Hyaluronidase mediated GBS Disease

Bacterial infections during pregnancy are a major risk factor for preterm birth (PTB), stillbirth, fetal injury and neonatal disease. Currently, there are no preventive measures for pregnancy associated adverse outcomes or neonatal disease due to bacterial infections. Group B Streptococci (GBS) are Gram-positive bacteria that asymptomatically colonize the lower genital tract but can cause PTB, stillbirth, early onset disease (EOD) or late onset disease (LOD) in human newborns. Using pregnant mice and nonhuman primates, we previously showed that hyaluronidase (HylB)-expressing GBS infect the amniotic cavity leading to fetal bacteremia and preterm labor. HylB breaks down host hyaluronan into immunosuppressive disaccharides, which inhibit TLR2 and TLR4 mediated proinflammatory signaling, thereby increasing the severity of GBS infections. In new studies, we show that HylB exacerbates GBS early and late onset neonatal disease. Together, these data identify HylB as a key virulence factor crucial for many facets of GBS disease during pregnancy and in newborns. Here, we will utilize novel ex vivo human organotypic models and in vivo mouse models of GBS EOD and LOD using hyaluronan receptor proficient and deficient mice to elucidate how HylB modulates immune responses for GBS neonatal disease. We will also determine if vaccine strategies targeting HylB can diminish GBS infection mediated preterm births and neonatal disease. These results will have broad relevance for pathogens that utilize hyaluronidase or immune suppression for disease pathogenesis. Project Number: 1R01AI192624-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Lakshmi Rajagopal | Institution: SEATTLE CHILDREN'S HOSPITAL, SEATTLE, WA | Award Amount: $3,613,118 | Activity Code: R01 | Study Section: Bacterial-Host Interactions Study Section [BHI] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI19262401