Platelet Antistaphylococcal Responses Occur through P2X 1 and P2Y 12 Receptor-Induced Activation and Kinocidin Release

• Published in: Infection and immunity Vol. 76; no. 12; pp. 5706 - 5713
• Main Authors: Trier, Darin A., Gank, Kimberly D., Kupferwasser, Deborah, Yount, Nannette Y., French, William J., Michelson, Alan D., Kupferwasser, Leon I., Xiong, Yan Q., Bayer, Arnold S., Yeaman, Michael R.
• Format: Journal Article
• Language: English
• Published: 01-12-2008
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00935-08

Platelets (PLTs) act in antimicrobial host defense by releasing PLT microbicidal proteins (PMPs) or PLT kinocidins (PKs). Receptors mediating staphylocidal efficacy and PMP or PK release versus isogenic PMP-susceptible (ISP479C) and -resistant (ISP479R)
Staphylococcus aureus
strains were examined in vitro. Isolated PLTs were incubated with ISP479C or ISP479R (PLT/
S. aureus
ratio range, 1:1 to 10,000:1) in the presence or absence of a panel of PLT inhibitors, including P2X and P2Y receptor antagonists of increasingly narrow specificity, and PLT adhesion receptors (CD41, CD42b, and CD62P). PLT-to-
S. aureus
exposure ratios of ≥10:1 yielded significant reductions in the viability of both strains. Results from reversed-phase high-performance liquid chromatography indicated that staphylocidal PLT releasates contained PMPs and PKs. At ratios below 10:1, the PLT antistaphylococcal efficacy relative to the intrinsic
S. aureus
PMP-susceptible or -resistant phenotype diminished. Apyrase (an agent of ADP degradation), suramin (a general P2 receptor antagonist), pyridoxal 5′-phosphonucleotide derivative (a specific P2X
1
antagonist), and cangrelor (a specific P2Y
12
antagonist) mitigated the PLT staphylocidal response against both strains, correlating with reduced levels of PMP and PK release. Specific inhibition occurred in the presence and absence of homologous plasma. The antagonism of the thromboxane A
2
, cyclooxygenase-1/cyclooxygenase-2, or phospholipase C pathway or the hindrance of surface adhesion receptors failed to impede PLT anti-
S. aureus
responses. These results suggest a multifactorial PLT anti-
S. aureus
response mechanism involving (i) a PLT-to-
S. aureus
ratio sufficient for activation; (ii) the ensuing degranulation of PMPs, PKs, ADP, and/or ATP; (iii) the activation of P2X
1
/P2Y
12
receptors on adjacent PLTs; and (iv) the recursive amplification of PMP and PK release from these PLTs.