1. Introduction
Infective endocarditis (IE) is a life threatening disease caused by a bacterial infection of the endocardial surfaces of the heart. It is typified by the formation of septic thrombi or vegetative growth on the heart valve. Typically, both platelets and fibrin are deposited on exposed extracellular matrix proteins as part of the normal response to damage of the endocardium [1]. However, this sterile platelet-fibrin nidus facilitates colonisation of the endocardium by bacteria in the bloodstream [2]. Following attachment, bacteria can recruit platelets from the circulation inducing platelet activation and platelet aggregation. This results in the development of large macroscopic vegetations which resist infiltration by both immune cells and antibiotics making IE a difficult disease to treat. These vegetations commonly occur on the heart valves and can disrupt hemodynamic patterns within the heart. This puts undue force on often already compromised valves, leading to congestive heart failure [3]. IE is notoriously difficult to treat, requiring aggressive multi-antibiotic therapy often coupled with surgery to remove vegetations and/or replace the infected valve [4]. Therapy is successful when all traces of bacteria are absent from the blood stream. Multiple species of bacteria have been isolated from the infected vegetations of patients [5, 6] with IE but the streptococci are amongst the most common cause, second only to the staphylococci whose interactions with human platelets are discussed elsewhere in this book (Chapter X). Indeed, in a recent prospective study, the role of streptococci in IE is masked by the growing incidence of staphylococcal IE resulting from the increased use of medical procedures leaving streptococci as a main cause of IE in the normal population [7, 8].
2. The Streptococcus
The streptococci are a large family of gram positive coccus shaped bacteria that reside in the mouth, intestine, upper respiratory tract and the skin. Most have a commensal relationship with their host. However, as opportunistic pathogens they can cause disease if they gain access to normally sterile sites of the body such as the bloodstream. Most streptococci isolated from patients with IE are of oral origin [9], normally found colonising the salivary tooth pellicle through the interactions of surface expressed virulence factors, called adhesins, with specific moieties or motifs on host proteins or cells. When these streptococci enter the bloodstream these bacterial components participate in additional interactions with platelets. Whether this is by design or simply as a consequence of conserved motifs within the human host is unknown but regardless their interaction with human platelets is a key step in the pathogenesis of IE.
3. Platelet biology I: Haemostatic function
In the absence of infection, platelets act as sentinels of vascular integrity, patrolling the endothelium for sites of damage. Upon vascular damage these small anucleate cells interact with exposed extracellular matrix proteins via specific receptors expressed on their surface and a complex yet coordinated series of interactions and signalling events proceed, culminating in the formation of a haemostatic plug. Platelet receptor complex GPIb-IX-V recognises von Willebrand Factor (vWF) bound to exposed collagen fibrils in the subendothelial matrix, tethering the platelet to the site of damage [10, 11]. This initial interaction is relatively weak and has a fast on-off rate [12] so the platelet characteristically rolls along the endothelium breaking and remaking the vWF-GPIb-IV-X interaction [1]. This ‘rolling’ mechanism slows the platelet sufficiently for additional receptor-ligand contacts and triggers an intracellular signal resulting in integrin activation and firm adhesion. Firm adhesion is mediated by a combination of ligand receptor engagements: integrin α2β1 - collagen [13-15]; glycoprotein GPVI - collagen [16]; α5β1-fibronectin [17]; and αIIbβ3 with fibrinogen and vWF [12, 18]. Once firmly adhered, the platelet undergoes dramatic rearrangement of its cytoskeleton causing platelet shape change from its resting discoid form to a dendritic form and finally, to a fully spread platelet with characteristic filipodia and llamelipodia [19]. During this process, the platelet secretes signalling molecules, proteins and platelet agonists (ADP, ATP and serotonin) from its cytoplasmic granules (α- and dense- granules) and synthesizes and secretes thromboxane, amplifying the platelet response, recruiting and activating nearby platelets. Activated platelets can undergo platelet aggregation, cross linking with one another via their αIIbβ3 receptors and the divalent plasma protein fibrinogen. This activation and recruitment of platelets to the site of injury, in addition to stimulation of the coagulation system and formation of a fibrin network, forms the haemostatic plug.
