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Identified virulence factors of Staphylococcus: Adherence


Clumping factor  

Related genes: clfA; clfB;
Keywords: Adherence;
Characteristics:
Belongs to MSCRAMMs family.
Ser-Asp rich fibrinogen-binding proteins (the proteins having the SD dipeptide repeats have so far been found only in S. aureus and S. epidermidis).
The clfA and clfB genes are not allelic variants but are distinct genes. They are not closely linked, in contrast to the fnbA and fnbB genes.
Structure features:
The structural organization of ClfA and ClfB is very similar.
Anchored to the cell wall by LPXTG motif (the LPXTG motif is cleaved between the Thr and Gly residues by a transpeptidase called sortase. The carboxyl group of Thr is covalently joined to the pentaglycine cross-link of peptidoglycan).
Figures:
Structural organization of ClfA and ClfB


Functions:
ClfA and ClfB bind to different sites in fibrinogen. ClfA binds to the γ-chain whereas ClfB binds to the α-chain.
ClfA through its fibrinogen-binding function is a mediator of S. aureus-induced platelet aggregation.
Mechanism:
Fibrinogen is a large protein composed of three polypeptide chains (α, β, γ) that are extensively linked by disulphide bonds to form an elongated dimeric structure. It is the ligand for the integrin αIIb/β3 on the surface of platelets. This binding of fibrinogen to the integrin receptor on activated platelets results in platelet aggregation and the formation of platelet-fibrin thrombi. ClfA exhibits fibrinogen-binding characteristics similar to those of the platelet integrin αIIb/β3.
References:
McDevitt D, et al., 1995. Identification of the ligand-binding domain of the surface-located fibrinogen receptor (clumping factor) of Staphylococcus aureus. Mol. Microbiol. 16(5):895-907.
McDevitt D, et al., 1994. Molecular characterization of the clumping factor (fibrinogen receptor) of Staphylococcus aureus. Mol. Microbiol. 11(2):237-248.
McDevitt D, et al., 1997. Characterization of the interaction between the Staphylococcus aureus clumping factor (ClfA) and fibrinogen. Eur. J. Biochem. 247(1):416-424.
Ni Eidhin D, et al., 1998. Clumping factor B (ClfB), a new surface-located fibrinogen-binding adhesin of Staphylococcus aureus. Mol. Microbiol. 30(2):245-257.
Josefsson E, et al., 1998. Three new members of the serine-aspartate repeat protein multigene family of Staphylococcus aureus. Microbiology. 144:3387-3395.
Foster TJ, Hook M, 1998. Surface protein adhesins of Staphylococcus aureus. Trends Microbiol. 6(12):484-488.
Siboo IR, et al., 2001. Clumping factor A mediates binding of Staphylococcus aureus to human platelets. Infect. Immun. 69(5):3120-3127.
Perkins S, et al., 2001. Structural organization of the fibrinogen-binding region of the clumping factor B MSCRAMM of Staphylococcus aureus. J. Biol. Chem. 276(48):44721-44728.
O'Brien L, et al., 2002. Multiple mechanisms for the activation of human platelet aggregation by Staphylococcus aureus: roles for the clumping factors ClfA and ClfB, the serine-aspartate repeat protein SdrE and protein A. Mol. Microbiol. 44(4):1033-1044.
Deivanayagam CC, et al., 2002. A novel variant of the immunoglobulin fold in surface adhesins of Staphylococcus aureus: crystal structure of the fibrinogen-binding MSCRAMM, clumping factor A. EMBO J. 21(24):6660-6672.


CNA (collagen binding protein)  

Related genes: cna;
Keywords: Adherence;
Characteristics:
Belongs to MSCRAMMs family.
Structure features:
Consists of an N-terminal signal peptide, a non-repetitive A region, one to four repeated units (B-region), followed by a cell wall anchor region, a transmembrane segment, and a short positively charged cytoplasmic tail. The A region of CNA-(30-531) was found to be fully responsible for the collagen binding activity of CNA.
PDB code : 1AMX.
Functions:
Not generally expressed by the majority of strains.
Mediates bacterial adherence to collagen substrates and collagenous tissues, strongly associated with pathogenesis of osteomyelitis and septic arthritis.
References:
Patti JM, et al., 1992. Molecular characterization and expression of a gene encoding a Staphylococcus aureus collagen adhesin. J. Biol. Chem. 267(7):4766-4772.
Patti JM, et al., 1994. The Staphylococcus aureus collagen adhesin is a virulence determinant in experimental septic arthritis. Infect. Immun. 62(1):152-161.
Symersky J, et al., 1997. Structure of the collagen-binding domain from a Staphylococcus aureus adhesin. Nat. Struct. Biol. 4(10):833-838.
Foster TJ, Hook M, 1998. Surface protein adhesins of Staphylococcus aureus. Trends Microbiol. 6(12):484-488.
Rhem MN, et al., 2000. The collagen-binding adhesin is a virulence factor in Staphylococcus aureus keratitis. Infect. Immun. 68(6):3776-3779.


