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

A streptococcal lipid toxin induces membrane permeabilization and pyroptosis leading to fetal injury
Published: 
Mar 2015
Publisher: 
EMBO Mol Med. 2015 Mar 6;7(4):488-505. doi: 10.15252/emmm.201404883.
Author: 
Lakshmi Rajagopal, Ph.D.

Whidbey C1, Vornhagen J1, Gendrin C2, Boldenow E2, Samson JM3, Doering K3, Ngo L2, Ezekwe EA Jr4, Gundlach JH3, Elovitz MA5, Liggitt D6, Duncan JA4, Adams Waldorf KM7, Rajagopal L8.

Author information

  • 1Department 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.
  • 2Department of Pediatric Infectious Diseases, University of Washington and Seattle Children's Research Institute, Seattle, WA, USA.
  • 3Department of Physics, University of Washington, Seattle, WA, USA.
  • 4Department 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.
  • 5Maternal 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.
  • 6Department of Comparative Medicine, School of Medicine University of Washington, Seattle, WA, USA.
  • 7Department of Obstetrics and Gynecology, School of Medicine University of Washington, Seattle, WA, USA.
  • 8Department 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.

Abstract

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.

© 2015 The Authors. Published under the terms of the CC BY 4.0 license.

KEYWORDS:

Group B streptococcus; cell death; hemolytic pigment; inflammasome; preterm birth

PMID: 25750210