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The Pathophysiology of Pneumococcal Pneumonia: European Respiratory Monograph March 2014
The Pathophysiology of Pneumococcal Pneumonia: European Respiratory Monograph March 2014
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P neumonia caused by infection with Streptococcus pneumoniae is the most common and most
studied bacterial cause of pneumonia [1], the pathogenesis of which has been recently
reviewed [2]. Classical studies of human pathological specimens described severe (fatal) disease but,
more recently, murine models have substantially advanced our understanding of the pathophysiol-
ogy of infection [3]. More recently, human experimental infection studies [4] have confirmed many
of the observations regarding colonisation and carriage first described in mice [5, 6]. The successful
global implementation of effective vaccines to prevent pneumonia in childhood is underway but
more work is needed in order to understand the means of improving survival in early, severe disease
and, most importantly, the means to protect elderly people from this severe mucosal infection.
lower airway [45]. The human anti-microbial peptides (hAMPs) called human b-defensins
(hBD1–hBD4) and the human cathelicidin-related antimicrobial peptide LL-37 [46] act
synergistically with lysozyme and secreted phospholipases A2 to lyse bacteria, as well as limiting
growth by restricting bacterial nutrient uptake [47–49]. Two collectins, surfactant proteins A and
Inhibitory
Inhibitory CD200R/CD200
SIRPα/SP interaction
Pneumococci C interaction
B
A NF-κB
Endothelium Epithelium
Figure 1. Key factors in the maintenance of lung immune homeostasis. A healthy alveolar epithelium is vital to
the maintenance of innate immune homeostasis in the lung. A: Alveolar lining fluid is nutritionally barren and
replete with antimicrobial compounds. B: Bacteria are lysed by secreted innate factors such as lysozyme,
phospholipase-A2 and surfactant proteins (SP) A and D. C: Induction of an anti-inflammatory phenotype in
alveolar macrophages. Phagocytic functions are maintained but the ability to present antigen and secrete pro-
inflammatory cytokines is suppressed by surfactant proteins, granulocyte-macrophage colony-stimulating factor,
interleukin-10 and transforming growth factor-b, and the CD200 and signal regulatory protein (SIRP)a
interactions. NF-kB: nuclear factor-kB.
44
D (SP-A and SP-D, respectively), as well as being important opsonins, exert direct antimicrobial
effects against pneumococci by altering cell permeability and by interfering with nutrient uptake
[50, 51]. In homeostasis, resident alveolar macrophages can ingest the limited numbers of
pneumococci that survive to reach the lung [52], but are actively suppressed to prevent
disproportionate responses to innocuous stimuli.
B
C
NLRP3
A
Figure 2. Escalation of the pneumonic immune response to pneumococcal threat. The clinical manifestation of
pneumonia is the result of overwhelming numbers of pneumococci provoking an inflammatory response
orchestrated by alveolar macrophages that have been unrestrained by a damaged, activated epithelium. A:
Pneumolysin breaches the integrity of the cell walls releasing intracellular components, some of which are
damage-associated molecular patterns. B: Macrophages recognise opsonised pneumococci and non-
opsonised pneumococci via Toll-like receptor-2 and platelet activating factor receptor interactions with the
pneumococcal cell wall constituents. C: Pneumolysin recognition leads to activation of the NLRP3
inflammasome. D: Activated neutrophils are recruited and translocate across the endothelium (integrin/
intracellular adhesion molecule interaction) and epithelium (triggering receptor expressed on myeloid cells
interaction (TREM)-1) into the alveolar lumen. E: Macrophages present antigen to dendritic cells and migrate to
regional lymph nodes. The red arrows represent inflammatory cytokine and chemokine (e.g. CXCL8) release by
activated macrophages and epithelium.
45
and the host must therefore rely on a rapid amplification of innate responses (fig. 2). The early
response cells of the alveolus are the epithelium and the alveolar macrophage, which must sound
an alarm of sufficient clarity to overcome the Treg [57] and alveolar macrophage [58]
maintenance of normal quiescent lung homeostasis.
Epithelium
The lung epithelium orchestrates the innate response to local damage, sets the threshold for this
response, actively contributes to inhibiting excess bacterial growth, signals the escalation of an
innate response, and escalates its own contribution to killing before returning the system to its
homeostatic state [66]. The epithelium itself is highly plastic and many studies have shown that it
MONOGRAPH 63: COMMUNITY-ACQUIRED PNEUMONIA
can rapidly scale up its production of the antimicrobial effector molecules discussed previously.
