Staphylococcus (page 3)
© Kenneth Todar, PhD
Adherence to Host Cell Proteins
S. aureus cells express surface proteins that
promote attachment to host proteins such as laminin and fibronectin that form
the extracellular matrix of epithelial and endothelial surfaces. In
addition, most strains express a fibrin/fibrinogen binding protein (clumping
factor) which promotes attachment to blood clots and traumatized tissue. Most
strains of S. aureus express both fibronectin and fibrinogen-binding
proteins. In addition, an adhesin that promotes attachment to collagen has been
found in strains that cause osteomyelitis and septic arthritis. Interaction
with collagen may also be important in promoting bacterial attachment to
damaged tissue where the underlying layers have been exposed.
Evidence that staphylococcal matrix-binding proteins are virulence
factors has come from studying defective mutants in adherence assays. Mutants
defective in binding to fibronectin and to fibrinogen have reduced virulence in a
rat model for endocarditis, and mutants lacking the collagen-binding
protein have reduced virulence in a mouse model for septic arthritis,
suggesting that bacterial colonization is ineffective. Furthermore, the isolated
ligand-binding domain of the fibrinogen, fibronectin and collagen receptors strongly
blocks attachment of bacterial cells to the corresponding host proteins.
The invasion of host tissues by staphylococci apparently involves the
production of a huge array of extracellular proteins, some of which may occur also
as cell-associated proteins. These proteins are described below with
some possible explanations for their role in invasive process.
alpha toxin (alpha-hemolysin)
The best characterized and most potent membrane-damaging toxin of S. aureus
is alpha toxin. It is expressed as a monomer that binds to the membrane of
susceptible cells. Subunits then oligomerize to form heptameric rings with a
central pore through which cellular contents leak.
In humans, platelets and monocytes are particularly sensitive to alpha toxin.
Susceptible cells have a specific receptor for alpha
toxin which allows the toxin to bind causing small pores through which
monovalent cations can pass. The mode of action of alpha hemolysin is likely by
ß-toxin is a
sphingomyelinase which damages membranes rich in this lipid. The classical test for
ß-toxin is lysis of sheep erythrocytes. The majority of human isolates of S. aureus
do not express ß-toxin. A lysogenic bacteriophage is
known to encode the toxin.
delta toxin is a very small peptide toxin produced by most strains of S. aureus.
It is also produced by S. epidermidis. The role of delta toxin in disease is unknown.
Leukocidin is a multicomponent protein toxin produced as separate
components which act together to damage membranes. Leukocidin forms a
hetero-oligomeric transmembrane pore composed of four LukF and four LukS
subunits, thereby forming an octameric pore in the affected membrane.
Leukocidin is hemolytic, but less so than alpha hemolysin.
Only 2% of all of S. aureus isolates express leukocidin, but
nearly 90% of the strains isolated from severe dermonecrotic lesions
express this toxin, which suggests that it is an important factor in
necrotizing skin infections.
Coagulase and clumping factor
Coagulase is an extracellular protein which binds to prothrombin in
the host to form a complex called staphylothrombin. The protease
activity characteristic of thrombin is activated in the complex, resulting in
the conversion of fibrinogen to fibrin. Coagulase is a traditional marker
for identifying S aureus in the clinical microbiology laboratory.
However, there is no overwhelming evidence that it is a virulence factor,
although it is reasonable to speculate that the bacteria could protect
themselves from phagocytic and immune defenses by causing localized clotting.
There is some confusion in the literature concerning coagulase and
clumping factor, the fibrinogen-binding determinant on the S. aureus
cell surface. Partly the confusion results from the fact that a small amount
of coagulase is tightly bound on the bacterial cell surface where it
can react with prothrombin leading to fibrin clotting. However, genetic
studies have shown unequivocally that coagulase and clumping factor are
distinct entities. Specific mutants lacking coagulase retain clumping factor
activity, while clumping factor mutants express coagulase normally.
Many strains of S aureus express a plasminogen activator called
staphylokinase. This factor lyses fibrin. The genetic determinant is
associated with lysogenic bacteriophages. A complex formed between staphylokinase
and plasminogen activates plasmin-like proteolytic activity which
causes dissolution of fibrin clots. The mechanism is identical to
streptokinase, which is used in medicine to treat patients suffering from coronary
thrombosis. As with coagulase, there is no strong evidence that staphylokinase is a
virulence factor, although it seems reasonable to imagine that localized fibrinolysis
might aid in bacterial spreading.
Other extracellular enzymes
S. aureus can express proteases, a lipase, a
deoxyribonuclease (DNase) and a fatty acid modifying enzyme (FAME). The first three
probably provide nutrients for the bacteria, and it is unlikely that they have
anything but a minor role in pathogenesis. However, the FAME enzyme may be
important in abscesses, where it could modify anti-bacterial lipids and prolong
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