Article first published online: 9 SEP 2009
© 2009 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 7, Issue 11, pages 1865–1866, November 2009
How to Cite
COX, D. (2009), Bacteria–platelet interactions. Journal of Thrombosis and Haemostasis, 7: 1865–1866. doi: 10.1111/j.1538-7836.2009.03611.x
- Issue published online: 21 OCT 2009
- Article first published online: 9 SEP 2009
The conventional view of platelets as regulators of thrombosis is gradually changing as awareness of the role of platelets in inflammation and the host response to infection grows. When infectious agents gain access to the circulatory system, some of the first cells that they come into contact with are platelets, primarily because of the high concentration of platelets in the blood. Bacteria, especially, have been shown to interact with platelets in the circulation . These interactions have three components: adhesion, phagocytosis, and activation. Adhesion allows bacteria and platelets to bind together in a firm manner, which, like the adhesion of platelets to extracellular matrix proteins, is often shear-dependent . Bacteria can also trigger platelet activation and subsequent aggregation. The fact that this can happen with bacteria that do not adhere to platelets suggests that this is a distinct property of some bacteria. In fact, bacteria can be adhesive, proaggregatory, both, or neither . The aggregation response is unique, in that there is a species-dependent variable lag time before aggregation occurs and aggregation is always maximal, that is, an all-or-nothing response. There is also growing evidence of the ability of platelets to phagocytose bacteria [4,5].
The interaction of bacteria with platelets can occur through three distinct mechanisms: direct binding, indirect binding, and secreted products. A number of different bacteria have been shown to be capable of binding directly to platelets, including Streptococcus gordonii and Streptococcus sanguinis, which both bind to glycoprotein (GP)Ib via Hs antigen (Hsa)  and serine-rich protein (Srp) A , respectively, and Staphylococcus epidermidis, which binds to GPIIb–IIIa . More commonly, bacteria bind plasma proteins that, in turn, can bind to platelet receptors; for example, Helicobacter pylori  and Staphylococcus aureus protein A  bind von Willebrand factor (VWF), which subsequently binds GPIb. S. aureus clumping factor (Clf) , Streptococcus agalactiae FbsA  and S. epidermidis serine-aspartate repeat protein G  bind fibrinogen, and S. aureus fibronectin-binding protein (Fnbp) binds fibronectin ; all of these can subsequently bind to GPIIb–IIIa. Another, more generic, approach to interacting with platelets is for bacteria to bind antibody and complement, which can then bind to platelet FcγRIIa (platelet IgG Fc receptor) or to a yet to be identified complement receptor on the platelet surface .
The third and less well-characterized interaction between platelets and bacteria is via secreted (or shed) products of bacteria. One such secreted product is the enzyme gingipain, which is secreted by Porphyromonas gingivalis and activates platelet by having a thrombin-like effect on protease-activated receptor-1 . In this issue, de Haas et al.  report on a secreted product [staphylococcal superantigen-like 5 (SSL5)] from S. aureus and describe the process by which it activates platelets. They show that SSL5 can bind to GPIbα, triggering platelet activation; however, they also show that it can bind to GPIIb–IIIa and that these two receptors work synergistically under shear to facilitate firm adhesion. One limitation of this study is the requirement for washed platelet preparations to observe platelet activation. This would appear to be due to plasma protein binding (specifically albumin) by SSL5, and thus raises the question of whether free SSL5 would reach a high enough concentration in plasma to mediate an interaction with platelets; it may be possible during S. aureus septicemia, but this would need to be further investigated.
However, when dealing with S. aureus, no single factor is likely to be responsible for platelet activation. S. aureus has two clumping factors (Clf A and Clf B), two fibronectin-binding proteins (Fnbp A and Fnbp B), protein A, and SSL5, and it also binds antibody and complement. The result is a bacterium that is strongly primed to interact with platelets under both static and shear conditions and to trigger platelet activation as a result. This role for multiple activating signals is important, as it has been shown that no single activating signal is effective. Although H. pylori binds VWf, which in turn binds to GPIb, platelet activation only occurs in H. pylori-positive patients, as antibody binding and subsequent engagement of platelet FcγRIIa is required . Subsequently, GPIb and FcγRIIa were shown to colocalize on the platelet surface . Similarly, although Clf and Fnbp can bind fibrinogen and/or fibronectin, which subsequently bind GPIIb/IIIa, this only leads to platelet activation in the presence of specific antibody that interacts with FcγRIIa [12,17]. This is similar to the situation where low-dose GPIIb–IIIa antagonists can, in fact, induce platelet activation in the presence of a low dose of an agonist such as ADP . Recently, a role for cooperation between GPIIb–IIIa and FcγRIIa in signaling has been identified . This recent paper by de Haas et al.  suggests another association, that between GPIb and GPIIb–IIIa, where engagement of both can trigger platelet activation.
Why does S. aureus have so many different mechanisms for activating platelets or, rather, why do platelets have so many different mechanisms for interacting with S. aureus? It is likely that platelets are acting as part of the innate immune system as, once activated, they release their granule contents and can bind to leukocytes. Platelet granules contain a number of bactericidal peptides  that, along with binding to leukocytes, aid in fighting the infection. However, many strains of staphylococci and streptococci are resistant to these antimicrobial peptides ; as a result, rather than the bacteria being killed, the activation of the platelets by the bacteria leads to the formation of bacteria–platelet thrombi, as seen in infective endocarditis, or to disseminated intravascular coagulation, as occurs in sepsis. In fact, the formation of infected thrombi aids in the survival of the bacteria by protecting them from the immune system.
Thus, the article by de Haas et al.  adds further to our understanding of platelet function; however, there is much more to learn. More studies are required on the cooperation between platelet receptors and the signaling pathways involved. Ultimately, targeting the host response, and in particular the platelet, may be an important strategy in the treatment of serious infections caused by resistant strains of S. aureus.
Disclosure of Conflict of Interests
The author states that he has no conflict of interest.
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