Variant codes:

1 = icaABCD operon is present
2 = no icaABCD operon can be identified in a genome, but other biofilm-formation-related factors are present
9 = genome sequence is incomplete (just one plasmid available in most cases)
-1 = all organisms other than Staphylococci

See also Subsystem: Adhesins in Staphylococcus

Infections involving Staphylococcus aureus are often more severe and difficult to treat when the organism assumes a biofilm mode of growth. Biofilm formation is an important aspect of endocarditis, osteomyelitis, and corneal and medical device infections related to S. aureus. It is a muti-step process (for a review see Fitzpatrick et al., 2005; Mack et al., 2004; Gotz, 2002) with the two major stages:
(i) adherence of cells to a surface (encoded in SS: Adhesins in Staphylococcus) and
(ii) growth-dependent multilayered cell cluster accumulation mediated by intercellular adhesion (which is a focus of this SS).

The key role in the latter process is played by PNAG, partially N-acetylated linear beta-1–6-linked glucosaminoglycan, also known as polysaccharide intercellular adhesin (PIA). It’s biosynthesis is catalyzed by the products of the icaABCD operon (ICA = intercellular adhesion (Heilmann et al., 1996)). The icaR gene is transcribed divergently from the icaABCD genes and encodes a regulatory protein that binds to the ica promoter just upstream of the initiation codon for the IcaA protein. PNAG (PIA) is also involved in haemagglutination and acts as an intercellular adhesin on glass and (probably) other hydrophilic surfaces (McKenney D et al.,1998; Crampton, et al.,1999; Kropec etal.,2005)

Numerous conditions and exogenous factors influence ica transcription and PNAG synthesis, but the regulatory factors relaying these stimuli have been only partially characterized (Jefferson et al., 2004), regulators identified so far are included in this SS. Regulation of ica operon and biofilm development:
(i) negatively controlled by ica operon regulator IcaR (strong repressor) and
(ii) teicoplasmin-associated locus regulator TcaR (weak repressor) (Jefferson et al., 2004).
(iii) SarA is an essential positive regulator of biofilm development in Staphylococcus epidermidis (ref) and S. aureus (Tormo et al., 2005).
(iv) in S. epidermidis the alternative sigma factor B positively influences ica operon expression by negatively regulating icaR expression. However, mutations in the S. aureus sigB locus do not result in a biofilm-negative phenotype, thus highlighting an important difference in biofilm development between these species (Fitzpatrick et al., 2005).
(v) Disruption of Arg (accessory gene regulator) system, the only known quorum-sensing system in staphylococci (not included here, see SS: Accessory_Gene_Regulator), leads to increased biofilm development, hence Arg activation may contribute to biofilm detachment and metastatic spread to secondary infection sites (Firzpatrick et al., 2005)

In addition to PIA, another carbohydrate-containing polymer, extracellular teichoic acid (EC TA), has recently been clearly identified as the second major essential component of S. epidermidis RP62A biofilms (Sadovskaya et al., 2005). The poly(glycerol phosphate) EC TA is a highly polar and hydrophilic molecule, while PIA is rich in relatively hydrophobic N-acetyl groups. Various relative amounts of extracellular PIA and EC TA are produced depend on the growth conditions. This capacity to regulate positive and negative charges, as well as hydrophilic properties of its biofilm constituents might increase the ability of S. epidermidis RP62A to form biofilms on surfaces with different physicochemical properties under various environmental conditions.

Analysis of biofilm-negative mutants, in which PIA production was unaffected lead to identification of additional factors involved in biofilm formation in S. epidermidis and S. aureus:
(i) Accumulation-associated protein AAP (Hussain, et al., 1997). To gain adhesive function, full-length AAP has to be proteolytically processed through staphylococcal or host proteases. It is therefore possible that in vivo effector mechanisms of the innate immunity can directly induce protein-dependent S. epidermidis cell aggregation and biofilm formation (Rohde et al., 2005).
(ii) Antiadhesin Pls, binding to squamous nasal epithelial cells. Pls could at one point of an infection prevent adhesion, allowing cells to spread, and at another point help staphylococci to adhere to tissues and structures of the host. Pls is cleaved as a result of the activation of receptor-bound plasminogen on the MRSA surface in vitro. The cleavage of Pls might reveal its as-yet-unknown, possibly adhesive properties (Savolainen et al., 2001), e.g. similar to a proteolytic activation mechanism of AAP (Rohde et al., 2005).
(iii) The major autolysin AtlE – bifunctional: N-acetylmuramoyl-L-alanine amidase (EC 3.5.1.28)/ endo-beta-N-acetylglucosaminidase (EC 3.2.1.96)
(iv) Staphylococcal surface protein SSP1 (not included in SS: no sequence has been associated with it yet (Veenstra et al., 1996))
(v) Biofilm-associated protein Bap - a novel cell wall-anchored, 2276-amino-acid protein found in 5% of the S. aureus bovine mastitis isolates, but absent in the 75 clinical human S. aureus isolates analyzed (Cucarella et al., 2001). Not included in this SS yet –complete genomes of Staph associated with bovine mastitis are not yet available in SEED (e.g. Staphylococcus aureus strain RF122), will be added soon.
(vi) D-alanine esterification of teichoic acids (dltA) (not included in this SS, see SS: D-alanyl_lipoteichoic_acid_Biosynthesis).


References:

Cramton SE, et al., 1999. The intercellular adhesion (ica) locus is present in Staphylococcus aureus and is required for biofilm formation. Infect. Immun. 67(10):5427-5433.
Cucarella, C., Solano, C., Valle, J., Amorena, B., Lasa, I., and Penades, J.R. (2001) Bap, a Staphylococcus aureus surface protein involved in bioilm formation. J Bacteriol, 183, p.2888–2896.
Fitzpatrick, F., H. Humphreys, and J. P. O’Gara. 2005. The genetics of staphylococcal biofilm formation—will a greater understanding of pathogenesis lead to better management of device-related infection? Clin Microbiol Infect, 11: 967–973
Gotz F. Staphylococcus and biofilms. Mol Microbiol 2002; 43: 1367–1378.
Heilmann C, et al., 1996. Molecular basis of intercellular adhesion in the biofilm-forming Staphylococcus epidermidis. Mol. Microbiol. 20(5):1083-1091
Hussain, M., Herrmann, M., von Eiff, C., Perdreau-Remington, F., and Peters, G. (1997) A140-kilodalton extracellular protein is essential for the accumulation of Staphylococcus epidermidis strains on surfaces. Infect. Immun65:519–524.
Jefferson KK, Pier DB, Goldmann DA, Pier GB. The teicoplanin-associated locus regulator (TcaR) and the intercellular adhesin locus regulator (IcaR) are transcriptional inhibitors of the ica locus in Staphylococcus aureus. J Bacteriol. 2004 Apr;186(8):2449-56.
Kropec A, Maira-Litran T, Jefferson KK, Grout M, Cramton SE, Gotz F, Goldmann DA, Pier GB. 2005. Poly-N-acetylglucosamine production in Staphylococcus aureus is essential for virulence in murine models of systemic infection. Infect Immun. 73(10):6868-76.
Mack D, Becker P, Chatterjee I, Dobinsky S, Knobloch JK, Peters G, Rohde H, Herrmann M. 2004. Mechanisms of biofilm formation in Staphylococcus epidermidis and Staphylococcus aureus: functional molecules, regulatory circuits, and adaptive responses. Int J Med Microbiol. 294(2-3):203-12.
McKenney D, et al., 1998. The ica locus of Staphylococcus epidermidis encodes production of the capsular polysaccharide/adhesin. Infect. Immun. 66(10):4711-4720.
Rohde H, Burdelski C, Bartscht K, Hussain M, Buck F, Horstkotte MA, Knobloch JK, Heilmann C, Herrmann M, Mack D. 2005. Induction of Staphylococcus epidermidis biofilm formation via proteolytic processing of the accumulation-associated protein by staphylococcal and host proteases. Mol Microbiol. 55(6):1883-95.
Sadovskaya I, Vinogradov E, Flahaut S, Kogan G, Jabbouri S. 2005. Extracellular carbohydrate-containing polymers of a model biofilm-producing strain, Staphylococcus epidermidis RP62A. Infect Immun. 2005 May;73(5):3007-17.
Tormo MA, Marti M, Valle J, Manna AC, Cheung AL, Lasa I, Penades JR. SarA is an essential positive regulator of Staphylococcus epidermidis biofilm development. J Bacteriol. 2005 Apr;187(7):2348-56.
Valle J, Toledo-Arana A, Berasain C, Ghigo JM, Amorena B, Penades JR, Lasa I. SarA and not sigmaB is essential for biofilm development by Staphylococcus aureus. Mol Microbiol. 2003 May;48(4):1075-87.