Platelets in defense against bacterial pathogens

Abstract

Platelets interact with bacterial pathogens through a wide array of cellular and molecular mechanisms. The consequences of this interaction may significantly influence the balance between infection and immunity. On the one hand, recent data indicate that certain bacteria may be capable of exploiting these interactions to gain a virulence advantage. Indeed, certain bacterial pathogens appear to have evolved specific ways in which to subvert activated platelets. Hence, it is conceivable that some bacterial pathogens exploit platelet responses. On the other hand, platelets are now known to possess unambiguous structures and functions of host defense effector cells. Recent discoveries emphasize critical features enabling such functions, including expression of toll-like receptors that detect hallmark signals of bacterial infection, an array of microbicidal peptides, as well as other host defense molecules and functions. These concepts are consistent with increased risk and severity of bacterial infection as correlates of clinical abnormalities in platelet quantity and quality. In these respects, the molecular and cellular roles of platelets in host defense against bacterial pathogens are explored with attention on advances in platelet immunobiology.

Figures

Fig. 1

Model of platelet interactions with Staphylococcus aureus. Based upon recent evidence, the model illustrates how platelets may sense and respond via parallel pathways that promote anti-staphylococcal host defense. a On the cellular level, interactions with S. aureus evoke: (1) platelet activation via specific receptors; (2) liberation and processing of PMPs and PKs which exert direct microbicidal effects, and (3) secretion of adenosine nucleotides (ADP/ATP) triggering a recursive cascade for activation of adjacent platelets. Note that inhibitors of the purinergic pathway of activation preclude anti-staphylococcal responses. b On the molecular level, specific sense and response pathway components are illustrated. Purinergic agonists such as ADP are known stimulants of strong platelet activation. Thus, degradation of extracellular ADP by apyrase (APY) or the inhibition of P2X or P2Y12 adenosine nucleotide receptors by suramin (SUR; general P2 inhibitor), pyridoxal-5′-phosphonucleotide derivative (PND; high-affinity P2X1 inhibitor), or cangrelor (CNG; high-affinity P2Y12 inhibitor) specifically prevents platelet (PLT) sense and response activation for staphylocidal efficacy. In contrast, antagonism of the P2Y1, phospholipase C (PLC), thromboxane A2 (TXA2), or cyclooxygenase (COX) pathways, or inhibition of the CD41, CD42b, or CD62P platelet adhesin receptors do not impede the sense and response activation of platelets versus S. aureus. Thus, the antistaphylococcal efficacy of platelets involves a self-amplifying, recursive sense and response mechanism: (1) direct or indirect interactions of platelets and S. aureus (SA); (2) platelet activation, via autocrine or intercrine P2X1 or P2Y12 receptor-mediated signal transduction prompting granule mobilization; (3) degranulation and liberation of ADP/ATP from δ-granules; (4) deployment of direct antimicrobial effector molecules (PMPs and PKs) from α-granules; and (5) adenosine nucleotide-mediated activation of adjacent platelets, with the ensuing amplification of antimicrobial responses. Such interactions are likely influenced by platelet-to-S. aureus ratios. In this respect, staphylocidal efficacy appears to involve a threshold platelet ratio to generate and sustain an intercrine platelet cascade required to achieve PMP/PK concentrations for staphylocidal efficacy. Adapted from [173]