Polysaccharide intercellular adhesin (PIA) also known as poly-N-acetyl-β-(1-6)-glucosamine (PIA/PNAG) is an important component of biofilms and also contributes to resistance to phagocytosis. fitness by an unknown mechanism in the absence of an intact gene and PIA/PNAG production. Author Summary Staphylococcal polysaccharide intercellular adhesin (PIA) also Wortmannin known as β-1-6-linked N-acetylglucosamine (PNAG) plays a role in immune evasion and biofilm formation. Evidence suggests that under certain circumstances PIA/PNAG production is beneficial whereas at times it may be advantageous for the bacteria to turn production off. In locus of that can undergo expansion and contraction. The addition or subtraction of non-multiples of three of Rabbit polyclonal to DFFA. this repeat shifts the reading frame of the gene resulting in the Wortmannin complete loss of PIA/PNAG production. We hypothesize that certain conditions that make the PIA/PNAG-negative phenotype advantageous during infection such as the development of an effective immune response to PIA/PNAG on the bacterial surface would select for repeat mutants. In support of this hypothesis we found clinical isolates with expansion and deletion of the repeat. These findings reveal a new on-off switch for the expression of PIA/PNAG. Introduction Phase variation functions as a reversible on/off switch for the expression of a particular gene. The result is commonly an alteration in the expression of some cell surface-expressed antigen. Slipped-strand mispairing is one mechanism that can lead to the production of a phase variant. Slipped-strand mispairing occurs during DNA replication when there is mispairing between mother and daughter DNA strands in regions of DNA that contain simple 1-10 nucleotide repeats [1]. This results in the addition or subtraction of one or more repeats that can bring about a change in transcriptional efficiency or shift the reading frame to alter or halt translation. infections are responsible for an enormous loss of life; deaths from methicillin resistant (MRSA) alone exceed 18 0 yearly in the United States making it Wortmannin the leading cause of death by a single Wortmannin infectious agent [2]. Antibiotic resistance is a mounting problem and an effective vaccine is not yet available. Biofilm formation plays an important role particularly in device-related infections and it contributes to antibiotic failure and resistance of the bacteria to host immune defenses. Biofilm formation is the aggregation of bacteria on a solid surface within a self-produced extracellular polymeric matrix. Formation of a biofilm confers several survival advantages to the resident bacteria. The biofilm provides protection from adverse environmental conditions such as heat shear force and UV damage; as well as protection from the host immune system and antibiotic challenge [3]. Biofilm bacteria are resistant to antibiotic levels up to 1 1 0 higher than planktonic bacteria that are genetically identical [4] [5]. A major component of the biofilm extracellular matrix is the polysaccharide poly-N-acetylglucosamine. The staphylococcal polysaccharide intracellular adhesin (PIA) is a high molecular weight polymer of β-1-6-linked N-acetyl-glucosamine (PNAG) [6] [7]. In addition to its role in intercellular adhesion and biofilm formation PIA/PNAG also plays a role in immune evasion [8] [9]. Evidence suggests that antibodies against PIA/PNAG often recognize secreted PIA/PNAG rather than the surface-associated form resulting in an ineffective immune response [8]. In contrast an effective immune response against surface-associated PIA/PNAG which can be directed by a conjugate vaccine can successfully eradicate an infection [10]. Thus PIA/PNAG protects the bacteria from immune defenses but under certain circumstances could actually be the target of an effective immune response. PIA/PNAG is synthesized by the proteins encoded in the intercellular adhesin locus [11] [12]. IcaA is a transmembrane glucosyltransferase that together with IcaD produces short PIA/PNAG oligomers [13]. IcaC is an integral membrane protein that is necessary for linking the short oligomers into longer polymer chains and is thought to be involved in translocation of these chains to the cell surface [13]. Once there IcaB is responsible for partial deacetylation of the PIA/PNAG molecule which is required for retention at the cell surface [14]. A number of regulators modulate transcription including IcaR and CodY which are repressors and SarA and GraRS which are positive regulators [15] [16] [17] [18]. Other regulatory mechanisms have been implicated as well and are described in Wortmannin a recent review [19]. We found previously.

Polysaccharide intercellular adhesin (PIA) also known as poly-N-acetyl-β-(1-6)-glucosamine (PIA/PNAG) is an

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