A streptococcal lipid toxin induces membrane permeabilization and pyroptosis leading to fetal injury.
Bottom Line: Here, we show that the GBS pigment induces membrane permeability in artificial lipid bilayers and host cells.Macrophages lacking the NLRP3 inflammasome recovered from pigment-induced cell damage.These results demonstrate that the dual mechanism of action of the bacterial pigment/lipid toxin leading to hemolysis or pyroptosis exacerbates fetal injury and suggest that preventing both activities of the hemolytic lipid is likely critical to reduce GBS fetal injury and preterm birth.
Affiliation: Department of Pediatric Infectious Diseases, University of Washington and Seattle Children's Research Institute, Seattle, WA, USA Department of Global Health, University of Washington, Seattle, WA, USA.Show MeSH
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Mentions: This study demonstrates how the GBS hemolytic pigment/lipid toxin causes cell death, triggers inflammation, and promotes fetal injury. Although the hemolytic nature of GBS was described almost a century ago (Brown, 1920; Rosa-Fraile et al, 2014) and is associated with virulence of the pathogen (Pritzlaff et al, 2001; Doran et al, 2003; Liu et al, 2004; Hensler et al, 2005; Lembo et al, 2010), mechanistic insight into this potent virulence factor was lacking. We recently showed that the molecular basis of hemolytic activity in GBS is the pigment/lipid toxin (Whidbey et al, 2013). In the current study, we utilized artificial lipid bilayers, RBC, and macrophages to understand how a bacterial pigment/lipid toxin disrupts these host cells. The trans-membrane conductance observed in artificial lipid bilayers suggests that the pigment/lipid toxin does not induce the formation of large, multimeric pores (commonly observed with protein toxins) but rather induces membrane permeabilization by forming variably sized membrane defects similar to those previously observed with the cyclic antimicrobial peptide, Gramicidin S (Ashrafuzzaman et al, 2008). The predicted length of the polyene moiety of the GBS pigment is approximately 32 Å (determined using a molecular model generated by the National Cancer Institute's Online SMILES Translator and modeled using PyMol), which is similar to the average thickness of the plasma membrane at 30–40 Å (Schrodinger, 2010). Thus, we predict that insertion of the GBS hemolytic pigment may span the host cell membrane, with the rhamnose and ornithine moieties acting as polar head groups. Insertion of the GBS pigment into RBC membranes triggers membrane disruption leading to colloidal osmotic lysis (see proposed model in Fig8).
Affiliation: Department of Pediatric Infectious Diseases, University of Washington and Seattle Children's Research Institute, Seattle, WA, USA Department of Global Health, University of Washington, Seattle, WA, USA.