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In this study, we investigated the impact of the cell membrane composition of  E .  faecalis  on its recognition by the host immune system. To this end, we employed an  E .  faecalis  deletion mutant (Δ bgsA ) that does not synthesize the major cell membrane glycolipid diglycosyl-diacylglycerol (DGlcDAG). Proteomic analysis revealed that 13 of a total of 21 upregulated surface-associated proteins of  E .  faecalis  Δ bgsA  were lipoproteins. This led to a total lipoprotein content in the cell membrane of 35.8% in Δ bgsA  compared to only 9.4% in wild-type bacteria. Increased lipoprotein content strongly affected the recognition of Δ bgsA  by mouse macrophages in vitro with an increased stimulation of TNF-α production by heat-fixed bacteria and secreted antigens. Inactivation of the prolipoprotein diacylglycerol transferase ( lgt ) in Δ bgsA  abrogated TNF-α induction by a Δ bgsA_lgt  double mutant indicating that lipoproteins mediate increased activation of mouse macrophages by Δ bgsA . Heat-fixed Δ bgsA  bacteria, culture supernatant, or cell membrane lipid extract activated transfected HEK cells in a TLR2-dependent fashion; the same was not true of wild-type bacteria. In mice infected intraperitoneally with a sublethal dose of  E .  faecalis  we observed a 70% greater mortality in mice infected with Δ bgsA  compared with wild-type-infected mice. Increased mortality due to Δ bgsA  infection was associated with elevated plasma levels of the inflammatory cytokines TNF-α, IL-6 and MIP-2. In summary, our results provide evidence that an  E .  faecalis  mutant lacking its major bilayer forming glycolipid DGlcDAG upregulates lipoprotein expression leading to increased activation of the host innate immune system and virulence in vivo.

Enterococcus faecalis Glycolipids Modulate Lipoprotein-Content of the Bacterial Cell Membrane and Host Immune Response