For example, changes in levels of SP-A and SP-D modulate the functions of antigen presenting
cells such that the dynamics of neutrophil and T-cell recruitment are altered [51, 67]. Indeed
several groups have shown that augmenting the innate immune response by stimulating the
epithelium with microbial products allows a potentially lethal inoculum of pneumococci to be
overcome [68]. When a more potent reaction is required, epithelial responses to intact
pneumococci include production of soluble innate factors including CXCL8 [69] and
upregulation of the platelet activating factor receptor (PAFr). The CXCL8 signal recruits
neutrophils to the lung from the blood to tackle pneumococci but epithelial binding of
pneumococcal cell wall phosphorylcholine by the PAFr [70] accelerates bacterial invasion. This
example is typical of each phase of the host response to pneumococcus where a well-adapted host
response has, in many cases, been abrogated by pathogen counter-evolution [71].
Alveolar macrophage
The alveolar macrophage has roles in pathogen detection, early alarm signalling and phagocytosis,
followed by antigen presentation, neutrophil and lymphocyte recruitment, and coordination of
the resolution of inflammation. Macrophage behaviour in the healthy alveolus is essentially anti-
inflammatory. This is, in a large part, due to the inhibitory consequences of close physical
interaction between alveolar macrophages and the airway epithelium. CD200 receptor (CD200R)
on the macrophage surface binds the CD200 ligand on the surface of the epithelium [72]. Alveolar
macrophages are induced to express very high levels of CD200R by high local levels of interleukin
(IL)-10 and transforming growth factor-b, which are expressed on and secreted by the epithelium
[73]. Another receptor expressed at high levels on alveolar macrophages is signal regulatory
protein-a, which, via its interaction with SP-A and SP-D renders the cell quiescent [74].
Moreover, the uniquely high levels of granulocyte-macrophage colony-stimulating factor and
SP-D to which alveolar macrophages are exposed lead to a dramatic reduction in their ability to
present antigen in comparison with peritoneal counterparts [75]. Despite these restraints,
macrophages can still recognise and phagocytose pneumococci but this does not result in an
46
escalation of inflammation whilst in their quiescent state. If bacterial density exceeds more than
single numbers per macrophage, active phagocytosis is reduced and cytokine production increases.
What is not clear is how macrophages become unbound by this suppression in the context of
pneumonia. One possibility is that physical damage to the epithelium, for example due to lytic
viruses such as influenza, leads macrophages to become detached from the CD200 interaction,
releasing them from suppression [76]. In this context, the combined TLR signalling of
pneumococcal PAMPs and DAMPs released from the lysed epithelium leads macrophages,
released from the restraints imposed by the epithelium, to become activated. In the activated state,
the phagocytosis of pneumococci leads to recognition by cytoplasmic nucleotide binding
oligomerisation domain (NOD)-like receptors [77] and nuclear factor-kB transduced upregula-
tion of multiple pro-inflammatory genes. The result of phagocytosis in this context is dramatic
increases in the production of pro-inflammatory cytokines such as tumour necrosis factor
(TNF)-a, IL-1b, IL-6 and the neutrophil recruiting chemokine CXCL8 along with increased
expression of a range of receptors for pathogen recognition [78]. Levels of pro-inflammatory
cytokines seem to be similar when patients with pneumococcal pneumonia are compared to
pneumonia caused by atypical pathogens, but the use of corticosteroids had little effect on
cytokine levels in the context of pneumococcal pneumonia [79].
Neutrophils
The essential output of the epithelial and macrophage signalling pathways described earlier is the
rapid recruitment of large numbers of these professional phagocytes. Neutrophils respond to
CXCL8 by upregulating integrins [80] in order to bind endothelium and migrate into the alveolar
space [81]. Neutrophils circulate in the pulmonary microvasculature at three times the
concentration in peripheral venous blood owing to the stoichiometry of the phagocytes (stiff
and large) compared with the microvasculature (narrow and compressed) [82]. This allows very
population, macrophage phenotype changes again to support repair and macrophage apoptotic
mechanisms allow the non-inflammatory resolution of some of the inflammatory exudates.
