Bacterial membrane vesicles shape <i>Staphylococcus aureus</i> skin colonization and induction of innate immune responses

Staudenmaier, Lena; Focken, Jule; Schlatterer, Katja; Kretschmer, Dorothee; Schittek, Birgit

doi:10.1111/exd.14478

Cited by 11 publications

(22 citation statements)

References 48 publications

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“…The ability of coagulasenegative strains, such as S. epidermidis, to induce NETs has remained a matter of debate. 39,45,46 In parallel to our in vitro findings, S. aureus USA300, Newman, and the clinical strain induced dense areas of NETs and NETreleasing neutrophils in mice with IE.…”

Section: Discussionsupporting

confidence: 84%

Neutrophils Protect Against Staphylococcus aureus Endocarditis Progression Independent of Extracellular Trap Release

Meyers

Lox

Kraisin

et al. 2023

ATVB

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Background: Infective endocarditis (IE) is characterized by an infected thrombus at the heart valves. How bacteria bypass the immune system and cause these thrombi remains unclear. Neutrophils releasing NETs (neutrophil extracellular traps) lie at this interface between host defense and coagulation. We aimed to determine the role of NETs in IE immunothrombosis. Methods: We used a murine model of Staphylococcus aureus endocarditis in which IE is provoked on inflamed heart valves and characterized IE thrombus content by immunostaining identifying NETs. Antibody-mediated neutrophil depletion and neutrophil-selective PAD4 (peptidylarginine deiminase 4)-knockout mice were used to clarify the role of neutrophils and NETs, respectively. S. aureus mutants deficient in key virulence factors related to immunothrombosis (nucleases or staphylocoagulases) were investigated. Results: Neutrophils releasing NETs were present in infected thrombi and within cellular infiltrates in the surrounding vasculature. Neutrophil depletion increased occurrence of IE, whereas neutrophil-selective impairment of NET formation did not alter IE occurrence. Absence of S. aureus nuclease, which degrades NETs, did not affect endocarditis outcome. In contrast, absence of staphylocoagulases (coagulase and von Willebrand factor binding protein) led to improved survival, decreased bacteremia, smaller infiltrates, and decreased tissue destruction. Significantly more NETs were present in these vegetations, which correlated with decreased bacteria and cell death in the adjacent vascular wall. Conclusions: Neutrophils protect against IE independent of NET release. Absence of S. aureus coagulases, but not nucleases, reduced IE severity and increased NET levels. Staphylocoagulase-induced fibrin likely hampers NETs from constraining infection and the resultant tissue damage, a hallmark of valve destruction in IE.

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Section: Discussionsupporting

confidence: 84%

Neutrophils Protect Against Staphylococcus aureus Endocarditis Progression Independent of Extracellular Trap Release

Meyers

Lox

Kraisin

et al. 2023

ATVB

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“…In order to elucidate whether FPR ligands can also activate keratinocytes, we stimulated PHK and N/TERT-1 with synthetic FPR1 and FPR2 ligands and included the TLR2 ligand Pam2Cys (P2C) as a positive control. It is well documented that staphylococci release TLR2 ligands ( 20 ) and TLR2 activation in keratinocytes leads to IL-8 release ( 21 ). We assessed whether FPR activation by the FPR1 ligand fMLF, the staphylococcal FPR2 ligand phenol-soluble modulin α3 (PSMα3), or the synthetic FPR2 ligand MMK1 can trigger the release of proinflammatory cytokines by differentiated PHK.…”

