiple conditions relevant to mammalian infection. The subdermal abscess model can serve as a novel experimental system for studying the E. faecalis stringent response in the context of the mammalian immune system.
Highlights
Many Gram-positive cocci, including staphylococci, streptococci, and enterococci, maintain commensal relationships with mammals by occupying specific biological niches, yet maintain the potential to become pathogenic when colonizing alternate sites within the same hosts
We previously used the rabbit subdermal abscess model for a recombinase-based in vivo expression technology (RIVET) genetic screen to identify promoters in E. faecalis that are up-regulated in infection [11]
Since the model enables sampling of the same infection site over time and has been used for Staphylococcus aureus in vivo gene expression profiling [25], we used the model in this work to continue our investigations of E. faecalis OG1RF gene expression during infection
Summary
Many Gram-positive cocci, including staphylococci, streptococci, and enterococci, maintain commensal relationships with mammals by occupying specific biological niches, yet maintain the potential to become pathogenic when colonizing alternate sites within the same hosts. The enterococci, which naturally reside in the human gastrointestinal tract, are distinct from staphylococci and streptococci in the diverse range of non-mammalian environments that they inhabit, from soil and water to plants and the guts of insects [1]. Many studies report a lack of correlation between the presence of virulence factors in the genomes of isolates and the types of infectious or non-infectious sources from which the isolates originated [4,5,6,7,8]. These data suggest that a complex combination of factors contribute to the virulence of E. faecalis
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