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.
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.
Christopher
C
Whidbey
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.
Jay
J
Vornhagen
Department of Pediatric Infectious Diseases, University of Washington and Seattle Children's Research Institute, Seattle, WA, USA.
Claire
C
Gendrin
Department of Pediatric Infectious Diseases, University of Washington and Seattle Children's Research Institute, Seattle, WA, USA.
Erica
E
Boldenow
Department of Physics, University of Washington, Seattle, WA, USA.
Jenny Mae
JM
Samson
Department of Physics, University of Washington, Seattle, WA, USA.
Kenji
K
Doering
Department of Pediatric Infectious Diseases, University of Washington and Seattle Children's Research Institute, Seattle, WA, USA.
Lisa
L
Ngo
Department of Medicine, Division of Infectious Diseases and Pharmacology, School of Medicine and Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Ejiofor A D
EA
Ezekwe
Department of Physics, University of Washington, Seattle, WA, USA.
Jens H
JH
Gundlach
Maternal and Child Health Research Program, Department of Obstetrics and Gynecology, Center for Research on Reproduction and Women's Health Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA.
Michal A
MA
Elovitz
Department of Comparative Medicine, School of Medicine University of Washington, Seattle, WA, USA.
Denny
D
Liggitt
Department of Medicine, Division of Infectious Diseases and Pharmacology, School of Medicine and Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Joseph A
JA
Duncan
Department of Obstetrics and Gynecology, School of Medicine University of Washington, Seattle, WA, USA.
Kristina M
KM
Adams Waldorf
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 lakshmi.rajagopal@seattlechildrens.org.
Lakshmi
L
Rajagopal
D000818:Animals; D001427:Bacterial Toxins / Q000276:immunology / Q000633:toxicity; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D005260:Female; D005315:Fetal Diseases / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D006801:Humans; D008297:Male; D008563:Membrane Lipids / Q000276:immunology / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D000069292:Pyroptosis / Q000276:immunology*; D013290:Streptococcal Infections / Q000276:immunology / Q000473:pathology; D013292:Streptococcus agalactiae / Q000276:immunology / Q000472:pathogenicity
D001427:Bacterial Toxins; D008563:Membrane Lipids
Group B streptococcus; cell death; hemolytic pigment; inflammasome; preterm birth