Dataset Information

Lugdunin amplifies innate immune responses in the skin in synergy with host- and microbiota-derived factors.

ABSTRACT: Recently our groups discovered lugdunin, a new cyclic peptide antibiotic that inhibits Staphylococcus aureus epithelial colonization in humans and rodents. In this work, we analyzed its immuno-modulatory and antimicrobial potential as a single agent or in combination with other microbiota- or host-derived factors. We show that pretreatment of primary human keratinocytes or mouse skin with lugdunin in combination with microbiota-derived factors results in a significant reduction of S. aureus colonization. Moreover, lugdunin increases expression and release of LL-37 and CXCL8/MIP-2 in human keratinocytes and mouse skin, and results in the recruitment of monocytes and neutrophils in vivo, both by a TLR/MyD88-dependent mechanism. Interestingly, S. aureus elimination by lugdunin is additionally achieved by synergistic antimicrobial activity with LL-37 and dermcidin-derived peptides. In summary, our results indicate that lugdunin provides multi-level protection against S. aureus and may thus become a promising treatment option for S. aureus skin infections in the future.

SUBMITTER: Bitschar K

PROVIDER: S-EPMC6588697 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Lugdunin amplifies innate immune responses in the skin in synergy with host- and microbiota-derived factors.

Bitschar Katharina K Sauer Birgit B Focken Jule J Dehmer Hanna H Moos Sonja S Konnerth Martin M Schilling Nadine A NA Grond Stephanie S Kalbacher Hubert H Kurschus Florian C FC Götz Friedrich F Krismer Bernhard B Peschel Andreas A Schittek Birgit B

Nature communications 20190621 1

Recently our groups discovered lugdunin, a new cyclic peptide antibiotic that inhibits Staphylococcus aureus epithelial colonization in humans and rodents. In this work, we analyzed its immuno-modulatory and antimicrobial potential as a single agent or in combination with other microbiota- or host-derived factors. We show that pretreatment of primary human keratinocytes or mouse skin with lugdunin in combination with microbiota-derived factors results in a significant reduction of S. aureus colo ...[more]

PMID: 31227691

Similar Datasets

Project description:Prevalence of the members of herpesvirus family in oral inflammatory diseases is increasingly acknowledged suggesting their likely role as an etiological factor. However, the underlying mechanisms remain obscure. In our recent miRNA profiling of healthy and diseased human tooth pulps, elevated expression of human herpesvirus encoded viral microRNAs (v-miRs) were identified. Based on the fold induction and significance values, we selected three v-miRs namely miR-K12-3-3p [Kaposi sarcoma-associated virus (KSHV)], miR-H1 [herpes simplex virus 1 (HSV1)], and miR-UL-70-3p [human cytomegalovirus (HCMV)] to further examine their impact on host cellular functions. We examined their impact on cellular miRNA profiles of primary human oral keratinocytes (HOK). Our results show differential expression of several host miRNAs in v-miR-transfected HOK. High levels of v-miRs were detected in exosomes derived from v-miR transfected HOK as well as the KSHV-infected cell lines. We show that HOK-derived exosomes release their contents into macrophages (M?) and alter expression of endogenous miRNAs. Concurrent expression analysis of precursor (pre)-miRNA and mature miRNA suggest transcriptional or posttranscriptional impact of v-miRs on the cellular miRNAs. Employing bioinformatics, we predicted several pathways targeted by deregulated cellular miRNAs that include cytoskeletal organization, endocytosis, and cellular signaling. We validated three novel targets of miR-K12-3-3p and miR-H1 that are involved in endocytic and intracellular trafficking pathways. To evaluate the functional consequence of this regulation, we performed phagocytic uptake of labeled bacteria and noticed significant attenuation in miR-H1 and miR-K12-3-3p but not miR-UL70-3p transfected primary human M?. Multiple cytokine analysis of E. coli challenged M? revealed marked reduction of secreted cytokine levels with important roles in innate and adaptive immune responses suggesting a role of v-miRs in immune subversion. Our findings reveal that oral disease associated v-miRs can dysregulate functions of key host cells that shape oral mucosal immunity thus exacerbating disease severity and progression.

Project description:Human enterovirus D68 (EV-D68) has received considerable attention recently as a global reemergent pathogen because it causes severe respiratory tract infections and acute flaccid myelitis (AFM). The nonstructural protein 2A protease (2Apro) of EVs, which functions in the cleavage of host proteins, comprises a pivotal part of the viral immune evasion process. However, the pathogenic mechanism of EV-D68 is not fully understood. In this study, we found that EV-D68 inhibited antiviral type I interferon responses by cleaving tumor necrosis factor receptor-associated factor 3 (TRAF3), which is the key factor for type I interferon production. EV-D68 inhibited Sendai virus (SEV)-induced interferon regulatory factor 3 (IRF3) activation and beta interferon (IFN-β) expression in HeLa and HEK293T cells. Furthermore, we demonstrated that EV-D68 and 2Apro were able to cleave the C-terminal region of TRAF3 in HeLa and HEK293T cells, respectively. A cysteine-to-alanine substitution at amino acid 107 (C107A) in the 2Apro protease resulted in the loss of cleavage activity to TRAF3, and mutation of glycine at amino acid 462 to alanine (G462A) in TRAF3 conferred resistance to 2Apro These results suggest that control of TRAF3 by 2Apro may be a mechanism EV-D68 utilizes to subvert host innate immune responses.IMPORTANCE Human enterovirus 68 (EV-D68) has received considerable attention recently as a global reemergent pathogen because it causes severe respiratory tract infections and acute flaccid myelitis. The nonstructural protein 2A protease (2Apro) of EV, which functions in cleavage of host proteins, comprises an essential part of the viral immune evasion process. However, the pathogenic mechanism of EV-D68 is not fully understood. Here, we show for the first time that EV-D68 inhibited antiviral type I interferon responses by cleaving tumor necrosis factor receptor-associated factor 3 (TRAF3). Furthermore, we identified the key cleavage site in TRAF3. Our study may suggest a new mechanism by which the 2Apro of EV facilitates subversion of host innate immune responses. These findings increase our understanding of EV-D68 infection and may help identify new antiviral targets against EV-D68.

Dataset Information

Lugdunin amplifies innate immune responses in the skin in synergy with host- and microbiota-derived factors.

Publications

Lugdunin amplifies innate immune responses in the skin in synergy with host- and microbiota-derived factors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets