Streptococcus pyogenes and Streptococcal Disease (page 3)
(This chapter has 4 pages)
© Kenneth Todar, PhD
Post streptococcal sequelae
Infection with Streptococcus pyogenes can give rise to serious
nonsuppurative sequelae: acute rheumatic fever and acute glomerulonephritis.
These pathological events begin 1-3 weeks after an acute streptococcal
illness, a latent period consistent with an immune-mediated etiology.
all S. pyogenes strains are rheumatogenic is controversial;
clearly not all strains are nephritogenic.
Acute rheumatic fever is a sequel only of pharyngeal
but acute glomerulonephritis can follow infections of the
or the skin. Although there is no adequate explanation for the precise
pathogenesis of acute rheumatic fever, an abnormal or enhanced immune
seems essential. Also, persistence of the organism on pharyngeal
(i.e., the tonsils) is associated with an increased likelihood of
fever. Acute rheumatic fever can result in permanent damage to the
valves. Less than 1% of sporadic streptococcal pharyngitis infections
in acute rheumatic fever; however, recurrences are common, and
antibiotic prophylaxis is recommended following a single case.
The occurrence of cross-reactive antigens in S. pyogenes and
heart tissues possibly explains the autoimmune responses that develop
some infections. The antibody mediated immune (AMI) response (i.e.,
of serum antibody) is higher in patients with rheumatic fever than in
with uncomplicated pharyngitis. In addition, cell-mediated immunity
seems to play a role in the pathology of acute rheumatic fever.
Acute glomerulonephritis results from deposition of
complexes on the basement membrane of kidney glomeruli. The antigen may
be streptococcal in origin or it may be a host tissue species with
determinants similar to those of streptococcal antigen (cross-reactive
epitopes for endocardium, sarcolemma, vascular smooth muscle). The
of acute glomerulonephritis in the United States is variable, perhaps
to cycling of nephritogenic strains, but it appears to be decreasing.
are uncommon, and prophylaxis following an initial attack is
S. pyogenes is usually an exogenous secondary invader,
viral disease or disturbances in the normal bacterial flora. In the
human the skin is an effective barrier against invasive streptococci,
nonspecific defense mechanisms prevent the bacteria from penetrating
the superficial epithelium of the upper respiratory tract. These
include mucociliary movement, coughing, sneezing and epiglottal
The host phagocytic system is a second line of defense
streptococcal invasion. Organisms can be opsonized by activation of the
classical or alternate complement pathway and by anti-streptococcal
in the serum. S. pyogenes is rapidly killed following
enhanced by specific antibody. The bacteria do not produce catalase or
significant amounts of superoxide dismutase to inactivate the oxygen
(hydrogen peroxide, superoxide) produced by the oxygen-dependent
of the phagocyte. Therefore, they are quickly killed after engulfment
phagocytes. The streptococcal defense must be one to stay out of
In immune individuals, IgG antibodies reactive with M protein
phagocytosis which results in killing of the organism. This is the
mechanism by which AMI is able to terminate Group A streptococcal
protein vaccines are a major candidate for use against rheumatic
but certain M protein types cross-react antigenically with the heart
themselves may be responsible for rheumatic carditis. This risk of
has prevented the use of Group A streptococcal vaccines. However, since
the cross-reactive epitopes of the M-protein are now known, it
that limited anti-streptococcal vaccines are on the horizon.
FIGURE 4. Phagocytosis of Streptococcus
pyogenes by a macrophage. CELLS
The hyaluronic acid capsule allows the organism to evade
The capsule is also an antigenic disguise that hides bacterial antigens
and is non antigenic to the host. Actually, the hyaluronic acid outer
of S. pyogenes is weakly antigenic, but it does not result in
of protective immunity. The only protective immunity that results from
infection by Group A streptococcus comes from the development of
antibody to the M protein of the fimbriae, which protrude from the cell
wall through the capsular structure. This antibody, which follows
and skin infections, is persistent. Presumably, protective levels of
IgA is produced in the respiratory secretions while protective levels
IgG are formed in the serum. Sometimes, intervention of an infection
effective antibiotic treatment precludes the development of this
antibody. This accounts, in part, for recurring infections in an
by the same streptococcal strain. Antibody to the erythrogenic toxin
in scarlet fever is also long lasting.
Treatment and prevention
Penicillin is still uniformly effective in treatment of Group A
disease. It is important to identify and treat Group A streptococcal
in order to prevent sequelae. No effective vaccine has been produced,
specific M-protein vaccines are being tested.
Table 1. Summary of virulence
determinants of Streptococcus pyogenes
Adherence (colonization) surface macromolecules
Lipoteichoic acid (LTA)
Protein F and Sfb (fibronectin-binding proteins)
Enhancement of spread in tissues
Hyaluronidase hydrolyses hyaluronic acid, part of the ground substance
in host tissues.
Streptokinase lyses fibrin
Evasion of phagocytosis
Capsule: hyaluronic acid is produced.
C5a peptidase: C5a enhances chemotaxis of phagocytes .
M protein is a fibrillar surface protein. Its distal end bears a
charge that interferes with phagocytosis. It also blocks complement
on the cell surface. Mutations during the course of infection alter the
structure of M proteins, rendering some antibodies ineffective. Strains
that persist in carriers frequently exhibit altered M proteins.
Leukocidins, including streptolysin S and streptolysin O, are
secreted by the streptococci to kill phagocytes (and probably to
nutrients for their growth)
Defense against host immune responses
Antigenic disguise and tolerance provided by hyaluronic acid capsule
Antigenic variation. Antibody against M protein (antigen) is the
effective protective antibody, but there are more than 50 different M
and subsequent infections may occur with a different M serotype.
Production of toxins and other systemic effects
Toxic shock: Exotoxin is superantigen that binds directly to MHC II
(without being processed) and binds abnormally to the T cell receptor
many (up to 20% of) T cells. Exaggerated production of cytokines causes
the signs of shock: fever, rash, low blood pressure. aberrant
between toxin, macrophage, and T cells.
Induction of circulating, cross-reactive antibodies
Some of the antibodies produced during infection by certain strains
of streptococci cross-react with certain host tissues. These antibodies
can indirectly damage host tissues, even after the organisms have been
cleared, and cause autoimmune complications.
Table 2. Summary of diseases
caused by Streptococcus pyogenes
Suppurative conditions (active infections associated with
occur in the throat, skin, and systemically.
Streptococcal pharyngitis is acquired by inhaling aerosols emitted
by infected individuals. The symptoms reflect the inflammatory events
the site of infection. A few (1-3%) people develop rheumatic fever
after the infection has cleared.
Impetigo involves the infection of epidermal layers of skin.
children are the most susceptible. Cellulitis occurs when the infection
spreads subcutaneous tissues. Erysipelas is the infection of the
About 5% of patients will develop more disseminated disease.
fasciitis involves infection of the fascia and may proceed rapidly to
Scarlet fever is caused by production of erythrogenic toxin by a few
strains of the organism.
Toxic shock is caused by a few strains that produce a toxic
Some of the antibodies produced during the above infections cross-react
with certain host tissues. These can indirectly damage host tissues,
after the organisms have beencleared, and cause non suppurative
Rheumatic fever. M protein cross reacts with sarcolemma. Antibodies
cross-react with heart tissue, fix complement, and cause damage.
Glomerulonephritis. Antigen-antibody complexes may be deposited in
fix complement, and damage glomeruli. Only a few M-types are