Principles and Practice of Clinical Bacteriology Second Edition - Free

26 ORAL AND OTHER NON-β-HAEMOLYTIC STREPTOCOCCI
to fibrin clots, and inactivation of the fimA gene in S. parasanguis
abrogates the ability of cells to bind to fibrin and to cause endocarditis
in rats (Burnette-Curley et al., 1995). Further, immunization of rats with
S. parasanguis FimA conferred protection against subsequent challenge
with S. parasanguis (Viscount et al., 1997). FimA homologues in
diverse streptococcal species share significant antigenic similarity,
and Kitten et al. (2002) have demonstrated that vaccination with
S. parasanguis FimA protected rats from endocarditis caused by
other oral streptococci, raising the possibility of FimA being used
as a vaccine for at-risk individuals. Studies have demonstrated that
the FimA-like family of proteins function in manganese transport
(Kolenbrander et al., 1998) and so may also contribute to infective
endocarditis through acquisition of this essential growth factor.
Many of the oral streptococcal species produce high-molecular
mass glucans, through the enzymatic activity of glucosyltransferase
(GTF), when grown in the presence of sucrose, a property that has
been implicated in the pathogenesis of infective endocarditis. Thus,
rats inoculated with an isogenic mutant of S. mutans lacking GTF
activity developed endocarditis less frequently than those inoculated
with the parental strain, and additionally, the isogenic mutant adhered
in lower numbers to fibrin in vitro (Munro and Macrina, 1993). In
contrast, there was no difference in virulence between sucrose-grown
wild-type S. gordonii and its isogenic GTF-negative mutant (Wells
et al., 1993), highlighting species differences and indicating that
multiple virulence factors may be involved in pathogenesis.
Bacterial interaction with platelets is considered a major factor in
endocarditis (reviewed by Herzberg, 1996; Herzberg et al., 1997). As
well as the direct adhesion of bacteria to platelets (Table 2.3), many
streptococci, particularly S. sanguis strains, induce the aggregation of
platelets in vitro. These aggregates show densely compacted and
degranulated platelets and contain entrapped streptococcal cells. Thus,
bacterial aggregation of platelets has been proposed to contribute to
the establishment and persistence of adherent bacteria through the
creation of a protective thrombus. The interactions between S. sanguis
and platelets have been studied in some detail (Herzberg, 1996). Interactions
are complex and involve at least three streptococcal sites, and
these interactions result in platelet activation and the release of
ATP-rich dense granules. Platelet aggregation-associated protein
(PAAP) plays an important role through interaction with a signaltransducing
receptor on the platelet surface, inducing platelet activation
and aggregation. Platelet-aggregating strains of S. sanguis induce
significantly larger vegetations than nonaggregating strains in a rabbit
model of endocarditis, and antibodies to PAAP can ameliorate the
clinical severity of disease (Herzberg et al., 1992). Nevertheless, nonplatelet-aggregating
S. sanguis isolates can still cause endocarditis,
again highlighting the multiplicity of bacterial–host interactions that
are involved in the disease process (Douglas, Brown and Preston, 1990;
Herzberg et al., 1992).
In addition to contributing to the disease process, platelet activation
and aggregation are also a key aspect of host defence against disease,
and the persistence of adherent streptococci is related, at least in part,
to their resistance to microbicidal factors released from activated
platelets as well as to circulating defence mechanisms (Dankert et al.,
1995). In one study over 80% of the oral streptococcal strains isolated
from the blood of patients with infective endocarditis were resistant to
platelet microbicidal activity compared with only 23% of streptococcal
strains isolated from the blood of neutropenic patients without
infective endocarditis (Dankert et al., 2001). Further, immunizing
rabbits to produce neutralizing antibodies against platelet microbicidal
components rendered these animals more susceptible to infective
endocarditis when challenged with a sensitive S. oralis strain (Dankert
et al., 2001).
Two studies have applied modern molecular screens to identify
streptococcal genes encoding potential virulence factors for endocarditis.
Using in vivo expression technology (IVET) in conjunction with a
rabbit model of endocarditis, Kiliç et al. (1999) identified 13 genes
whose expression was required for S. gordonii growth within valvular
vegetations. One of these genes encoded methionine sulphoxide
reductase (MSR), a protein involved in the repair of oxidized proteins.
MSR has been proposed to play a role in the maintenance of the
structure and function of proteins, including adhesins, where sulphur
groups of methionine residues are highly sensitive to damage by
oxygen radicals. In a separate study a shift in pH from 6.2 to 7.3 was
used to mimic the environmental clues experienced by S. gordonii
entering the blood stream from their normal habitat of the mouth
(Vriesema, Dankert and Zaat, 2000). Among five genes induced by
this pH shift was one encoding the MSR described above. Further
application of molecular techniques should help dissect the complex
host–bacterial interactions required for disease caused by these
otherwise nonpathogenic bacteria.
Epidemiology
It has been estimated that about 20 cases of infective endocarditis
per million of the population per year can be expected in England
and Wales, with an associated mortality rate of approximately
20% (Young, 1987). Between 1975 and 1987 around 200 (±30) deaths
per year were recorded in these countries. There have been numerous
surveys of the causative agents in infective endocarditis over the
years. Streptococci remain the predominant cause of infective
endocarditis, accounting for up to 50% of cases in most published
series, despite reported changes in the spectrum of disease due, in
part, to an increased frequency of intravenous drug abuse, more
frequent use of invasive procedures involving intravenous devices and
heart surgery with prosthetic valves and a decrease in the incidence of
rheumatic fever-associated cardiac abnormalities. It has sometimes
been difficult to equate the identity of streptococci reported in earlier
studies with the currently accepted classification and nomenclature,
particularly with respect to the continued use of the term Streptococcus
viridans as a catch-all for streptococci that are α-haemolytic
on blood agar. Nevertheless, a study by Douglas et al. (1993) of
47 streptococcal isolates from 42 confirmed cases of infective endocarditis
revealed that members of the mitis group of streptococci, particularly
S. sanguis, S. oralis and S. gordonii, comprised the most commonly
isolated oral streptococci (Table 2.4). Nonoral S. bovis is also a significant
aetiological agent of both native and prosthetic heart valve
infections (Duval et al., 2001; Siegman-Igra and Schwartz, 2003). In a
French study (390 patients) the incidence of infective endocarditis
was 31 cases per million of the population (Hoen et al., 2002).
Streptococci were isolated in 48% of these cases, with the second
Table 2.4
Species
Streptococci isolated from infective endocarditis
Isolation frequency (% of streptococcal isolates)
Douglas et al. (1993) Hoen et al. (2002)
Mitis and sanguis groups
S. sanguis 31.9 4
S. oralis 29.8 5.8
S. gordonii 12.7 1.3
S. parasanguis 4.2 0.9
S. mitis 4.2 9.8
S. mutans 4.2 4.0
Salivarius group 4.2 1.8
Anginosus group Not detected 0.9
Group D streptococci Not detected 43.5
Nutritionally variant Not detected 1.3
streptococci
Enterococci Not detected 12.9
Pyogenic group Not detected 9.8
S. pneumoniae Not detected 1.8
Unidentified/other 2.1 2.2
The Douglas et al. (1993) study focused on oral viridans streptococci.