Streptococcus pyogenes and Streptococcal Disease (page 2)
(This chapter has 4 pages)
© Kenneth Todar, PhD
Streptococcus pyogenes owes its major success as a pathogen
its ability to colonize and rapidly multiply and spread in its host
evading phagocytosis and confusing the immune system.
Acute diseases associated with Streptococcus pyogenes
occur chiefly in the respiratory tract, bloodstream, or
skin. Streptococcal disease is most often a respiratory infection
or tonsillitis) or a skin infection (pyoderma). Some strains of
show a predilection for the respiratory tract; others, for the skin.
streptococcal isolates from the pharynx and respiratory tract do not
skin infections. Figure 3 describes the pathogenesis of S. pyogenes
S. pyogenes is the leading cause of uncomplicated bacterial pharyngitis
and tonsillitis commonly referred to a strep throat.
respiratory infections include sinusitis,
otitis, and pneumonia.
Infections of the skin can be superficial (impetigo) or deep
(cellulitis). Invasive streptococci cause joint or bone
destructive wound infections (necrotizing fasciitis) and
endocarditis. Two post streptococcal sequelae,
fever and glomerulonephritis, may follow streptococcal
and occur in 1-3% of untreated infections. These conditions and their
are not attributable to dissemination of bacteria, but to aberrent
reactions to Group A streptococcal antigens.
Scarlet fever and streptococcal
toxic shock syndrome are systemic responses to circulating
The cell surface of Streptococcus pyogenes accounts
many of the bacterium's determinants of virulence, especially those
with colonization and evasion of phagocytosis and the host immune
The surface of Streptococcus pyogenes is incredibly complex and
chemically-diverse. Antigenic components include capsular
(C-substance), cell wall peptidoglycan and lipoteichoic
(LTA), and a variety of surface proteins, including M protein,
proteins, fibronectin-binding proteins, (e.g. Protein F)
and cell-bound streptokinase.
The cytoplasmic membrane of S. pyogenes contains some
similar to those of human cardiac, skeletal, and smooth muscle, heart
fibroblasts, and neuronal tissues, resulting in molecular mimicry
and a tolerant or suppressed immune response by the host.
The cell envelope of a Group A streptococcus is illustrated in
2. The complexity of the surface can be seen in several of the electron
micrographs of the bacterium that accompany this article.
Figure 2. Cell surface
of Streptococcus pyogenes and secreted products involved in
In Group A streptococci, the R and T proteins are
as epidemiologic markers and have no known role in virulence. The group
carbohydrate antigen (composed of N-acetylglucosamine and
has been thought to have no role in virulence, but emerging strains
increased invasive capacity produce a very mucoid colony, suggesting a
role of the capsule in virulence.
The M proteins are clearly virulence factors associated with
both colonization and resistance to phagocytosis. More than 50
of S. pyogenes M proteins have been identified on the basis of
specificity, and it is the M protein that is the major cause of
shift and antigenic drift in the Group A streptococci. The M protein
in fimbriae) also binds fibrinogen from serum and blocks the binding of
complement to the underlying peptidoglycan. This allows survival of the
organism by inhibiting phagocytosis.
The streptococcal M protein, as well as peptidoglycan,
and group-specific carbohydrate, contain antigenic epitopes that mimic
those of mammalian muscle and connective tissue. As mentioned above,
cell surface of recently emerging strains of streptococci is distinctly
mucoid (indicating that they are highly encapsulated). These strains
also rich in surface M protein. The M proteins of certain M-types are
since they contain antigenic epitopes related to heart muscle, and they
therefore may lead to autoimmune rheumatic carditis (rheumatic fever)
an acute infection.
The Hyaluronic Acid Capsule
The capsule of S. pyogenes is non antigenic since it
composed of hyaluronic acid, which is chemically similar to
of host connective tissue. This allows the bacterium to hide its own
and to go unrecognized as antigenic by its host. The Hyaluronic acid
also prevents opsonized phagocytosis by neutrophils or mancrophages.
Colonization of tissues by S. pyogenes is thought to result
a failure in the constitutive defenses (normal flora and other
defense mechanisms) which allows establishment of the bacterium at a
of entry (often the upper respiratory tract or the skin) where the
multiplies and causes an inflammatory purulent lesion.
It is now realized that S. pyogenes (like many other
pathogens) produces multiple adhesins with varied specificities. There
is evidence that Streptococcus pyogenes utilizes lipoteichoic
acids (LTA), M protein, and multiple fibronectin-binding
proteins in its repertoire of adhesins. LTA is anchored to proteins
on the bacterial surface, including the M protein. Both the M proteins
and lipoteichoic acid are supported externally to the cell wall on
and appear to mediate bacterial adherence to host epithelial
The fibronectin-binding protein, Protein F, has also been shown
to mediate streptococcal adherence to the amino terminus of fibronectin
on mucosal surfaces.