4. Platelet biology II: Immune function
The platelet role in haemostasis and thrombosis is well characterised but, at the same time, their activities can be viewed from an immunological perspective [20]. Their primary role of maintaining vascular integrity is an essential process in preventing entry of foreign particles into the blood stream. The epithelial barrier performs a similar function. More specifically, however, they produce antimicrobial peptides [21]; possess pathogen recognition receptors (TLRs)[22, 23]; secrete immunomodulatory molecules [24]; and have specific receptors for chemokines [25], antibody complexes [26] and complement factors [27]. Critically, as outlined in this chapter, they interact with and respond to bacteria, all hallmarks of true immune cells. It is this response, or activation, that is important in the context of IE and provides the basis for the formation of platelet-bacterial vegetations which characterise this disease.
5. Platelet-bacterial interactions: General observations
Platelet interactions are examined under the broad headings of platelet adhesion, activation and aggregation. Platelet aggregometry is a useful tool in assessing platelet activation. In contrast to conventional stimuli such as ADP and thrombin, there is a significant lag time to the onset of platelet aggregation in response to bacteria [28].The length of this lag is defined by the sum of platelet-bacterial interactions occurring and can vary between donors, most likely due to variation in the levels of platelet receptors expressed on the surface and the concentration of plasma proteins. Platelet-bacterial interactions can be categorized into direct, indirect or mediated by a secreted bacterial product [29]. A direct interaction occurs when a bacterial adhesin binds directly to a platelet receptor or other surface expressed component [30]. Bacteria can participate in indirect interactions with platelets through a bridging protein which binds to the bacterium and then to its cognate platelet receptor [31]. When bacteria enter the bloodstream they can bind plasma proteins through specific plasma binding proteins or they can simply be recognised by soluble elements of the immune system such as immunoglobulins and complement proteins. Finally, and less common for the streptococcal bacteria, a secreted bacterial product may bind to the platelet causing activation independently of bacterial attachment. The ability of bacteria to propagate platelet activation and aggregation facilitates growth of the vegetation and effectively encapsulates the bacteria, hiding them from conventional immune cells and bacterial killing mechanisms. This chapter will focus on the specific molecular events that lead to initiation of IE, namely recognition of the platelet by the bacteria (and vice versa) and the ensuing intracellular signalling events that lead to platelet activation and amplification of the platelet response. As will be evident from the discussion to follow, platelet bacterial interactions are heterogeneous in nature and additionally they are multifactorial, with most bacteria interacting with platelets through more than one mechanism.
6. Streptococcus — Platelet interactions
6.1. Early findings
6.2. Serine rich repeat glycoproteins
The serine rich repeat (SRR) proteins are a large family of glycosylated bacterial adhesins. SRR proteins of
Fimbriae-associated protein 1 (Fap1) of
In contrast to the conserved structural organisation of SRR proteins, the peptide sequence of the non repetitive region varies significantly and is suggested to explain the differing affinity of SRR proteins to platelets and other cell types. To date only the SRR proteins of
GPIbα is a glycosylated, type one transmembrane receptor. A long highly glycosylated region called the macroglobulin region, or mucin-like core, extends from the cell surface presenting ligand binding domains to the extracellular milieu [55]. The macroglobulin region is decorated in predominantly O-linked but some N-linked carbohydrates terminating in sialic acid[55]. This highly glycosylated protein backbone is followed by a sulphated tyrosine region, a leucine rich repeat domain and an N-terminal domain decorated with N-linked sialic acid oligosaccharides [55]. Hsa is proposed to bind to both the N-terminal domain and the macroglobulin region while GspB interactions are isolated to the macroglobulin stalk [43]. Further complexity is added as GspB and Hsa display distinct preferences for O-linked and N-linked glycosylations respectively [43]. The subtle differences in binding affinity of SrpA to sialic acid moieties remain to be elucidated but studies using anti-GPIbα site specific antibodies isolated the
7. Antigen I/II family of bacterial adhesins
The antigen I/II family of proteins are ubiquitous to streptococci being found in most published genomes to date with roles in the development of microbial communities and adhesion to host cells and proteins [57]. Like the SRR proteins they share a common domain organisation: a signal sequence; an N-terminal region; an alanine rich repeat domain; a variable domain; a proline rich repeat region; a C-terminal region and a cell wall anchor domain [58].
