scholarly journals NOD2 Stimulation by Staphylococcus aureus-Derived Peptidoglycan Is Boosted by Toll-Like Receptor 2 Costimulation with Lipoproteins in Dendritic Cells

2014 ◽  
Vol 82 (11) ◽  
pp. 4681-4688 ◽  
Author(s):  
Holger Schäffler ◽  
Dogan Doruk Demircioglu ◽  
Daniel Kühner ◽  
Sarah Menz ◽  
Annika Bender ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Dendritic Cells ◽  
Immune System ◽  
Cytokine Secretion ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Murine Bone Marrow ◽  
J774 Cells ◽  
Toll Like Receptor 2

ABSTRACTMutations in the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) play an important role in the pathogenesis of Crohn's disease. NOD2 is an intracellular pattern recognition receptor (PRR) that senses bacterial peptidoglycan (PGN) structures, e.g., muramyl dipeptide (MDP). Here we focused on the effect of more-cross-linked, polymeric PGN fragments (PGNpol) in the activation of the innate immune system. In this study, the effect of combined NOD2 and Toll-like receptor 2 (TLR2) stimulation was examined compared to single stimulation of the NOD2 receptor alone. PGNpol species derived from a lipoprotein-containingStaphylococcus aureusstrain (SA113) and a lipoprotein-deficient strain (SA113 Δlgt) were isolated. While PGNpol constitutes a combined NOD2 and TLR2 ligand, lipoprotein-deficient PGNpolΔlgtleads to activation of the immune system only via the NOD2 receptor. Murine bone marrow-derived dendritic cells (BMDCs), J774 cells, and Mono Mac 6 (MM6) cells were stimulated with these ligands. Cytokines (interleukin-6 [IL-6], IL-12p40, and tumor necrosis factor alpha [TNF-α]) as well as DC activation and maturation parameters were measured. Stimulation with PGNpolΔlgtdid not lead to enhanced cytokine secretion or DC activation and maturation. However, stimulation with PGNpol led to strong cytokine secretion and subsequent DC maturation. These results were confirmed in MM6 and J774 cells. We showed that the NOD2-mediated activation of DCs with PGNpol was dependent on TLR2 costimulation. Therefore, signaling via both receptors leads to a more potent activation of the immune system than that with stimulation via each receptor alone.

scholarly journals Mycobacterium tuberculosisLipoprotein and Lipoglycan Binding to Toll-Like Receptor 2 Correlates with Agonist Activity and Functional Outcomes

2018 ◽  
Vol 86 (10) ◽  
Author(s):  
Supriya Shukla ◽  
Edward T. Richardson ◽  
Michael G. Drage ◽  
W. Henry Boom ◽  
Clifford V. Harding
Keyword(s):  
Immune Responses ◽  
Agonist Activity ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Tlr2 Agonist ◽  
Content Type ◽  
Host Immune Responses ◽  
Extracellular Signal ◽  
Toll Like Receptor 2 ◽  
Tlr2 Signaling

ABSTRACTMycobacterium tuberculosiscauses persistent infection due to its ability to evade host immune responses.M. tuberculosisinduces Toll-like receptor 2 (TLR2) signaling, which influences immune responses toM. tuberculosis. TLR2 agonists expressed byM. tuberculosisinclude lipoproteins (e.g., LprG), the glycolipid phosphatidylinositol mannoside 6 (PIM6), and the lipoglycan lipomannan (LM). AnotherM. tuberculosislipoglycan, mannose-capped lipoarabinomannan (ManLAM), lacks TLR2 agonist activity. In contrast, PILAM, fromMycobacterum smegmatis, does have TLR2 agonist activity. Our understanding of howM. tuberculosislipoproteins and lipoglycans interact with TLR2 is limited, and binding of these molecules to TLR2 has not been measured directly. Here, we directly measuredM. tuberculosislipoprotein and lipoglycan binding to TLR2 and its partner receptor, TLR1. LprG, LAM, and LM were all found to bind to TLR2 in the absence of TLR1, but not to TLR1 in the absence of TLR2. Trimolecular interactions were revealed by binding of TLR2-LprG or TLR2-PIM6 complexes to TLR1, whereas binding of TLR2 to TLR1 was not detected in the absence of the lipoprotein or glycolipid. ManLAM exhibited low affinity for TLR2 in comparison to PILAM, LM, and LprG, which correlated with reduced ability of ManLAM to induce TLR2-mediated extracellular-signal-regulated kinase (ERK) activation and tumor necrosis factor alpha (TNF-α) secretion in macrophages. We provide the first direct affinity measurement and kinetic analysis ofM. tuberculosislipoprotein and lipoglycan binding to TLR2. Our results demonstrate that binding affinity correlates with the functional ability of agonists to induce TLR2 signaling.

scholarly journals Staphylococcus aureus Releases Proinflammatory Membrane Vesicles To Resist Antimicrobial Fatty Acids

mSphere ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Arnaud Kengmo Tchoupa ◽  
Andreas Peschel
Keyword(s):  
Fatty Acids ◽  
Staphylococcus Aureus ◽  
Immune Responses ◽  
Membrane Vesicle ◽  
Membrane Vesicles ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Content Type ◽  
Healthy Humans ◽  
Toll Like Receptor 2

ABSTRACT Staphylococcus aureus is a major pathogen, which colonizes one in three otherwise healthy humans. This significant spread of S. aureus is largely due to its ability to circumvent innate immune responses, including antimicrobial fatty acids (AFAs) on the skin and in nasal secretions. In response to AFAs, S. aureus swiftly induces resistance mechanisms, which have yet to be completely elucidated. Here, we identify membrane vesicle (MV) release as a resistance strategy used by S. aureus to sequester host-specific AFAs. MVs protect S. aureus against a wide array of AFAs. Strikingly, beside MV production, S. aureus modulates MV composition upon exposure to AFAs. MVs purified from bacteria grown in the presence of linoleic acid display a distinct protein content and are enriched in lipoproteins, which strongly activate Toll-like receptor 2 (TLR2). Cumulatively, our findings reveal the protective capacities of MVs against AFAs, which are counteracted by an increased TLR2-mediated innate immune response. IMPORTANCE The nares of one in three humans are colonized by Staphylococcus aureus. In these environments, and arguably on all mucosal surfaces, bacteria encounter fatty acids with antimicrobial properties. Our study uncovers that S. aureus releases membrane vesicles (MVs) that act as decoys to protect the bacterium against antimicrobial fatty acids (AFAs). The AFA-neutralizing effects of MVs were neither strain specific nor restricted to one particular AFA. Hence, MVs may represent “public goods” playing an overlooked role in shaping bacterial communities in AFA-rich environments such as the skin and nose. Intriguingly, in addition to MV biogenesis, S. aureus modulates MV composition in response to exposure to AFAs, including an increased release of lipoproteins. These MVs strongly stimulate the innate immunity via Toll-like receptor 2 (TLR2). TLR2-mediated inflammation, which helps to fight infections, may exacerbate inflammatory disorders like atopic dermatitis. Our study highlights intricate immune responses preventing infections from colonizing bacteria.

scholarly journals Purified Streptococcus pneumoniae Endopeptidase O (PepO) Enhances Particle Uptake by Macrophages in a Toll-Like Receptor 2- and miR-155-Dependent Manner

2017 ◽  
Vol 85 (4) ◽  
Author(s):  
Hua Yao ◽  
Hong Zhang ◽  
Kai Lan ◽  
Hong Wang ◽  
Yufeng Su ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Host Defense ◽  
Defense Response ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Content Type ◽  
Host Defense Response ◽  
Toll Like Receptor 2 ◽  
In Cells

