Staphylococcus epidermidis is the preeminent cause of infections involving biomaterial-based devices. The most important step in the pathogenesis of S. epidermidis mediated foreign body infections is the ability of the organism to adhere and to produce biofilm on the surface of the biomaterial. After initial adherence, certain strains of S epidermidis produce an extracellular biofilm, or polysaccharide intracellular adhesin (PIA), that is encoded by a four gene (icaA, icaD, icaB, and icaC) operon ica. Strains of S. epidermidis deficient in the production of PIA are significantly less adherent in in vitro studies and are less virulent in in vivo models of biomaterial based infections. Preliminary data suggest that PTA production is governed by multiple layers of gene regulation. The ica operon has been shown to undergo a phenomenon termed phase variation, whereby a certain proportion of the population do not produce PTA (biofilm-negative). Phase variation has been hypothesized to have pathogenic significance in that those cells not producing biofilm are less adherent and may be free to disperse and colonize other fertile areas resulting in metastatic disease. Data presented in this proposal demonstrate that there are at least three classes of phase variants. Class I variants can be termed true """"""""phase variants"""""""" as they readily revert to wild-type (biofilm forming). These variants do not produce detectable ica transcript yet have an intact ica operon. Class II variants produce little biofilm presumably due to mutations within ica. Class III variants do not produce biofilm due to the loss of a large genomic region which includes ica. The major goal of this study is to elucidate the genetic regulation of PIA production and better characterize the importance of phase variation in the pathogenesis of prosthetic device infection. This proposal has four specific aims:
Specific aim 1 : Genetic loci that are responsible for regulation of ica transcription, and their relationship to the mechanism governing loss of ica transcription in class I phase variants, will be defined.
Specific aim 2 : Mutational events responsible for class II phase variants will be characterized and it will be determined whether these mutational events are random or whether they preferentially occur in an ordered manner.
Specific aim 3 : Class III phase variants will be studied in order to ascertain whether the excision site is conserved amongst different strains of S. epidermidis.
Specific aim 4 : A guinea pig tissue cage model and mouse foreign body infection model will be utilized to ascertain the pathogenic significance of phase variants. This proposal will yield significant new information regarding fundamental questions of S. epidermidis pathogenesis and biology. Novel means to prevent and treat biomaterial-based infections may be suggested as a result of these studies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Nebraska Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Rowe, Sarah E; Campbell, Christopher; Lowry, Colm et al. (2016) AraC-Type Regulator Rbf Controls the Staphylococcus epidermidis Biofilm Phenotype by Negatively Regulating the icaADBC Repressor SarR. J Bacteriol 198:2914-2924
Olson, Michael E; Todd, Daniel A; Schaeffer, Carolyn R et al. (2014) Staphylococcus epidermidis agr quorum-sensing system: signal identification, cross talk, and importance in colonization. J Bacteriol 196:3482-93
Fey, Paul D; Olson, Michael E (2010) Current concepts in biofilm formation of Staphylococcus epidermidis. Future Microbiol 5:917-33
Rogers, K L; Rupp, M E; Fey, P D (2008) The presence of icaADBC is detrimental to the colonization of human skin by Staphylococcus epidermidis. Appl Environ Microbiol 74:6155-7
Holland, Linda M; O'Donnell, Sinead T; Ryjenkov, Dmitri A et al. (2008) A staphylococcal GGDEF domain protein regulates biofilm formation independently of cyclic dimeric GMP. J Bacteriol 190:5178-89
Handke, L D; Rogers, K L; Olson, M E et al. (2008) Staphylococcus epidermidis saeR is an effector of anaerobic growth and a mediator of acute inflammation. Infect Immun 76:141-52
Handke, L D; Slater, S R; Conlon, K M et al. (2007) SigmaB and SarA independently regulate polysaccharide intercellular adhesin production in Staphylococcus epidermidis. Can J Microbiol 53:82-91
Handke, L D; Conlon, K M; Slater, S R et al. (2004) Genetic and phenotypic analysis of biofilm phenotypic variation in multiple Staphylococcus epidermidis isolates. J Med Microbiol 53:367-74