Eap/Map (Extracellular adherence protein/MHC analogous protein)  

Related genes: map;
Keywords: Adherence;
Characteristics:
Belongs to MSCRAMMs family.
Unusual property: Eap can bind back to the S. aureus cell wall.
Structure features:
No cell-wall-spanning domain or a membrane anchor and LPXTG motif.
Comprises six repeats of a 110 amino acid residue motif with a central portion composed of a subdomain with high homology to the peptide-binding groove of mammalian major histocompatibility complex class II (MHCII) molecules.
Functions:
High affinity for various extracellular-matrix proteins including fibronectin, fibrinogen, vitronectin, bone sialoprotein and thrombospondin, promoting bacterial attachment.
Capable of modulating the inflammatory response through its interactions with ICAM-1 (intercellular adhesion molecula-1).
References:
Palma M, et al., 1999. Adherence of Staphylococcus aureus is enhanced by an endogenous secreted protein with broad binding activity. J. Bacteriol. 181(9):2840-2845.
Hussain M, et al., 2001. Identification and characterization of a novel 38.5-kilodalton cell surface protein of Staphylococcus aureus with extended-spectrum binding activity for extracellular matrix and plasma proteins. J. Bacteriol. 183(23):6778-6786.
Hussain M, et al., 2002. Insertional inactivation of Eap in Staphylococcus aureus strain Newman confers reduced staphylococcal binding to fibroblasts. Infect. Immun. 70(6):2933-2940.
Chavakis T, et al., 2002. Staphylococcus aureus extracellular adherence protein serves as anti-inflammatory factor by inhibiting the recruitment of host leukocytes. Nat. Med. 8(7):687-693.
Haggar A, et al., 2003. Extracellular adherence protein from Staphylococcus aureus enhances internalization into eukaryotic cells. Infect. Immun. 71(5):2310-2317.
Harraghy N, et al., 2003. The adhesive and immunomodulating properties of the multifunctional Staphylococcus aureus protein Eap. Microbiology. 149:2701-2707.


EbpS (elastin-binding protein)  

Related genes: ebp;
Keywords: Adherence;
Characteristics:
Belongs to MSCRAMMs family.
Structure features:
An integral membrane protein, the elastin-binding domain is located at the N-terminus and is exposed at the surface.
Lacks a signal sequence and the C-terminal LPXTG motif.
Functions:
Promotes bacterial colonization to facilitate pathogenesis.
Mechanism:
Elastin, along with microfibrillar components, are a major component of the elastic fiber ECM. Elastin and elastic fibers are present in abundance in tissues that require elasticity such as the lung, skin, and major blood vessels. Elastin is a polymer of tropoelastin monomers that are secreted from mammalian cells prior to deposition in tissue and cross-linking via modified lysine side chains. EbpS binds to the N-terminal 30-kDa region of elastin, which does not contain the VGVAPG hexapeptide recognition motif for the mammalian elastin receptor.
References:
Park PW, et al., 1996. Molecular cloning and expression of the gene for elastin-binding protein (ebpS) in Staphylococcus aureus. J. Biol. Chem. 271(26):15803-15809.
Park PW, et al., 1999. Characterization of the elastin binding domain in the cell-surface 25-kDa elastin-binding protein of Staphylococcus aureus (EbpS). J. Biol. Chem. 274(5):2845-2850.
Foster TJ, Hook M, 1998. Surface protein adhesins of Staphylococcus aureus. Trends Microbiol. 6(12):484-488.
Downer R, et al., 2002. The elastin-binding protein of Staphylococcus aureus (EbpS) is expressed at the cell surface as an integral membrane protein and not as a cell wall-associated protein. J. Biol. Chem. 277(1):243-250.


FnBPs (fibronectin binding proteins)  

Related genes: fnbA; fnbB;
Keywords: Adherence;
Characteristics:
Belongs to MSCRAMMs family.
Most strains of S. aureus express two related Fn-binding proteins FnBPA and FnBPB, which are encoded by closely linked genes.
Structure features:
Anchored to the cell wall by LPXTG motif.
The primary ligand binding domain, which is almost identical in FnBPA and FnBPB, is located very close to the cell-wall-spanning domain and consists of 3 - 5 repeats of a <= 40-aa motif, this repeat domain appears to lack a folded secondary structure. When binds to fibronectin it takes structural rearrangements in the D repeat region. This conformational change is accompanied by the formation of neo-epitopes called ligand-induced binding site (LIBS) epitopes.
Figures:
Structural organization of fibronectin-binding protein A