ABSTRACT Insights into the host-microbial virulence factor interaction, especially the immune signaling mechanisms, could provide novel prevention and treatment options for pneumococcal diseases. Streptococcus pneumoniae endopeptidase O (PepO) is a newly discovered and ubiquitously expressed pneumococcal virulence protein. A PepO-mutant strain showed impaired adherence to and invasion of host cells compared with the isogenic wild-type strain. It is still unknown whether PepO is involved in the host defense response to pneumococcal infection. Here, we demonstrated that PepO could enhance phagocytosis of Streptococcus pneumoniae and Staphylococcus aureus by peritoneal exudate macrophages (PEMs). Further studies showed that PepO stimulation upregulated the expression of microRNA-155 (miR-155) in PEMs in a time- and dose-dependent manner. PepO-induced enhanced phagocytosis was decreased in cells transfected with an inhibitor of miR-155, while it was increased in cells transfected with a mimic of miR-155. We also revealed that PepO-induced upregulation of miR-155 in PEMs was mediated by Toll-like receptor 2 (TLR2)–NF-κB signaling and that the increased expression of miR-155 downregulated expression of SHIP1. Taken together, these results indicate that PepO induces upregulation of miR-155 in PEMs, contributing to enhanced phagocytosis and host defense response to pneumococci and Staphylococcus aureus.

scholarly journals Group B Streptococcus and Streptococcus suis Capsular Polysaccharides Induce Chemokine Production by Dendritic Cells via Toll-Like Receptor 2- and MyD88-Dependent and -Independent Pathways

2013 ◽  
Vol 81 (9) ◽  
pp. 3106-3118 ◽  
Author(s):  
Cynthia Calzas ◽  
Guillaume Goyette-Desjardins ◽  
Paul Lemire ◽  
Fleur Gagnon ◽  
Claude Lachance ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Capsular Polysaccharides ◽  
Toll Like Receptor ◽  
Chemokine Production ◽  
Content Type ◽  
Toll Like Receptor 2 ◽  
Group B ◽  
Necrosis Factor

ABSTRACTStreptococcus agalactiae(also known as group BStreptococcus[GBS]) andStreptococcus suisare encapsulated streptococci causing severe septicemia and meningitis. Bacterial capsular polysaccharides (CPSs) are poorly immunogenic, but anti-CPS antibodies are essential to the host defense against encapsulated bacteria. The mechanisms underlying anti-CPS antibody responses are not fully elucidated, but the biochemistry of CPSs, particularly the presence of sialic acid, may have an immunosuppressive effect. We investigated the ability of highly purifiedS. suisand GBS native (sialylated) CPSs to activate dendritic cells (DCs), which are crucial actors in the initiation of humoral immunity. The influence of CPS biochemistry was studied using CPSs extracted from different serotypes within these two streptococcal species, as well as desialylated CPSs. No interleukin-1β (IL-1β), IL-6, IL-12p70, tumor necrosis factor alpha (TNF-α), or IL-10 production was observed inS. suisor GBS CPS-stimulated DCs. Moreover, these CPSs exerted immunosuppressive effects on DC activation, as a diminution of gamma interferon (IFN-γ)-induced B cell-activating factor of the tumor necrosis factor family (BAFF) expression was observed in CPS-pretreated cells. However,S. suisand GBS CPSs induced significant production of CCL3, via partially Toll-like receptor 2 (TLR2)- and myeloid differentiation factor 88 (MyD88)-dependent pathways, and CCL2, via TLR-independent mechanisms. No major influence of CPS biochemistry was observed on the capacity to induce chemokine production by DCs, indicating that DCs respond to these CPSs in a patterned way rather than a structure-dedicated manner.

scholarly journals Toll-Like Receptor 2 Modulates the Proinflammatory Milieu in Staphylococcus aureus-Induced Brain Abscess

2005 ◽  
Vol 73 (11) ◽  
pp. 7428-7435 ◽  
Author(s):  
Tammy Kielian ◽  
Anessa Haney ◽  
Patrick M. Mayes ◽  
Sarita Garg ◽  
Nilufer Esen
Keyword(s):  
Staphylococcus Aureus ◽  
Brain Abscess ◽  
Complex Nature ◽  
Interleukin 17 ◽  
Immune Recognition ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Proinflammatory Mediators ◽  
Brain Abscesses ◽  
Toll Like Receptor 2

