A streptococcal lipid toxin induces membrane permeabilization and pyroptosis leading to fetal injury.

Group B streptococci (GBS) are Gram-positive bacteria that cause infections in utero and in newborns. We recently showed that the GBS pigment is hemolytic and increased pigment production promotes bacterial penetration of human placenta. However, mechanisms utilized by the hemolytic pigment to induce host cell lysis and the consequence on fetal injury are not known. Here, we show that the GBS pigment induces membrane permeability in artificial lipid bilayers and host cells. Membrane defects induced by the GBS pigment trigger K(+) efflux leading to osmotic lysis of red blood cells or pyroptosis in human macrophages. Macrophages lacking the NLRP3 inflammasome recovered from pigment-induced cell damage. In a murine model of in utero infection, hyperpigmented GBS strains induced fetal injury in both an NLRP3 inflammasome-dependent and NLRP3 inflammasome-independent manner. 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.

Whidbey C ，Vornhagen J ，Gendrin C ，Boldenow E ，Samson JM ，Doering K ，Ngo L ，Ezekwe EA Jr ，Gundlach JH ，Elovitz MA ，Liggitt D ，Duncan JA ，Adams Waldorf KM ，Rajagopal L ... -  《-》

Prothrombotic and Proinflammatory Activities of the β-Hemolytic Group B Streptococcal Pigment.

A prominent feature of severe streptococcal infections is the profound inflammatory response that contributes to systemic toxicity. In sepsis the dysregulated host response involves both immunological and nonimmunological pathways. Here, we report a fatal case of an immunocompetent healthy female presenting with toxic shock and purpura fulminans caused by group B streptococcus (GBS; serotype III, CC19). The strain (LUMC16) was pigmented and hyperhemolytic. Stimulation of human primary cells with hyperhemolytic LUMC16 and STSS/NF-HH strains and pigment toxin resulted in a release of proinflammatory mediators, including tumor necrosis factor, interleukin (IL)-1β, and IL-6. In addition, LUMC16 induced blood clotting and showed factor XII activity on its surface, which was linked to the presence of the pigment. The expression of pigment was not linked to a mutation within the CovR/S region. In conclusion, our study shows that the hemolytic lipid toxin contributes to the ability of GBS to cause systemic hyperinflammation and interferes with the coagulation system.

Siemens N ，Oehmcke-Hecht S ，Hoßmann J ，Skorka SB ，Nijhuis RHT ，Ruppen C ，Skrede S ，Rohde M ，Schultz D ，Lalk M ，Itzek A ，Pieper DH ，van den Bout CJ ，Claas ECJ ，Kuijper EJ ，Mauritz R ，Sendi P ，Wunderink HF ，Norrby-Teglund A ... -  《-》

A hemolytic pigment of Group B Streptococcus allows bacterial penetration of human placenta.

Whidbey C ，Harrell MI ，Burnside K ，Ngo L ，Becraft AK ，Iyer LM ，Aravind L ，Hitti J ，Adams Waldorf KM ，Rajagopal L ... -  《-》

Mast cell degranulation by a hemolytic lipid toxin decreases GBS colonization and infection.

Gendrin C ，Vornhagen J ，Ngo L ，Whidbey C ，Boldenow E ，Santana-Ufret V ，Clauson M ，Burnside K ，Galloway DP ，Adams Waldorf KM ，Piliponsky AM ，Rajagopal L ... -  《Science Advances》

Hemolytic Membrane Vesicles of Group B Streptococcus Promote Infection.

Group B streptococci (GBS) are β-hemolytic, Gram-positive bacteria associated with fetal injury, preterm birth, spontaneous abortion, and neonatal infections. A key factor promoting GBS virulence is the β-hemolysin/cytolysin, a pigmented ornithine rhamnolipid (also known as granadaene) associated with the bacterial surface. A previous study indicated that GBS produce small structures known as membrane vesicles (MVs), which contain virulence-associated proteins. In this study, we show that GBS MVs are pigmented and hemolytic, indicating that granadaene is functionally active in MVs. In addition, MVs from hyperhemolytic GBS induced greater cell death of neutrophils, T cells, and B cells compared with MVs from isogenic nonhemolytic GBS, implicating MVs as a potential mechanism for granadaene-mediated virulence. Finally, hemolytic MVs reduced oxidative killing of GBS and aggravated morbidity and mortality of neonatal mice infected with GBS. These studies, taken together, reveal a novel mechanism by which GBS deploy a crucial virulence factor to promote bacterial dissemination and pathogenesis.

Armistead B ，Quach P ，Snyder JM ，Santana-Ufret V ，Furuta A ，Brokaw A ，Rajagopal L ... -  《-》