Dockrell.qxp 24/1/08 9:20 am Page 111
Recent Discoveries in the Pathogenesis of Pneumococcal Pneumonia
favour higher levels of bacterial replication as well as pspA and the heat
Figure 1: Pneumococcal Virulence Factors
shock regulator gene hrcA.
14–15
1gG
Bacteriocins
C1q
DNA
BlpN
Virulence Factors
Ply
Ply
Zmp B/C
Polysaccharide capsule is a classic virulence factor and inhibits
Allolysis
CibAB
pneumococcal phagocytosis.
17
More recently, it has been demonstrated
Release upon
CbpD
autolysis/allolysis Lyt C
blp gene cluster
that the negative charge on pneumococcal polysaccharide capsule (cps)
Factor B
Lyt A Nan A/B
CibC
facilitates penetration through the mucus layer and allows mucosal Lfn ComM
PspA IAP
interaction.
18
Unencapsulated mutants aggregate in mucus and are
C1q
C3
cleared. Moreover, the role of genes in the cps biosynthesis locus have
Capsule
Ply EndA
iC3b
PspC IgA
been clarified and a model proposed.
19
CpsC and D function together to
Neutrophil
allow polymerisation and export of cps, with CpsD in its non-
Factor H NETs
phosphorylated state. Upon CpsD phosphorylation, CpsC is released
from CpsD, capsular biosynthesis slows and the cps polymer is transferred
Cell wall Hyaluronate
Sugars
lyase
to a putative cell wall–cps ligase to allow cell wall attachment (see Figure
Pili
PsaA
P
CpsC
Glycogen
1). CpsB encodes a phosphatase that dephosphorylates CpsD to restore
CpsB α-glucans
P
the form that is active in cps biosynthesis. Therefore, mutants defective
CpsD
CpsD
CpsC SpuA
CpsD
in cps genes can have either defective production of cps or decreased
CPP
Mn
2+
attachment of the capsule to the cell wall. Mouse studies have CWCPL
demonstrated that cps loci mutants have an attenuated capacity to
The pneumococcal surface proteins (Psp) A and C inhibit a number of humoral factors. PspC
binds factor H, which inhibits C3b generation. PspA inhibits C1q and iC3b deposition and
colonise and/or survive in the respiratory tract and some, though not all,
lactoferrin (Lfn). Polysaccharide capsule also limits factor B binding to C3b. Pneumolysin (Ply)
mutants are less virulent when administered systemically.
19–20
They also
binds both immunoglobulin (Ig)-G and C1q. The bacteriocin CibAB acts on non-competent
cells that lack the immunity factor CibC, and induces allolysis in bacteria that lack immunity
emphasise an important role for capsule attachment to the cell wall to factor M. The process of transformation is aided by the binding of DprA to single-stranded
enable full virulence.
19
DNA, and enhances binding of the recombinase RecA. Bacteriocins such as BlpN inhibit the
growth of closely related strains of pneumococci. Surface-expressed proteases include zinc
metalloproteinases (Zmp) B and C, neuraminidases (Nan) A and B and IgA protease (IAP),
which is secreted from the cell surface and cleaves secretory IgA. Endonuclease (End) A
Invasive disease requires proteases such as IgA protease and
degrades neutrophil extracellular traps (NETs). Surface factors include hyaluronate lyase and
carbohydrases such as NanA and B that enhance colonisation
pneumococcal surface antigen (Psa) A. The polysaccharide capsule is synthesised by capsular
polysaccharide synthesis (Cps) proteins and cell wall–capsular polysaccharide ligase (CWCPL).
and invasion.
21,22
Bacterial neuraminidase cleaves sialic acid unmasking
surface receptors required for attachment and, at least in the case of eukaryotic cell membrane. Recent observations have implicated
Pseudomonas aeruginosa, facilitates biofilm formation,
23
which as cylindromatosis – a host cell de-ubiquitinating enzyme – as contributing
described above may be important in allowing survival in the upper and to pneumolysin-induced lung injury via downregulation of the
lower airway.
15
Zinc metalloproteinase (Zmp) B enhances tumour necrosis antiprotease plasminogen activator inhibitor-1 (PAI-1).
37
factor (TNF)-α expression and pulmonary inflammation
24
and ZmpC
enhances invasive potential.
25
Hyaluronan lyase degrades hyaluronan, a A variety of techniques have identified novel virulence factors.
ubiquitous component of the extracellular matrix (ECM), to aid Comparative genomic techniques were used to make the novel
pneumococcal tissue invasion.
26
Non-catalytic surface proteins are also observation of a putative pilus gene cluster.
38
In murine models, piliated
important for virulence, and recent publications have highlighted the strains are associated with higher mortality.
38
The role of bacteriocins is
important role of PspC, which binds complement factor H and C3, being increasingly elucidated by comparative techniques. In particular,
secretory IgA and the polymeric Ig receptor aiding attachment and recent work highlights the blp gene cluster as mediating intraspecies
penetration of the epithelial barrier.
27–29
PspC can also inhibit CXC competition for nasopharyngeal colonisation.
39
Serotype 6A inhibits
chemokine production, thus limiting recruitment of phagocytes.
30
PspA a competing TIGR4 strain. This inhibition requires blpM/N and may be
binds lactoferrin, resulting in a prevention of its bactericidal action by explained by subtle genetic differences in the sequence of these genes.
blocking its penetration of the bacterial membrane.
31
PspA also has an The inter-strain amino acid sequence variation in BlpN results in inhibition
important role in inhibiting complement activation and iC3b deposition of the heterologous TIGR4 strain by a BlpN that the TIGR4 specific
on pneumococci.
32
In addition, PspA inhibits C1q deposition on the immunity protein cannot protect against.
surface of pneumococci.
33
PspA and PspC act synergistically to inhibit
both classic and alternative complement pathway activation in A model for the link between competence – the ability of
combination with pneumolysin.
33–34
S. pneumoniae to take up and be transformed by external DNA – and
virulence has been proposed.
40
Competence is regulated by the
A major virulence factor for the pneumococcus is the pleiotropic expression of CSP acting via a two-component regulatory system to
cholesterol-dependent cytolysin pneumolysin, which possesses induce expression of the competence regulon (com), but mutants
complement-activating and pore-forming activities.
35
Cryoelectron lacking key com genes also have attenuated virulence, as reviewed by
microscopy and image processing have delineated the molecular basis of Camilli and colleagues.
41
Competent cells release a two-peptide
pore conformation.
36
The pore contains up to 44 subunits and 176 beta bacteriocin, CibAB, which acts on non-competent cells that lack the
(β) strands and contains a channel 230–260Å in diameter. immunity factor CibC.
40
This triggers activation of choline-binding
Conformational changes in the four domains of pneumolysin during protein D, an amidase, and hydrolases (LytA (autolysin) and LytC),
formation of the mature pore include buckling of domain 2 with leading to cell wall disruption and release of virulence factors such as
unfolding of helical regions in domain 3 and their insertion into the pneumolysin, in addition to DNA from non-competent cells.
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