Pathogen and host-derived lipid membranes governing Staphylococcus aureus-mediated skin inflammation
Final Report Abstract
The bacterial pathogen Staphylococcus aureus is a frequent cause of skin inflammation in atopic dermatitis (AD) patients. It activates live keratinocytes by releasing bacterial lipoproteins, potent agonists of the Toll-like receptor (TLR) 2. We found that lipoproteins can only be efficiently released by S. aureus with the help of surfactant-like phenol-soluble modulin (PSM) peptides, which mobilize the hydrophobic lipoproteins. We show that PSMs promote the release of membrane vesicles (MVs) containing the membrane-embedded lipoproteins from S. aureus. PSMs promote the release of MV-embedded lipoproteins in S. aureus via an increase in membrane fluidity and the bacterial turgor is the driving force for MV release. The MV-embedded lipoproteins activate TLR2 by a mechanism which involves vesicle disruption by surfactant-like molecules such as PSMs. This releases the lipoproteins from the MVs and enables binding to TLR2 and induction of inflammation. Furthermore, we show that S. aureus releases MVs also in its natural environment on human skin and that MVs from S. aureus strains from the skin of AD patients have an enhanced proinflammatory potential, partially due to an enhanced lipid content. S. aureus MVs induce proinflammatory cytokines in human keratinocytes in a TLR2-and NFkB-dependent manner. We showed that not only PSMs, but also bacterial and host-derived antimicrobial peptides (AMPs) destroy MV integrity, releases lipoproteins and activates TLRs signaling. Furthermore, our data suggest that the contact of healthy and AD human skin with MVs of S. aureus induced either an increased release of skinderived membrane vesicles and/or that bacterial MVs can incorporate skin-derived lipids. These data suggest that skin lamellar membranes do not prevent the access of S. aureus MVs and by this activation of live keratinocytes in healthy and AD skin. Interestingly, we showed that MVs can also be released by skin commensals in a similar quantity and membrane lipid amount as those from pathogenic S. aureus. These, MVs can protect human skin from S. aureus skin colonization by reducing skin inflammation and reduction of neutrophil recruitment after S. aureus skin infection. In future work we will analyse how skin lipids and/or MVs can be used to (re)shape host immunity.
Publications
- (2018). The Mechanism behind Bacterial Lipoprotein Release: Phenol-Soluble Modulins Mediate Toll-Like Receptor 2 Activation via Extracellular Vesicle Release from Staphylococcus aureus. mBio 9:e01851-18
Schlatterer K, Beck C, Hanzelmann D, Lebtig M, Fehrenbacher B, Schaller M, Ebner P, Nega M, Otto M, Kretschmer D, Peschel A
(See online at https://doi.org/10.1128/mbio.01851-18) - (2019). Lugdunin amplifies innate immune responses in the skin in synergy with host- and microbiota-derived factors. Nat Commun. 10:2730
Bitschar K, Sauer B, Focken J, Dehmer H, Moos S, Konnerth M, Schilling NA, Grond S, Kalbacher H, Kurschus FC, Götz F, Krismer B, Peschel A, Schittek B
(See online at https://doi.org/10.1038/s41467-019-10646-7) - (2020). Staphylococcus aureus skin colonization is enhanced by the interaction of neutrophil extracellular traps with keratinocytes. J Invest Dermatol. S0022-202X:33474-8
Bitschar K, Staudenmaier L, Klink L, Focken J, Sauer B, Fehrenbacher B, Herster F, Bittner Z, Bleul L, Schaller M, Wolz C, Weber ANR, Peschel A, Schittek B
(See online at https://doi.org/10.1016/j.jid.2019.10.017) - (2022). Bacterial membrane vesicles shape Staphylococcus aureus skin colonization and induction of innate immune responses. Exp Dermatol. 31:349-361
Staudenmaier L, Focken J, Schlatterer K, Kretschmer D, Schittek B
(See online at https://doi.org/10.1111/exd.14478)