Furthermore, effective neutrophil apoptosis pathways allow alveolar damage to be minimised even
in the context of severe bacterial infection. At the height of the pneumonic illness, the alveolar
space is clogged with serum, organised inflammatory debris, bacterial DNA and cellular debris.
The process of macrophage efferocytosis (literally ‘‘burying the dead’’) allows restoration of
normal pulmonary architecture and respiratory function [98]. To facilitate the return to
homeostatic numbers, expanded populations of activated macrophages and dendritic cells in the
pneumonic lung are depleted by the direct cytotoxic activity of cdT-cells [99].
IRAK-4: interleukin-1 receptor-associated kinase-4; NF-kB: nuclear factor-kB; IL: interleukin; MBL: mannose
binding lectin; PAD: predominantly antibody defect; PID: primary immunodeficiencies; COPD: chronic
obstructive pulmonary disease; ILD: interstitial lung disease; TLR: Toll-like receptor; IL-1R: interleukin-1
receptor; TNF: tumour necrosis factor. #: e.g. trauma, sickle cell disease, systemic lupus erythematosus, coeliac
disease, alcoholism, etc.
49
epithelial surface to enhance bacterial binding [129] and lymphocyte cytokine production [130],
and to decrease opsonophagocytic function for prolonged periods following severe infection [131].
The pathogenesis of COPD, asthma and interstitial lung diseases and their effects on airway
defence have also been discussed elsewhere [119, 132]. However, emerging evidence suggests that
diseases associated with increased rates of cell apoptosis, and consequently high rates of TAM-
receptor mediated efferocytosis, may lead to exaggerated levels of macrophage suppression and
susceptibility to bacterial infection [133]. Nutritional deficiency and liver disease also result in
functional hypogammaglobulinaemia. Alcoholism is associated with increased susceptibility to
pneumonia and this is, in part, related to immune dysfunction caused by alcohol [134];
specifically, patients with alcohol problems have impaired macrophage function and this in turn
seems to be related to macrophage uptake of zinc [135].
however, important to appreciate that the clinical significance of many putative virulence factors
identified in murine models of infection has not been categorically demonstrated. It is notable that
the relevance of some putative virulence factors identified using STM in murine models has not
been corroborated in CGA of clinical isolates [166]. This distinction may prove prescient as the
therapeutic applications of protein virulence factors (e.g. vaccine candidates and targets for
immunomodulatory therapy) are explored.
Polysaccharide capsule
The extracellular polysaccharide capsule of S. pneumoniae potently inhibits phagocytosis and is
essential for the organism’s virulence [174]. The 93 antigenically distinct capsular serotypes differ
markedly in their potential to cause invasive disease in proportion with their relative resistance to
phagocytosis [136]. Furthermore, capsular serotype is an independent determinant of outcome of
invasive pneumococcal disease [175].
In the absence of capsule-specific antibodies, opsonophagocytosis of S. pneumoniae is
predominantly complement mediated. The polysaccharide capsule inhibits both the classical
and alternative pathways through distinct mechanisms, limiting the deposition of the C3b/iC3b on
the bacterial surface [136, 137]. The highly negatively charged capsule also sterically inhibits the
interaction between deposited C3b and complement receptors [176].
Whilst the importance of the capsule for systemic virulence is clear, its role in early infection is
more complicated. The capsule promotes transit of pneumococci to the nasopharyngeal epithelial
surface by inhibiting mucous binding [25]. However, once at the epithelial surface, organisms
expressing thin capsules (transparent phase) preferentially establish stable colonisation [177].
Following invasion, survival is favoured by increased capsular expression (opaque phase),
conferring resistance to opsonophagocytosis. The mechanisms whereby pneumococci alter the
51
Table 2. Pneumococcal virulence factors grouped according to main function in pneumonia
Virulence factor Main function in pneumococcal disease [Ref.]
