Enterococcus faecalis Inhibits Superantigen Toxic Shock Syndrome Toxin-1-Induced Interleukin-8 from Human Vaginal Epithelial Cells through Tetramic Acids

Abstract

The vaginal mucosa can be colonized by many bacteria including commensal organisms and potential pathogens, such as Staphylococcus aureus. Some strains of S. aureus produce the superantigen toxic shock syndrome toxin-1, which can penetrate the vaginal epithelium to cause toxic shock syndrome. We have observed that a female was mono-colonized with Enterococcus faecalis vaginally as tested in aerobic culture, even upon repeated culture for six months, suggesting this organism was negatively influencing colonization by other bacteria. In recent studies, we demonstrated an “outside-in” mechanism of cytokine signaling and consequent inflammation that facilitates the ability of potential pathogens to initiate infection from mucosal surfaces. Thus, we hypothesized that this strain of E. faecalis may make anti-inflammatory factors which block disease progression of more pathogenic organisms. E. faecalis MN1 inhibited interleukin-8 production from human vaginal epithelial cells in response to the vaginal pathogens Candida albicans, Gardnerella vaginalis, and Neisseria gonorrhoeae, as well as to toxic shock syndrome toxin-1. We further demonstrated that this organism secretes two tetramic acid compounds which appear responsible for inhibition of interleukin-8 production, as well as inhibition of T cell proliferation due to toxic shock syndrome toxin-1. Microbicides that include anti-inflammatory molecules, such as these tetramic acid compounds naturally produced by E. faecalis MN1, may be useful in prevention of diseases that develop from vaginal infections.

Enterococcus faecalisAHG0090 is a genetically tractable bacterium and produces a secreted peptidic bioactive that suppresses NF-kB activation in human gut epithelial cells

“…The early microbial colonisers of the gut help establish a homeostatic relationship between the host and its microbiota (Battersby and Gibbons, 2013;Fulde and Hornef, 2014). E. faecalis comprises part of the vaginal (Brosnahan et al, 2013;Nami et al, 2014) and breastmilk (Jimenez et al, 2008;Albesharat et al, 2011;Kozak et al, 2015) microbiota, and is widely shared between mothers and their infants. It is increasingly recognised that early life events (e.g.…”

“…The E. faecalis AHG0090 genome sequence allowed us to readily predict “known” functionalities. Both commensal and pathogenic strains of E. faecalis have previously been shown to produce NF-КB suppressive factors (Brosnahan et al, 2013;Zou et al, 2014). E. faecalis V583 encodes a TIR domain containing protein, TcpF, that suppresses NF-КB by interfering with MyD88 signalling (Zou et al, 2014).…”

“…E. faecalis PC1.1 (Ó Cuív et al, 2013), E. faecalis 62 (Brede et al, 2011)). Separately, the human vaginal isolate E. faecalis MN1 produces an NF-КB suppressive tetramic acid termed reutericyclin (Brosnahan et al, 2013). The reutericyclin regulon has been described in Lactobacillus reuteri and includes a non-ribosomal peptide synthetase (NRPS) and polyketide synthetase (PKS) enzymes that function in its biosynthesis (Lin et al, 2015).…”

“…Select E. faecalis infant derived strains also possess immunomodulatory capacities (Wang et al, 2008) and exert anti-inflammatory activities by modulating the nuclear factors kappa B (NF-КB), mitogen activated protein kinase and peroxisome proliferator-activated receptor-γ1 regulated pathways (Are et al, 2008;Wang et al, 2014). Some of the immunomodulatory factors produced by E. faecalis have been identified (Brosnahan et al, 2013;Zou et al, 2014;Im et al, 2015) however the extent of immunomodulatory capacities amongst non-pathogenic gut strains, and the identity of the bioactives that underpin them, remains largely unknown.…”

Enterococcus faecalis AHG0090 is a Genetically Tractable Bacterium and Produces a Secreted Peptidic Bioactive that Suppresses Nuclear Factor Kappa B Activation in Human Gut Epithelial Cells

“…Select E. faecalis infant derived strains also possess immunomodulatory capacities ( 9 ) and exert anti-inflammatory activities by modulating the nuclear factor kappa B (NF-κB), mitogen-activated protein kinase and peroxisome proliferator-activated receptor-γ1 regulated pathways ( 10 , 11 ). Some of the immunomodulatory factors produced by E. faecalis have been identified ( 12 – 14 ); however, the extent of immunomodulatory capacities among non-pathogenic gut strains, and the identity of the bioactives that underpin them, remains largely unknown.…”