Functions:
Facilitates attachment of the staphylococcus to host cells.
May function as invasin to invade non-professional phagocytes.
Mechanism:
Fibronectin is a dimeric glycoprotein that occurs in a soluble form in body fluids and in a fibrillar form in the ECM. The primary function of fibronectin is to act as a substratum for the adhesion of cells mediated by integrin receptors that bind to specific sites in the central part of fibronectin. FnBPs bind fibronectin via the type I modules at the N-terminus. Fn is bound to the α5β1 integrin on the surface of the host cell at the central fibronectin RGD (Arg-Gly-Asp) motif-bearing module. Thus fibronectin forms a bridge between the bacterial FnBP adhesin and the mammalian cell integrin.
References:
Foster TJ, Hook M, 1998. Surface protein adhesins of Staphylococcus aureus. Trends Microbiol. 6(12):484-488.
Dziewanowska K, et al., 1999. Fibronectin binding protein and host cell tyrosine kinase are required for internalization of Staphylococcus aureus by epithelial cells. Infect. Immun. 67(9):4673-4678.
Wann ER, et al., 2000. The fibronectin-binding MSCRAMM FnbpA of Staphylococcus aureus is a bifunctional protein that also binds to fibrinogen. J. Biol. Chem. 275(18):13863-13871.
Sinha B, et al., 1999. Fibronectin-binding protein acts as Staphylococcus aureus invasin via fibronectin bridging to integrin alpha5beta1. Cell Microbiol. 1(2):101-117.
Mongodin E, et al., 2002. Fibronectin-binding proteins of Staphylococcus aureus are involved in adherence to human airway epithelium. Infect. Immun. 70(2):620-630.
Menzies BE, 2003. The role of fibronectin binding proteins in the pathogenesis of Staphylococcus aureus infections. Curr. Opin. Infect. Dis. 16(3):225-229.


Intercellular adhesion proteins  

Related genes: icaA; icaB; icaC; icaD; icaR;
Keywords: Adherence; Biofilm formation;
Characteristics:
icaA, icaB, icaC, icaD synthesize a polysaccharide, poly-n-succinyl-β-1,6 glucosamine (PNSG) during infection.
Figures:
Model for PNSA biosynthesis (From: Whitfield GB, et al., 2015. Enzymatic modifications of exopolysaccharides enhance bacterial persistence. Front Microbiol 6:471.).


Functions:
PNSG is critical to biofilm elaboration, allowing bacteria to adhere to one another, and may also promote adherence to other molecules, such as ECM components.
References:
Heilmann C, et al., 1996. Molecular basis of intercellular adhesion in the biofilm-forming Staphylococcus epidermidis. Mol. Microbiol. 20(5):1083-1091.
McKenney D, et al., 1998. The ica locus of Staphylococcus epidermidis encodes production of the capsular polysaccharide/adhesin. Infect. Immun. 66(10):4711-4720.
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.
Gotz F, 2002. Staphylococcus and biofilms. Mol. Microbiol. 43(6):1367-1378.


SDr (Ser-Asp rich proteins)  

Related genes: sdrC; sdrD; sdrE;
Keywords: Adherence; MSCRAMMs;
Structure features:
Characterized by the R domain containing Ser-Asp dipeptide repeats.
Structural organization similar to that of ClfA and ClfB, except for an additional B repeat comprising 110-113 residues located between A domain and the R domain. The function of B domain is unknown. Each repeat has high affinity Ca2+ -binding sites. Bound Ca2+ is required to promote the rigid rod-like structure of the B repeat array.
Figures:
Structural organization of SDr proteins


Functions:
Binds to bone sialoprotein and fibrinogen.
References:
Josefsson E, et al., 1998. The binding of calcium to the B-repeat segment of SdrD, a cell surface protein of Staphylococcus aureus. J. Biol. Chem. 273(47):31145-31152.
Josefsson E, et al., 1998. Three new members of the serine-aspartate repeat protein multigene family of Staphylococcus aureus. Microbiology. 144:3387-3395.
Foster TJ, Hook M, 1998. Surface protein adhesins of Staphylococcus aureus. Trends Microbiol. 6(12):484-488.
Vazquez V, et al., 2011. Fibrinogen Is a Ligand for the Staphylococcus aureus Microbial Surface Components Recognizing Adhesive Matrix Molecules (MSCRAMM) Bone Sialoprotein-binding Protein (Bbp) J Biol. Chem. 286(34):29797-29805.






Terms
MSCRAMMs
Microbial surface components recognizing adhesive matrix molecules;
a sub-family of adhesins that specifically bind extracellular matrix molecules. In this respect, MSCRAMMs resemble integrins that are adhesion receptors on eukaryotic cells.
biofilm
Formed by bacteria attached to surfaces, which upon their aggregation release extracellular polysaccharides that form a polymeric matrix or glycocalyx. Biofilms are architecturally complex structures made up of microcolonies and characteristic mushroom or pillar-like arrangements that are separated by channels that permit the circulation of water and nutrients. Medically important biofilms, which can be found on catheters, artificial joints and stints for example, are extremely difficult to eradicate, because they are shielded from host defenses such as phagocytosis or antibodies and are resistant to antibiotics. In addition, biofilms can be the source of chronic infections, since they continuously shed planktonic bacteria that can multiply.
The formation of a biofilm occurs in three stages: initial attachment, proliferation resulting in the formation of microcolonies, and differentiation of the microcolonies into distinct structures







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