Resistance to
opsonophagocytosis
Polysaccharide capsule Resistance to opsonophagocytosis by inhibition of classical [3, 136–138]
and alternative complement pathways; reduces trapping by
NETs; inhibits mucus binding promoting transit to epithelial
surface
PspA Limits C3b deposition by blocking formation of alternative [139–141]
pathway C3 convertase; inhibits bactericidal actions of
apolactoferrin
PspC# Limits C3b formation by binding factor H; initiates invasion [27, 142]
through binding human polymeric immunoglobulin receptor
IgA protease Cleaves IgA-surface bound Fab fragments limiting [3]
opsonophagocytosis and exposing phosphorylcholine that
promotes adherence by binding PAFr
PhtA, B, D and E Reduction of complement deposition via factor H recruitment [143]
EndA Degradation of DNA in NETs favouring subsequent invasion [144]
Degradation of ECM
NanA Removes terminal sialic acid residues from cell surface [145, 146]
glycopeptides promoting adherence; confers resistance to
complement deposition
BgaA and StrH Expose glycopeptides for pneumococcal epithelial binding; [147]
reduce C3b deposition
Hyl Degrades hyaluronan in the ECM facilitating bacterial spread [148]
and tissue invasion
Enolase Binds plasminogen promoting transmigration through ECM; [149, 150]
contributes to complement evasion by binding complement
inhibitor C4b-binding protein
MONOGRAPH 63: COMMUNITY-ACQUIRED PNEUMONIA
PspA: pneumococcal surface protein A; PspC: pneumococcal surface protein C; Pht: polyhistidine triad; EndA:
endonuclease A; ECM: extracellular matrix; NanA: neuraminidase; BgaA: b-galactosidase; StrH: b-N-
acetylglucosaminidase; Hyl: hyaluronate lyase; SpuA: pullulanase; PsrP: pneumococcal serine-rich protein;
SrtA: sortase A; PavA: pneumococcal adhesion and virulence A; PavB: pneumococcal adhesion and virulence
B; PcpA: pneumococcal choline binding protein A; LytA: autolysin; PsaA: pneumococcal surface antigen A;
PiaA: pneumococcal iron acquisition A; PiuA: pneumococcal iron uptake A; SodA: manganese superoxide
dismutase; ClpP: ATP-dependent caseinolytic protease; SpxB: pyruvate oxidase; NET: neutrophil extracellular
trap; PAFr: platelet activating factor receptor; TLR: Toll-like receptor; ABC: ATP-binding cassette; CSP:
competence stimulating peptide. #: also known as choline binding protein A.
degree of expression of the capsule to adapt to particular host niches are yet to be fully elucidated,
but may relate to changes in oxygen tension [178].
Pneumolysin
Pneumolysin is a highly conserved toxin that is central to both pneumococcal virulence and the
Pilus proteins
The presence of a pilus in some pneumococcal strains has only been recognised recently [190].
This long structural organelle projects from the cell wall, protrudes through the capsule and
promotes adherence to the respiratory epithelium. Isolates with pili out-compete non-piliated
rivals to establish nasopharyngeal colonisation and have enhanced virulence in models of
pneumonia and bacteraemia [190]. The pilus is encoded by the rlrA pathogenicity islet (accessory
region), which comprises of genes for three structural proteins RrgA, RrgB and RrgC, and three
associated sortases [191]. The RrgA component is the main determinant of adhesion [152] and
MONOGRAPH 63: COMMUNITY-ACQUIRED PNEUMONIA
also invokes a host inflammatory response via TLR2 [192]. RrgA is also implicated in the systemic
invasion of pneumococci; pneumococci expressing RrgA are preferentially phagocytosed by
macrophages and show prolonged intracellular survival and higher rates of early bacteraemia
[153]. Immunisation with recombinant pilus subunits confers protection against lethal
pneumococcal challenge in mice [193]. However, the relevance of pilus in human pneumococcal
disease and its potential use as a vaccine candidate is unclear since it is expressed by as few as 21%
of invasive clinical isolates [194].
Conclusion
Pneumococcal pneumonia is an infrequent but severe consequence of frequent bacterial exposure.
Immune defence is usually effective at containing carriage but struggles in the face of full blown
55
infection. Modern scientific methods have generated information likely to lead to new vaccines
and treatments.
Acknowledgements
We would like to acknowledge A. Kadioglu (Institute of Infection and Global Health, University of
Liverpool, Liverpool, UK) for taking the time to critically appraise this manuscript.
Support Statement
D.G. Wootton is a fellow of the UK National Institute of Health Research (NIHR) supported by a
Doctoral Research Fellowship. S.J. Aston has received a report grant from the Wellcome Trust
(grant 099962).
Statement of Interest
None declared.
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