Review manuscript: Mechanisms of platelet activation by the pneumococcus and the role of platelets in community-acquired pneumonia

Abstract

There is increasing recognition of the involvement of platelets in orchestrating inflammatory responses, driving the activation of neutrophils, monocytes and vascular endothelium, which, if poorly controlled, may lead to microvascular dysfunction. Importantly, hyperreactivity of platelets has been implicated in the pathogenesis of myocardial injury and the associated particularly high prevalence of acute cardiovascular events in patients with severe community-acquired pneumonia (CAP), of which Streptococcus pneumoniae (pneumococcus) is the most commonly encountered aetiologic agent. In this context, it is noteworthy that a number of studies have documented various mechanisms by which the pneumococcus may directly promote platelet aggregation and activation. The major contributors to platelet activation include several different types of pneumococcal adhesin, the pore-forming toxin, pneumolysin, and possibly pathogen-derived hydrogen peroxide, which collectively represent a major focus of the current review. This is followed by an overview of the limited experimental studies together with a larger series of clinical studies mainly focused on all-cause CAP, which have provided evidence in support of associations between alterations in circulating platelet counts, most commonly thrombocytopenia, and a poor clinical outcome. The final section of the review covers, albeit briefly, systemic biomarkers of platelet activation which may have prognostic potential.

Platelets and Their Role in the Pathogenesis of Cardiovascular Events in Patients With Community-Acquired Pneumonia

“…Following translocation to the myocardium, the pneumococcus may intensify systemic platelet activation via interaction of these cells with various adhesins and other surface components of the pathogen, including complement activation products (40,(47)(48)(49)(50)(51)(52)(53)(54)(55).…”

Pathogenesis and prevention of risk of cardiovascular events in patients with pneumococcal community‐acquired pneumonia

“…Much recent research, largely based on murine and nonhuman primate models of experimental pneumococcal disease, has focused on the pathogenesis of CVEs during the early, acute phase of severe pneumococcal infection. Such research, which has been the subject of several recent reviews , is covered only briefly here as the primary focus of the current review is on the prevalence, pathogenesis and prevention of the longer‐term cardiac sequelae of severe pneumococcal disease, particularly in the context of persistent antigenaemia and associated inflammation.…”

“…The second, prothrombotic/pro‐inflammatory mechanism of pneumococcus‐mediated myocardial damage has been less well explored in comparison with that involving the direct cardiotoxic actions of PLY. The existence of this mechanism, which has recently been reviewed extensively elsewhere , is based predominantly on data derived from in vitro experiments, as well as limited data from experimental animal models and clinical studies of severe CAP. It proposes that pathogen‐driven systemic activation of platelets and neutrophils predisposes to the development of intravascular thrombosis, which may contribute to the pathogenesis of cardiovascular dysfunction .…”

Multifaceted Role of Pneumolysin in the Pathogenesis of Myocardial Injury in Community-Acquired Pneumonia

“…The therapeutic potential of anti-inflammatory and anti-thrombotic adjunctive strategies based on administration of corticosteroids, statins or anti-platelet therapies, which may also counter the harmful, pro-inflammatory/pro-thrombotic activities of PLY in patients with severe CAP have been reviewed elsewhere [ 18 , 19 , 20 , 21 ] and are not covered here. However, more recent developments with respect to the identification of novel, indirect, toxin-targeted, potential adjunctive therapeutic strategies which merit mention include the following:…”

“…In recognition of the strength of recent, albeit predominantly experimental, scientific evidence, implicating PLY in the etiology of myocardial injury in pneumococcal disease, the current review represents an updated overview of this important topic. It is focused primarily on immunopathogenesis [ 19 , 20 , 21 ], as well as on PLY-targeted therapies, some of which are also broadly operative against bacterial pore-forming toxins [ 18 , 20 ]. These sections of the review are preceded by overviews of the epidemiology of CAP and associated CV complications, followed by a brief description of the structure and biological activities of PLY.…”