title: Bacterial Hyaluronidase Promotes Ascending GBS Infection and Preterm Birth.
abstract: Preterm birth increases the risk of adverse birth outcomes and is the leading cause of neonatal mortality. A significant cause of preterm birth is in utero infection with vaginal microorganisms. These vaginal microorganisms are often recovered from the amniotic fluid of preterm birth cases. A vaginal microorganism frequently associated with preterm birth is group B streptococcus (GBS), or Streptococcus agalactiae However, the molecular mechanisms underlying GBS ascension are poorly understood. Here, we describe the role of the GBS hyaluronidase in ascending infection and preterm birth. We show that clinical GBS strains associated with preterm labor or neonatal infections have increased hyaluronidase activity compared to commensal strains obtained from rectovaginal swabs of healthy women. Using a murine model of ascending infection, we show that hyaluronidase activity was associated with increased ascending GBS infection, preterm birth, and fetal demise. Interestingly, hyaluronidase activity reduced uterine inflammation but did not impact placental or fetal inflammation. Our study shows that hyaluronidase activity enables GBS to subvert uterine immune responses, leading to increased rates of ascending infection and preterm birth. These findings have important implications for the development of therapies to prevent in utero infection and preterm birth.
  
  
  
  GBS are a family of bacteria that frequently colonize the vagina of pregnant women. In some cases, GBS ascend from the vagina into the uterine space, leading to fetal injury and preterm birth. Unfortunately, little is known about the mechanisms underlying ascending GBS infection. In this study, we show that a GBS virulence factor, HylB, shows higher activity in strains isolated from cases of preterm birth than those isolates from rectovaginal swabs of healthy women. We discovered that GBS rely on HylB to avoid immune detection in uterine tissue, but not placental tissue, which leads to increased rates of fetal injury and preterm birth. These studies provide novel insight into the underlying mechanisms of ascending infection.
authors.affiliation: Department of Global Health, University of Washington, Seattle, Washington, USA Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Vornhagen
authors.affiliation: Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Phoenicia
authors.initials: P
authors.lastname: Quach
authors.affiliation: Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Boldenow
authors.affiliation: Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Merillat
authors.affiliation: Department of Global Health, University of Washington, Seattle, Washington, USA Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Whidbey
authors.affiliation: Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Lisa Y
authors.initials: LY
authors.lastname: Ngo
authors.affiliation: Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Adams Waldorf
authors.affiliation: Department of Global Health, University of Washington, Seattle, Washington, USA Seattle Children's Research Institute, Seattle, Washington, USA Department of Pediatric Infectious Diseases, University of Washington, Seattle, Washington, USA lakshmi.rajagopal@seattlechildrens.org.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Rajagopal
mesh_terms: D000653:Amniotic Fluid / Q000382:microbiology; D005260:Female; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000378:metabolism*; D007231:Infant, Newborn; D007249:Inflammation; D010920:Placenta / Q000276:immunology / Q000382:microbiology; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000382:microbiology*; D047928:Premature Birth / Q000382:microbiology*; D060737:Reproductive Tract Infections / Q000150:complications / Q000382:microbiology*; D013290:Streptococcal Infections / Q000097:blood / Q000150:complications* / Q000276:immunology / Q000382:microbiology*; D013292:Streptococcus agalactiae / Q000201:enzymology* / Q000276:immunology / Q000302:isolation & purification; D014599:Uterus / Q000276:immunology / Q000382:microbiology; D014621:Vagina / Q000382:microbiology; D037521:Virulence Factors
chemical_list: D037521:Virulence Factors; D006821:Hyaluronoglucosaminidase