Hooven Laboratory Receives First NIH R01 Grant for Research into Group B Streptococcus Infections in Newborns

UPMC Newborn Medicine Program researcher Thomas Hooven, MD, was awarded his first National Institutes of Health (NIH) R01 grant in May 2024 for his research into the molecular interactions of Group B Streptococcus (GBS) infections in pregnancy and neonates and the search for potential therapeutic targets common to all GBS strains for which a vaccine could be developed. Dr. Hooven is an assistant professor of Pediatrics in the Division of Newborn Medicine at the University of Pittsburgh School of Medicine, and he also is an R.K. Mellon Institute Research Scholar at UPMC Children’s Hospital of Pittsburgh.

About the Hooven Laboratory

The Hooven Laboratory researches the pathogenesis of neonatal bacterial infections, particularly those caused by GBS. Dr. Hooven’s research aims are to understand how GBS interacts with the host during the initial colonization of the newborn intestine, the mechanisms of bacterial invasion and systemic spread, and the host's immune responses. The lab investigates the molecular interactions between GBS and neonatal tissues by employing advanced genetic tools, such as CRISPR/Cas, single-cell RNA sequencing, high throughput analytic techniques, and various tissue model systems. Dr. Hooven’s primary research goal is to uncover potential targets for developing vaccines or therapies to prevent severe bacterial infections in newborns.

The Problematic Nature of GBS for Neonates

GBS is a bacterial infection that poses a significant threat to newborns globally. Indeed, GBS infections during pregnancy are a leading cause of preterm labor and stillbirth in the world and the dominant infectious cause of neonatal morbidity. GBS causes approximately 400,000 infections every year and exacts a heavy toll of around 90,000 deaths worldwide.

GBS primarily causes infection during the perinatal period, which includes pregnancy and the early neonatal period – one to two weeks after birth. GBS preferentially targets fetuses, pregnant women, and newborns for as yet unknown reasons.

GBS infection in neonates can progress rapidly and lead to severe illness. GBS can colonize a neonate’s intestines, either during the birth process in which it is passed from mother to baby or after birth through any number of transmission routes. Not all babies will be colonized by GBS, but those born to mothers who are colonized with GBS in their intestines or reproductive tract have a higher risk of infection; hence, the current standard testing for colonization in pregnant women and those with a positive result, prophylactic antibiotic regimens. In a subset of babies colonized with GBS, the bacteria can invade the intestinal lining and enter the bloodstream. This invasion allows GBS to spread rapidly throughout the body and potentially cause systemic infection or lead to sepsis. GBS can also invade the central nervous system, causing meningitis or encephalitis.

“It’s a troubling pathogen,” says Dr. Hooven. “GBS is a commensal bacterium. About 30% of the adult population is colonized with it in the gut or reproductive tract, but it typically does no harm except in mothers, fetuses, and neonates. When it does hit, it hits fast and hard, and we don't yet know why it's only a problem during pregnancy and the neonatal period. What is it about the pregnancy and neonatal periods that create this vulnerability? It’s the big unknown question right now.”

Likely Origins of GBS Infections in Neonates

As Dr. Hooven explains, virulent GBS infections during pregnancy and in neonates are relatively new occurrences. They were first noticed in the United States in the 1950s and 1960s and subsequently spread around the world. It is believed that the emergence of GBS is attributable to the early use of tetracycline antibiotics during and after World War II, with the bacteria ultimately making the jump to humans and unleashing serious infections in babies.

“For a bacterium, it's a relatively recent emergence and one of the reasons we still have a lot to learn about how this organism and its various strains can preferentially target pregnant women and neonates,” says Dr. Hooven.

Grant Details and Research Aims

Given the limited window of vulnerability for GBS infections, infection prevention is paramount. As Dr. Hooven explains, vaccination could potentially block or prevent GBS from causing infection.

"However, to do that, we have to find a target that disrupts one or several key processes the bacteria use to persist and propagate,” says Dr. Hooven.

To develop an effective vaccine against GBS, researchers need to understand the molecular interactions between the bacterium and the human body during pregnancy and the neonatal period. Dr. Hooven’s research focuses on identifying the external proteins of GBS that are shared among different strains. These proteins could serve as potential targets for interfering with the infection process. By blocking specific molecular interactions that allow GBS to attack and harm pregnant women and newborns, a vaccine may be able to prevent the onset of GBS-related complications.

The Role of Surface Proteins

Surface proteins play an essential role in GBS infections. Dr. Hooven and his colleagues have developed innovative techniques, including using CRISPR Cas9, to modify the expression of surface protein genes in GBS. This breakthrough technology allows for a systematic evaluation of dozens of surface protein genes, enabling his team to identify potential key proteins that may be essential for driving GBS's pathogenicity.

“For this project, we are interrogating a collection of 70 different surface proteins that we have identified as potentially crucial for how GBS can set up shop in the neonatal intestinal tract,” says Dr. Hooven. “The proteins we are looking at are all highly conserved from an evolutionary standpoint. The goal is to systematically understand the functional role of each protein and its interaction with human tissues to try and locate ones we can interfere with from a disruption standpoint.”

A Collaborative Research Effort

For this research project, Dr. Hooven is collaborating with Tara Radis, MD, MS, the chief of Neonatology at the University of South Florida.

"Dr. Randis's specialty is in modeling the intestinal interactions between GBS and the intestinal epithelium, devising ways to understand the molecular biology at play," says Dr. Hooven. "We have developed a valuable partnership and synergistic approach that hasn't existed before in the study of GBS infection. Our approach will bridge the gap between basic research and clinical applications, ultimately leading to improved prevention and treatment strategies.”

Dr. Hooven’s research holds great promise in advancing the understanding of GBS infections and developing effective preventive measures for vulnerable neonates and pregnant women.

“With continued research and collaboration, we can work toward a future where GBS-related complications are significantly reduced or even eradicated worldwide,” says Dr. Hooven.

Grant Reference

Group B Streptococcus Surface Determinants of Neonatal Intestinal Colonization and Infection.

NIH Project Number: R01AI182835. PI: Thomas Hooven, MD.

Further Reading

Learn more about Dr. Hooven and the Hooven Laboratory. Also read previously published research by Dr. Hooven’s lab on GBS, including his study published in Communications Biology in 2023 titled “Group B Streptococcus Cas9 Variants Provide Insight into Programmable Gene Expression and CRISPR-Cas Transcriptional Effects.”