Section: Resultsmentioning

confidence: 99%

Keratinocytes use FPR2 to detect Staphylococcus aureus and initiate antimicrobial skin defense

et al. 2023

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IntroductionKeratinocytes form a multilayer barrier that protects the skin from invaders or injuries. The barrier function of keratinocytes is in part mediated by the production of inflammatory modulators that promote immune responses and wound healing. Skin commensals and pathogens such as Staphylococcus aureus secrete high amounts of phenol-soluble modulin (PSM) peptides, agonists of formyl-peptide receptor 2 (FPR2). FPR2 is crucial for the recruitment of neutrophils to the sites of infection, and it can influence inflammation. FPR1 and FPR2 are also expressed by keratinocytes but the consequences of FPR activation in skin cells have remained unknown.MethodsSince an inflammatory environment influences S. aureus colonization, e. g. in patients with atopic dermatitis (AD), we hypothesized that interference with FPRs may alter keratinocyte-induced inflammation, proliferation, and bacterial colonization of the skin. To assess this hypothesis, we investigated the effects of FPR activation and inhibition in keratinocytes with respect to chemokine and cytokine release as well as proliferation and skin wound gap closure.ResultsWe observed that FPR activation induces the release of IL-8, IL-1α and promotes keratinocyte proliferation in a FPR-dependent manner. To elucidate the consequence of FPR modulation on skin colonization, we used an AD-simulating S. aureus skin colonization mouse model using wild-type (WT) or Fpr2-/- mice and demonstrate that inflammation enhances the eradication of S. aureus from the skin in a FPR2-dependent way. Consistently, inhibition of FPR2 in the mouse model or in human keratinocytes as well as human skin explants promoted S. aureus colonization.DiscussionOur data indicate that FPR2 ligands promote inflammation and keratinocyte proliferation in a FPR2-dependent manner, which is necessary for eliminating S. aureus during skin colonization.

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“…Additionally, skin commensal‐derived bEVs can protect against pathogenic colonization with S. aureus and subsequent inflammation. In contrast, S. aureus ‐derived bEVs induce a proinflammatory response in human keratinocytes in a TLR2‐ and NFkB‐dependent manner, by this means recruiting neutrophils, and inducing neutrophil extracellular trap formation, all of which enhance skin colonization with S. aureus [11]. S. aureus ‐derived bEVs in patients with atopic dermatitis differ between lesional and nonlesional skin, especially in their membrane lipid and protein A content [11], indicating the immunoregulatory potential of bEVs in this context.…”

Section: Role Of Evs In Innate Immunitymentioning

confidence: 99%

Extracellular vesicles: Messengers of allergic immune responses and novel therapeutic strategy

Möbs,

Jung

2024

Eur J Immunol

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Extracellular vesicles (EVs) are nanosized particles released by nearly every cell type across all kingdoms of life. As a result, EVs are ubiquitously present in various human body fluids. Composed of a lipid bilayer, EVs encapsulate proteins, nucleic acids, and metabolites, thus playing a crucial role in immunity, for example, by enabling intercellular communication. More recently, there has been increasing evidence that EVs can also act as key regulators of allergic immune responses. Their ability to facilitate cell‐to‐cell contact and to transport a variety of different biomolecules enables active modulation of both innate and adaptive immune processes associated with allergic reactions. A comprehensive understanding of the intricate mechanisms underlying the interactions among allergens, immune cells, and EVs is imperative to develop innovative strategies for controlling allergic responses. This review highlights the recent roles of host cell‐ and bacteria‐derived EVs in allergic diseases, presenting experimental and clinical evidence that underscores their significance. Additionally, the therapeutic potential of EVs in allergy management is outlined, along with the challenges associated with targeted delivery and cargo stability for clinical use. Optimization of EV composition and targeting strategies holds promise for advancing translational applications and establishing EVs as biomarkers or safe therapeutics for assessing allergic reactions. For these reasons, EVs represent a promising avenue for advancing both our understanding and management of allergic immune processes.

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Bacterial membrane vesicles shape Staphylococcus aureus skin colonization and induction of innate immune responses

Cited by 11 publications

References 48 publications

Neutrophils Protect Against Staphylococcus aureus Endocarditis Progression Independent of Extracellular Trap Release

Neutrophils Protect Against Staphylococcus aureus Endocarditis Progression Independent of Extracellular Trap Release

Keratinocytes use FPR2 to detect Staphylococcus aureus and initiate antimicrobial skin defense

Extracellular vesicles: Messengers of allergic immune responses and novel therapeutic strategy

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