ABSTRACT Toll-like receptor 2 (TLR2) is a pattern recognition receptor (PRR) that plays an important role in innate immune recognition of conserved structural motifs on a wide array of pathogens, including Staphylococcus aureus. To ascertain the functional significance of TLR2 in the context of central nervous system (CNS) parenchymal infection, we evaluated the pathogenesis of S. aureus-induced experimental brain abscess in TLR2 knockout (KO) and wild-type (WT) mice. The expression of several proinflammatory mediators, including inducible nitric oxide synthase, tumor necrosis factor alpha, and macrophage inflammatory protein-2, was significantly attenuated in brain abscesses of TLR2 KO mice compared to WT mice during the acute phase of infection. Conversely, interleukin-17 (IL-17), a cytokine produced by activated and memory T cells, was significantly elevated in lesions of TLR2 KO mice, suggesting an association between innate and adaptive immunity in brain abscess. Despite these differences, brain abscess severity in TLR2 KO and WT animals was similar, with comparable mortality rates, bacterial titers, and blood-brain barrier permeability, implying a role for alternative PRRs. Expression of the phagocytic PRRs macrophage scavenger receptor type AI/AII and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) was increased in brain abscesses of both TLR2 KO and WT mice compared to uninfected animals. However, LOX-1 induction in brain abscesses of TLR2 KO mice was significantly attenuated compared to WT animals, revealing that the TLR2-dependent signal(s) influence LOX-1 expression. Collectively, these findings reveal the complex nature of gram-positive bacterial recognition in the CNS which occurs, in part, through engagement of TLR2 and highlight the importance of receptor redundancy for S. aureus detection in the CNS.

scholarly journals Toll-Like Receptor 2 Agonist Pam3CSK4 Alleviates the Pathology of Leptospirosis in Hamster

2016 ◽  
Vol 84 (12) ◽  
pp. 3350-3357 ◽  
Author(s):  
Wenlong Zhang ◽  
Naisheng Zhang ◽  
Xufeng Xie ◽  
Jian Guo ◽  
Xuemin Jin ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Interleukin 10 ◽  
Peritoneal Macrophages ◽  
High Ratio ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Target Organs ◽  
Toll Like Receptor 2

Leptospirosis, caused by pathogenic spirochetes, is a zoonotic disease of global importance. The detailed pathogenesis of leptospirosis is still unclear, which limits the ideal treatment of leptospirosis. In this study, we analyzed the expression of Toll-like receptor 2 (TLR2) and TLR4 in target organs of both resistant mice and susceptible hamsters after Leptospira interrogans serovar Autumnalis infection. TLR2 but not TLR4 transcripts in mouse organs contrasted with delayed induction and overexpression in hamster organs. Coinjection of leptospires and the TLR2 agonist Pam3CSK4 into hamsters improved their survival rate, alleviated tissue injury, and decreased the abundance of leptospires in target organs. The production of interleukin-10 (IL-10) from tissues was enhanced in hamsters of the group coinjected with leptospires and Pam3CSK4 compared with the leptospira-injected group. Similarly, IL-10 levels in TLR2-deficient mice were lower than those in wild-type mice. A high ratio of IL-10/tumor necrosis factor alpha (TNF-α) levels was found in both infected wild-type mice and hamsters coinjected with leptospires and Pam3CSK4. Moreover, TLR2-dependent IL-10 expression was detected in peritoneal macrophages after leptospira infection. Our data demonstrate that coinjection of leptospires and Pam3CSK4 alleviates the pathology of leptospirosis in hamsters; this effect may result from the enhanced expression of TLR2-dependent IL-10.

scholarly journals Toll-Like Receptor 2 Ligand Pretreatment Attenuates Retinal Microglial Inflammatory Response but Enhances Phagocytic Activity toward Staphylococcus aureus

2012 ◽  
Vol 80 (6) ◽  
pp. 2076-2088 ◽  
Author(s):  
Travis Kochan ◽  
Anuj Singla ◽  
Joaquin Tosi ◽  
Ashok Kumar
Keyword(s):  
Staphylococcus Aureus ◽  
Inflammatory Response ◽  
Phagocytic Activity ◽  
Toll Like Receptor ◽  
Innate Response ◽  
Content Type ◽  
Proinflammatory Mediators ◽  
Retinal Microglia ◽  
Tlr2 Ligand ◽  
Toll Like Receptor 2