Identification of Streptococcuspyogenes adhesins has long
a subject of conflict and debate. Most of the debate was between
of the LTA model and those of the M protein model. In 1972, Gibbons and
his colleagues proposed that attachment of streptococci to the oral
of mice is dependent on M protein. However, Olfek and Beachey argued
lipoteichoic acid (LTA), rather than M protein, was responsible for
adherence to buccal epithelial cells. In 1996, Hasty and Courtney
a two-step model of attachment that involved both M protein and
acids. They suggested that LTA loosely tethers streptococci to
cells, and then M protein and/or other fibronectin (Fn)-binding
secure a firmer, irreversible association. The first streptococcal
protein (Sfb) was demonstrated in 1992. Shortly thereafter, protein F
discovered. Most recently (1998), the M1 and M3 proteins were
to bind fibronectin.
Extracellular products: invasins and
Colonization of the upper respiratory tract and acute pharyngitis
spread to other portions of the upper or lower respiratory tracts
in infections of the middle ear (otitis media), sinuses (sinusitis), or
lungs (pneumonia). In addition, meningitis can occur by direct
of infection from the middle ear or sinuses to the meninges or by way
bloodstream invasion from the pulmonary focus. Bacteremia can also
in infection of bones (osteomyelitis) or joints (arthritis). During
aspects of acute disease the streptococci bring into play a variety of
secretory proteins that mediate their invasion.
For the most part, streptococcal invasins and protein toxins
with mammalian blood and tissue components in ways that kill host cells
and provoke a damaging inflammatory response. The soluble extracellular
growth products and toxins of Streptococcus pyogenes (see
2, above), have been studied intensely. Streptolysin S is an
leukocidin; Streptolysin O is an oxygen-labile leukocidin.
is also leukotoxic. Hyaluronidase (the original
factor") can digest host connective tissue hyaluronic acid, as well as
the organism's own capsule. Streptokinases participate in
lysis. Streptodornases A-D possess deoxyribonuclease activity;
B and D possess ribonuclease activity as well. Protease
similar to that in Staphylococcus aureus has been shown in
causing soft tissue necrosis or toxic shock syndrome. This large
of products is important in the pathogenesis of S. pyogenes
Even so, antibodies to these products are relatively insignificant in
of the host.
The streptococcal invasins act in a variety of ways summarized in
1 at the end of this article. Streptococcal invasins lyse eukaryotic
including red blood cells and phagocytes; they lyse other host
including enzymes and informational molecules; they allow the bacteria
to spread among tissues by dissolving host fibrin and intercellular
Three streptococcal pyrogenic exotoxins (SPE), formerly
as Erythrogenic toxin, are recognized: types A, B, C. These
act as superantigens by a mechanism similar to those described
staphylococci. As antigens, they do not requiring processing by antigen
presenting cells. Rather, they stimulate T cells by binding class II
molecules directly and nonspecifically. With superantigens about 20% of
T cells may be stimulated (vs 1/10,000 T cells stimulated by
antigens) resulting in massive detrimental cytokine release. SPE A and
SPE C are encoded by lysogenic phages; the gene for SPE B is located on
the bacterial chromosome.
The erythrogenic toxin is so-named for its association with scarlet
fever which occurs when the toxin is disseminated in the blood.
in the late 1980's of exotoxin-producing strains of S. pyogenes
has been associated with a toxic shock-like syndrome similar in
pathogenesis and manifestation to staphylococcal toxic shock syndrome,
and with other forms of invasive disease associated with severe tissue
destruction. The latter condition is termed necrotizing fasciitis.
Outbreaks of sepsis, toxic shock and necrotizing fasciitis have been
at increasing frequency. The destructive nature of wound infections
the popular press to refer to S. pyogenes as "flesh-eating
and "skin-eating streptococci". The increase in invasive
disease was associated with emergence of a highly virulent serotype
which is disseminated world-wide. The M1 strain produces the
toxin (Spe A), thought to be responsible for toxic shock, and the
enzyme cysteine protease which is involved in tissue destruction.
Because clusters of toxic shock were also associated with other
particularly M3 strains, it is believed that unidentified host factors
may also have played an important role in the resurgence of these
FIGURE 3. Pathogenesis of Streptococcus
pyogenes infections. Adapted from Baron's Medical
Chapter 13, Streptococcus
by Maria Jevitz Patterson.