Modular determinants of antimicrobial activity in platelet factor-4 family kinocidins

Yeaman, Michael R.; Yount, Nannette Y.; Waring, Alan J.; Gank, Kimberly D.; Kupferwasser, Deborah; Wiese, Robert; Bayer, Arnold S.; Welch, William H.

doi:10.1016/j.bbamem.2006.11.010

Cited by 75 publications

(81 citation statements)

References 61 publications

(151 reference statements)

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“…We previously discovered that human PMPs include the CXC chemokines platelet factor 4 and platelet basic peptide and derivatives, such as connective tissue-activating peptide 3 (CTAP-3) and interleukin-8, as well as the CC chemokine RANTES (released upon activation, normal T-cell expressed and secreted) (34,37,43). Microbicidal chemokines from platelets have been termed platelet kinocidins (PKs) (45), reflecting dual and complementary host defense roles likely bridging innate and adaptive immunity.…”

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confidence: 99%

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

et al. 2008

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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.

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confidence: 99%

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

et al. 2008

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“…Human ␤-defensin 2 (h␤D-2; Peptides International) is a predominant host defense peptide (HDP) elaborated by epithelial tissues throughout the body. The mimetic peptide RP-1 is a synthetic 18-amino-acid congener engineered in part from the microbicidal ␣-helix domains of the platelet factor 4 family of kinocidins (8). RP-1 was synthesized, purified, and authenticated as previously detailed (9).…”

Section: Methodsmentioning

confidence: 99%

“…RP-1 was synthesized, purified, and authenticated as previously detailed (9). Each study peptide has demonstrated in vitro antimicrobial activity against S. aureus (3,7,8,10). sEL sensor domain.…”

Section: Methodsmentioning

confidence: 99%

“…A "nonsense" peptide of the same composition but having a randomized (scrambled) sequence was also generated and was included in assays as a control. The sEL and nonsense peptides were synthesized, purified, and authenticated as previously described (8,9).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we showed that the two-component regulatory system (TCRS) GraSR plays a key role in S. aureus survival in the face of HDPs (6)(7)(8). Also known to be a component of the antibiotic peptide sensor (APS) (9,10), GraSR upregulates adaptive resistance genes such as mprF and dltA, which encode proteins that modulate net surface charge and influence the composition of the S. aureus envelope (11,12).…”

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The GraS Sensor in Staphylococcus aureus Mediates Resistance to Host Defense Peptides Differing in Mechanisms of Action

et al. 2016

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f Staphylococcus aureus uses the two-component regulatory system GraRS to sense and respond to host defense peptides (HDPs). However, the mechanistic impact of GraS or its extracellular sensing loop (EL) on HDP resistance is essentially unexplored. Strains with null mutations in the GraS holoprotein (⌬graS) or its EL (⌬EL) were compared for mechanisms of resistance to HDPs of relevant immune sources: neutrophil ␣-defensin (human neutrophil peptide 1 [hNP-1]), cutaneous ␤-defensin (human ␤-defensin 2 [hBD-2]), or the platelet kinocidin congener RP-1. Actions studied by flow cytometry included energetics (ENR); membrane permeabilization (PRM); annexin V binding (ANX), and cell death protease activation (CDP). Assay conditions simulated bloodstream (pH 7.5) or phagolysosomal (pH 5.5) pH contexts. S. aureus strains were more susceptible to HDPs at pH 7.5 than at pH 5.5, and each HDP exerted a distinct effect signature. The impacts of ⌬graS and ⌬⌭L on HDP resistance were peptide and pH dependent. Both mutants exhibited defects in ANX response to hNP-1 or hBD-2 at pH 7.5, but only hNP-1 did so at pH 5.5. Both mutants exhibited hyper-PRM, -ANX, and -CDP responses to RP-1 at both pHs and hypo-ENR at pH 5.5. The actions correlated with ⌬graS or ⌬⌭L hypersusceptibility to hNP-1 or RP-1 (but not hBD-2) at pH 7.5 and to all study HDPs at pH 5.5. An exogenous EL mimic protected mutant strains from hNP-1 and hBD-2 but not RP-1, indicating that GraS and its EL play nonredundant roles in S. aureus survival responses to specific HDPs. These findings suggest that GraS mediates specific resistance countermeasures to HDPs in immune contexts that are highly relevant to S. aureus pathogenesis in humans.

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Development of Antifouling and Bactericidal Coatings for Platelet Storage Bags Using Dopamine Chemistry

Hadjesfandiari

Weinhart

Kizhakkedathu

et al. 2017

Adv Healthcare Materials

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Platelets have a limited shelf life, due to the risk of bacterial contamination and platelet quality loss. Most platelet storage bags are made of a mixture of polyvinyl chloride with a plasticizer, denoted as pPVC. To improve biocompatibility of pPVC with platelets and to inhibit bacterial biofilm formation, an antifouling polymer coating is developed using mussel-inspired chemistry. A copolymer of N,N-dimethylacrylamide and N-(3-aminopropyl)methacrylamide hydrochloride is synthesized and coupled with catechol groups, named DA51-cat. Under mild aqueous conditions, pPVC is first equilibrated with an anchoring polydopamine layer, followed by a DA51-cat layer. Measurements show this coating decreases fibrinogen adsorption to 5% of the control surfaces. One-step coating with DA51-cat does not coat pPVC efficiently although it is sufficient for coating silicon wafers and gold substrates. The dual layer coating on platelet bags resists bacterial biofilm formation and considerably decreases platelet adhesion. A cationic antimicrobial peptide, E6, is conjugated to DA51-cat then coated on silicon wafers and introduces bactericidal activity to these surfaces. Time-of-flight second ion-mass spectroscopy is successfully applied to characterize these surfaces. pPVC is widely used in medical devices; this method provides an approach to controlling biofouling and bacterial growth on it without elaborate surface modification procedures.

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Modular determinants of antimicrobial activity in platelet factor-4 family kinocidins

Cited by 75 publications

References 61 publications

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

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

The GraS Sensor in Staphylococcus aureus Mediates Resistance to Host Defense Peptides Differing in Mechanisms of Action

Development of Antifouling and Bactericidal Coatings for Platelet Storage Bags Using Dopamine Chemistry

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Modular determinants of antimicrobial activity in platelet factor-4 family kinocidins

Cited by 75 publications

References 61 publications

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

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

The GraS Sensor in Staphylococcus aureus Mediates Resistance to Host Defense Peptides Differing in Mechanisms of Action

Development of Antifouling and Bactericidal Coatings for Platelet Storage Bags Using Dopamine Chemistry

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Product

Resources

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

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