ABSTRACTStaphylococcus aureusis a leading cause of severe endophthalmitis, which often results in vision loss in some patients. Previously, we showed that Toll-like receptor 2 (TLR2) ligand pretreatment prevented the development of staphylococcal endophthalmitis in mice and suggested that microglia might be involved in this protective effect (Kumar A, Singh CN, Glybina IV, Mahmoud TH, Yu FS. J. Infect. Dis. 201:255–263, 2010). The aim of the present study was to understand how microglial innate response is modulated by TLR2 ligand pretreatment. Here, we demonstrate thatS. aureusinfection increased the CD11b+CD45+microglial/macrophage population in the C57BL/6 mouse retina. Using cultured primary retinal microglia and a murine microglial cell line (BV-2), we found that these cells express TLR2 and that its expression is increased upon stimulation with bacteria or an exclusive TLR2 ligand, Pam3Cys. Furthermore, challenge of primary retinal microglia withS. aureusand its cell wall components peptidoglycan (PGN) and lipoteichoic acid (LTA) induced the secretion of proinflammatory mediators (tumor necrosis factor alpha [TNF-α] and MIP-2). This innate response was attenuated by a function-blocking anti-TLR2 antibody or by small interfering RNA (siRNA) knockdown of TLR2. In order to assess the modulation of the innate response, microglia were pretreated with a low dose (0.1 or 1 μg/ml) of Pam3Cys and then challenged with liveS. aureus. Our data showed thatS. aureus-induced production of proinflammatory mediators is dramatically reduced in pretreated microglia. Importantly, microglia pretreated with the TLR2 agonist phagocytosed significantly more bacteria than unstimulated cells. Together, our data suggest that TLR2 plays an important role in retinal microglial innate response toS. aureus, and its sensitization inhibits inflammatory response while enhancing phagocytic activity.

scholarly journals Essential Engagement of Toll-Like Receptor 2 in Initiation of Early Protective Th1 Response against Rough Variants of Mycobacterium abscessus

2015 ◽  
Vol 83 (4) ◽  
pp. 1556-1567 ◽  
Author(s):  
Jong-Seok Kim ◽  
Min-Jung Kang ◽  
Woo Sik Kim ◽  
Seung Jung Han ◽  
Hong Min Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Protective Immunity ◽  
Mycobacterium Abscessus ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Term Survival ◽  
Content Type ◽  
Specific Manner ◽  
Toll Like Receptor 2

AlthoughMycobacterium abscessus(M. abscessus) is becoming more prevalent in patients without overt immunodeficiency, little is known about the factors that contribute to disease susceptibility. This study was undertaken to investigate how Toll-like receptor 2 (TLR2) functionally contributes to the generation of protective immunity againstM. abscessusin a morphotype-specific manner. We found thatTlr2−/−mice were extremely susceptible to an intravenous (i.v.) model of infection byM. abscessusrough variants, displaying uncontrolled infection in the lungs and a significantly lower survival rate than with wild-type (WT) mice. This uncontrolled infection resulted from failures in the following processes: (i) production of the crucial cytokines gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin 12p70 (IL-12p70); (ii) early infiltration of neutrophils, monocytes, and dendritic cells (DCs) in the lungs ofTlr2−/−mice; (iii) rapid influx of CD4+and CD8+T cells; and (iv) the expansion of memory/effector T cells. Notably, systemic administration ofM. abscessusculture filtrate-treated syngeneic DCs from WT mice greatly strengthened immune primingin vivo, resulting in a dramatic reduction in bacterial growth and improved long-term survival inTlr2−/−mice, with a recovery of protective immunity. Our findings demonstrate that TLR2 is an essential contributor to instructive and effector immunity duringM. abscessusinfection in a morphotype-specific manner.

scholarly journals Microbial Amyloids Induce Interleukin 17A (IL-17A) and IL-22 Responses via Toll-Like Receptor 2 Activation in the Intestinal Mucosa