Investigation of the role of the antigen I/II family of adhesins in
The cariogenic and IE causing bacterium
8. High molecular weight repeat protein
Previous studies revealed that
9. Phage encoded proteins
Human and bacterial evolution is peppered with incidences of viral integration or endogenisation into host genomes. Indeed, when the human genome was sequenced it was found that only 1.5% was composed of defined genes [75, 76]. The remainder, formally referred to as “junk DNA”, is now known to contain critical regulatory sequences. Many of these regulatory sequences and indeed genes have been linked to viral origins [77-79]. Bacterial history is also littered with incidences of viral DNA integration. Bacterial viruses are called bacteriophages and in the cases below they confer an advantage to
Using a transposon generated mutant library of
Interestingly, during the investigation of PblA and PblB, a study revealed that mutation of the bacteriophage lysin gene,
10. Secreted products
Bacteria can secrete bioactive molecules that participate in platelet interactions
11. Streptococcal-platelet interactions — Signalling response
Following platelet activation platelets secrete signalling molecules and platelet agonists from their cytoplasmic granules to recruit and activate nearby platelets.
As mentioned, platelets spread on
Similarly, Pampolina et al. examined the phosphorylation state of the FcγRIIA and its downstream effectors during the platelet aggregation response to
12. Streptococcal-platelet interactions — Immunological response
When bacteria enter the bloodstream they are recognised by soluble elements of the immune system. These soluble elements, specifically immunoglobulins and complement proteins can bind to their respective receptors on professional immune cells and platelets forming indirect bridging interactions. As most bacteria causing infective endocarditis are in fact lifelong or transient residents of the host, most of the population inherently produce a humoral immune response to these bacteria.
The role of IgG in platelet bacterial interactions has been extensively studied and reaffirmed repeatedly in the literature [28, 102-105]. Its role was first confirmed by Sullam et al. who demonstrated that plasma components other than fibrinogen (a cofactor for ADP induced activation) was required for
The complement system is a series of proteins that bind to bacteria in a step wise fashion and culminate in the formation of an oligomeric pore, the membrane attack complex, which lyses the targeted bacterium. Roles for complement in bacterial-platelet interactions have been demonstrated in
While previous reports examined platelet secretion in terms of end stage platelet activation, namely aggregation and spreading, a number of studies exist investigating the role of platelet secretion in the context of platelet immunology. In addition to platelet agonists, platelet granules contain bacteriocidal proteins and cytokines. A recent study by McNicol et al. demonstrated platelet activity in the form of signalling and secretion in the absence of platelet aggregation. They examined platelet secretion of soluble inflammatory mediators (Platelet factor 4, RANTES, sCD40L, platelet derived growth factor) in response to a number of
13. Conclusion
The overall role of platelet activation in response to circulating bacteria and IE is controversial but recent studies have linked platelet activation to the ability of bacteria to resist antibiotics [112]. This is consistent with the concept that, in activating platelets, bacteria prevent infiltration by antibiotics (or recognition by the immune system). It is likely that the initial adhesion events occur independently of platelet activation and thus make suitable targets in the prevention of IE. In contrast, as the ability to induce platelet aggregation (activation)
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