@article {1591,
	title = {Can hemolytic streptococci be considered "forefathers" of modern phagocytes? Both cell types freely migrate in tissues and destroy host cells by a "synergistic cross-talk" among their secreted agonists.},
	journal = {Comparative Biochemistry and Physiology},
	volume = {109},
	number = {2},
	year = {1994},
	pages = {147-158},
	abstract = {The biochemical and biological properties
of many of the pro-inflammatory agonists
generated by catalase-negative hemolytic
streptococci and by activated human
phagocytes, and the mechanisms by which
both cell types destroy tissues in infections
and in inflammatory sites, are astonishingly
similar.
In the pre-antibiotic era, group A
hemolytic streptococci, also known by the
name Streptococcus pyogenes, were responsible
for causing serious and life-threatening
diseases, mainly in young individuals.
These highly virulent agents cause suppurative
lesions in virtually any part of
the body, due perhaps to their ability to
disseminate freely in tissues. They do this
by virtue of their ability to elaborate
numerous {\textquotedblleft}spreading factors{\textquotedblright} and tissuedamaging
agents. However, the hallmark of the streptococcus injuries is their
ability to initiate non-suppurative sequelae
(rheumatic fever, arthritis, chorea and
glomerulonephritis).
Activated phagocytes (neutrophils,
eosinophils, macrophages) might also be
involved in the pathogenesis of many
inflammatory diseases because of their
ability to generate and secrete numerous
tissue-damaging agonists.
It is perhaps paradoxical that both
phagocytes and hemolytic streptococci possess
adhesion molecules (Patarroyo, 199 1;
Ofek et al., 1975; Hasty et al., 1992; Sela
et al., 1993; Albelda et al., 1994), receptors
for IgG and for IgA (Christensen et al.,
1976; Ginsburg et al., 1982; Burova and
Schalen, 1993), receptors for complement
(Petty and Todd, 1993), receptors for a
variety of serum proteins, and for
fibronectin (Littenberg et al., 1987; Simpson
et al., 1987; Sela et al., 1993). Both
phagocytes (Greenwald and Jamison, 1977;
Wright, 1982; Gallin et al., 1992) and
streptococci (reviewed by Ginsburg, 1972,
1985, 1986), generate numerous spreading
factors (hyaluronidase, DNAse, RNAse,
proteinases, acid and neutral hydrolases and complement-destroying enzymes
(Wexler et al.. 1985). All these agents
might facilitate the movement of the
cells through the endothelial and epithelial
barriers and into the intercellular
spaces, and to depolymerize extracellular
matrix proteins and inflammatory exudates
which, otherwise, might limit cell movement
and their spread in the tissues of the
host. The non-immunogenic hyaluronic
acid capsule, present on the surface of
virulent streptococci, mimics similar components
also present on mammalian cells.
This mimicry allows the streptococci to
survive, unrecognized, by the phagocytic
cells.
Both streptococci (Ginsburg, 1972; Ginsburg,
1979b; Alouf, 1990; Bernheimer and
Rudy, 1986) and phagocytes (Victor et al.,
198 1; Kennedy and Becker, 1987; Gallin
et al., 1992) generate potent membraneperforating
agents (hemolysins, phospholipases)
which are capable of killing host
cells by boring {\textquotedblleft}holes{\textquotedblright} in their plasma
membranes. Both streptococci (Suzuki and
Vogt, 1966; Vogt et al., 1983) and phagocytes
(Elsbach and Weiss, 1992; Spitznagel,
1990; Lehrer, 1993) also generate a large
variety of highly cationic arginine- and
cysteine-rich bactericidal and cytocidal proteins.
These agents are also capable of
activating the respiratory burst in neutrophils
(Ginsburg, 1987, 1989) and also of
functioning as opsonins (Ginsburg, 1987,
1989). Polycations might also enhance the
adherence of neutrophils to targets (Oseas
et al., 1981) and thus facilitate delivery of
the toxic agonist directly upon the targets.
This property is also shared by
streptococci possessing cell-bound streptolysin
S (Ginsburg and Harris, 1965;
Ginsburg and Varani, 1993). Phagocytes
and hemolytic streptococci produce either
cytokines (West, 1990; Badwey et al.,
1991) or a pyrogenic super-antigen (erythrogenic
toxin; see Hensler et al., 1993),
respectively, which prime phagocytes to
generate excessive amounts of reactive
oxygen species (ROS) and of lipid
mediators of inflammation.
Streptococci also generate a surface
amphiphile (lipoteichoic acid-LTA)
(Ginsburg et al., 1988) which, like
lipopolysaccharides (LPS) of Gramnegative
rods (Forehand et al., 1989, 1991) also primes neutrophils to generate
excessive amounts of ROS.
A possible {\textquotedblleft}genetical{\textquotedblright} linkage between
the highly anti-phagocytic surface component,
the M-protein of streptococci and
human proteins, has been found (Fischetti
et al., 1988). Seventy percent of the Mprotein
molecule has a tertiary structure
of coiled-coil, which is also a characteristic
either of tropomyosin, myosin or
fibrinogen.
Group A hemolytic streptococci also
possess two sets of antigens which crossreact
with human heart, kidney, brain, skin,
myosin and perhaps also with leukocytes
(Ayoub and Kaplan, 1991: Stollerman,
1975, 1991; Trentin, 1967; Kaplan, 1967;
Ginsburg, 1972; Krisher and Cunningham,
1985; Swerlick and Cunningham. 1986).
This led to the hypothesis that the development
of crossreactive immunity, in
susceptible hosts (Stollerman, 1975, 1991)
might be responsible for the pathogenesis
of rheumatic fever. arthritis, chorea and
nephritis, that are the hallmarks of the
post-streptococcal sequelae. Since the crossreactive
antibodies isolated from rheumatic
fever patients were not cytotoxic to
cardiac tissue, their role, if any, in the
pathogenesis of tissue damage remains to
be established. Most importantly, however,
both activated phagocytes and the
catalase-negative hemolytic streptococci
generate large amounts of H2 O2 (Avery and
Morgan, 1924; Ginsburg, 1972; Halliwell
and Gutteridge, 1989; Klebanoff and Clark,
1978; Klebanoff, 1992).
It therefore stands to reason that both
phagocytes and streptococci might cause
cellular damage by a tight and wellorchestrated
and synergistic collaboration
among their secreted agonists (see below).
Furthermore, extracellular products elaborated
by both phagocytes and streptococci
during their encounter in infectious sites,
might also interact to amplify cellular damage.
Such interactions might take place
when H20Z generated by streptococci might
be effectively utilized by neutrophils of
patients suffering of chronic granulomatous
disease of childhood (CGD), which possess
a defective NADPH oxidase (Smith and
Curnutte, 1991). Such an interaction might
not only restore the ability of the CGD
phagocytes to kill bacteria, but might also, paradoxically, lead to enhanced cellular
damage provided that additional agonists
are also present (see below).
It is thus tempting to speculate that,
mainly from functional and perhaps also
from evolutionary points of view, hemolytic
streptococci and other toxigenic bacteria
(Clostridiae) might perhaps be considered
{\textquotedblleft}forefathers of modern phagocytes{\textquotedblright}.
However, it should also be emphasized
that evolution displays many examples
where basic and parallel biological phenomena
might appear in phyla far removed
from each other, with no apparent common
genetical basis. This emphasizes the successfulness
of the strategy, since two totally
separate evolutionary pathways have led
to it.},
	author = {Isaac Ginsburg}
}