2012 ◽  
Vol 80 (12) ◽  
pp. 4398-4408 ◽  
Author(s):  
Jessalyn H. Nishimori ◽  
Tiffanny N. Newman ◽  
Gertrude O. Oppong ◽  
Glenn J. Rapsinski ◽  
Jui-Hung Yen ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Intestinal Mucosa ◽  
Amyloid Fibrils ◽  
Inflammatory Responses ◽  
Toll Like Receptor ◽  
T Helper ◽  
Content Type ◽  
Interleukin 17A ◽  
Toll Like Receptor 2

ABSTRACTThe Toll-like receptor 2 (TLR2)/TLR1 receptor complex responds to amyloid fibrils, a common component of biofilm material produced by members of the phylaFirmicutes,Bacteroidetes, andProteobacteria. To determine whether this TLR2/TLR1 ligand stimulates inflammatory responses when bacteria enter intestinal tissue, we investigated whether expression of curli amyloid fibrils by the invasive enteric pathogenSalmonella entericaserotype Typhimurium contributes to T helper 1 and T helper 17 responses by measuring cytokine production in the mouse colitis model. AcsgBAmutant, deficient in curli production, elicited decreased expression of interleukin 17A (IL-17A) and IL-22 in the cecal mucosa compared to theS. Typhimurium wild type. In TLR2-deficient mice, IL-17A and IL-22 expression was blunted duringS. Typhimurium infection, suggesting that activation of the TLR2 signaling pathway contributes to the expression of these cytokines. T cells incubated with supernatants from bone marrow-derived dendritic cells (BMDCs) treated with curli fibrils released IL-17A in a TLR2-dependent mannerin vitro. Lower levels of IL-6 and IL-23 production were detected in the supernatants of the TLR2-deficient BMDCs treated with curli fibrils. Consistent with this, three distinct T-cell populations—CD4+T helper cells, cytotoxic CD8+T cells, and γδ T cells—produced IL-17A in response to curli fibrils in the intestinal mucosa duringS. Typhimurium infection. Notably, decreased IL-6 expression by the dendritic cells and decreased IL-23 expression by the dendritic cells and macrophages were observed in the cecal mucosa of mice infected with the curli mutant. We conclude that TLR2 recognition of bacterial amyloid fibrils in the intestinal mucosa represents a novel mechanism of immunoregulation, which contributes to the generation of inflammatory responses, including production of IL-17A and IL-22, in response to bacterial entry into the intestinal mucosa.

scholarly journals Platelets Enhance Dendritic Cell Responses againstStaphylococcus aureusthrough CD40-CD40L

2018 ◽  
Vol 86 (9) ◽  
Author(s):  
Sharmeen Nishat ◽  
Leah M. Wuescher ◽  
Randall G. Worth
Keyword(s):  
Staphylococcus Aureus ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Critical Role ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Enhanced Production ◽  
Bacterial Uptake ◽  
Direct Killing

ABSTRACTStaphylococcus aureusis a major human pathogen that can cause mild to severe life-threatening infections in many tissues and organs. Platelets are known to participate in protection againstS. aureusby direct killing and by enhancing the activities of neutrophils and macrophages in clearingS. aureusinfection. Platelets have also been shown to induce monocyte differentiation into dendritic cells and to enhance activation of dendritic cells. Therefore, in the present study, we explored the role of platelets in enhancing bone marrow-derived dendritic cell (BMDC) function againstS. aureus. We observed a significant increase in dendritic cell phagocytosis and intracellular killing of a methicillin-resistantStaphylococcus aureus(MRSA) strain (USA300) by thrombin-activated platelets or their releasates. Enhancement of bacterial uptake and killing by DCs is mediated by platelet-derived CD40L. Coculture of USA300 and BMDCs in the presence of thrombin-activated platelet releasates invokes upregulation of the maturation marker CD80 on DCs and enhanced production of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin 12 (IL-12), and IL-6. Overall, these observations support our hypothesis that platelets play a critical role in the host defense againstS. aureusinfection. Platelets stimulate DCs, leading to direct killing ofS. aureusand enhanced DC maturation, potentially leading to adaptive immune responses againstS. aureus.

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