When a team of Vanderbilt scientists in the Division of Allergy, Pulmonary and Critical Care Medicine received a $4.5 million grant to study the role of respiratory syncytial virus (RSV) in asthma development, they had no idea that a global pandemic would not only interfere with and delay their initial project, but also introduce an additional simultaneous study.
The Asthma and Allergic Diseases Cooperative Research Centers (AADCRC) award from the National Institute of Allergy and Infectious Diseases (NIAID) was primarily intended for a collaborative investigation with Emory University into the developmental origins of asthma.
The work functions as a “marriage of two projects, a clinical-translational and a basic science project, to answer questions and understand how an early life virus, RSV, contributes to later asthma development,” said Tina Hartert, MD, MPH, director of the Center for Asthma Research, VUMC’s Vice President for Translational Research, professor of Medicine and Pediatrics, and the Lulu H. Owen Professor of Medicine.
Hartert leads the clinical project, while the basic science project is directed by Stokes Peebles, MD, Elizabeth and John Murray Professor of Medicine, training program director of the Allergy Immunology Fellowship Program, professor of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, and professor of Pathology, Microbiology and Immunology at VUMC.
The clinical project follows 1,950 Middle Tennessee children to determine how genes and the environment interact with RSV infection during the first year of life and contribute to asthma development. However, in the midst of in-person follow-up visits for research participants, the emergence of COVID-19 propelled necessary modifications and a temporary change of course.
In March 2020, NIAID asked Hartert and her team to lead a study on COVID-19 infections in healthy families using already enrolled birth cohorts funded by the NIH. This study, HEROS (Human Epidemiology and Response to SARS-CoV-2), followed families from 12 cities in the U.S. for six months to learn about COVID-19 symptoms and immune responses in children with and without asthma and allergic diseases, and how they differ from those in adults.
The researchers discovered that children were just as commonly infected as adults, but that their infections were typically asymptomatic (75% of the time). On the other hand, adults were only asymptomatic about 25% of the time. Attending in-person school was the most significant risk factor for introducing COVID-19 into a household. Furthermore, they found that asthma and allergies were not risk factors for infection, a reassuring finding for those with these chronic diseases, but that food allergy was associated with a significant decreased risk of infection and household transmission.
Moreover, researchers also discovered that, likely due to the precautions taken against COVID-19, including donning masks and physically distancing, there was a near absence of RSV for almost a year, and an unusual summer peak of RSV infections.
The summer 2021 RSV season “changed the dogma of RSV infections which were thought to circulate only in the winter,” Peebles said.
Despite the challenges that the pandemic presented, the team adapted and persisted, with Hartert reflecting on the breadth of knowledge they gained about conducting research remotely, the remarkable versatility and creativity of her research team, and the VUMC research infrastructure’s ability to pivot.
“The HEROS study was up and enrolling study participants in fewer than six weeks,” Hartert said.
To the extent that the original research study focused on RSV and asthma, they embraced virtual visits and surveys and utilized already collected data and biospecimens to keep their research going. Hartert and Peebles, along with Dawn Newcomb, PhD, professor of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, and professor of Pathology, Microbiology, and Immunology at VUMC; Sergejs Berdnikovs, PhD, at Northwestern University Feinberg School of Medicine, and Chris McKennan, PhD, at the University of Pittsburgh, continued to make significant progress and discoveries.
The researchers found that RSV infection alters the metabolism of developing airway cells by driving epithelial cells to use different energy sources, resulting in altered barrier function, which predisposes these patients to sensitization to allergens characteristic of allergic asthma. That means that their work has revealed that metabolism of airway cells significantly differs between those with and without asthma.
While COVID-19 compelled Hartert and Peebles to play catch-up, they are once again back in full swing of their initial focus, with the investigation running until 2026. The team is studying airway epithelial cells from children who were and were not infected with RSV. The goal is to identify cell signatures that make infants more susceptible to the long-term effects caused by RSV and more likely to develop asthma later in childhood.
Additionally, they will be investigating the epigenetic changes that result from RSV infection, and how they contribute to the abnormal airway changes that characterize asthma.
This endeavor is driven by the team’s prior work suggesting that early life RSV infection may have long-term respiratory health effects. If the association between infant RSV infection and asthma is causal, prevention or delay in RSV infection could reduce the burden of both acute illness and chronic wheezing illness. These conclusions would lend support to RSV delay or prevention strategies as efficacious choices and public health priorities with both short- and long-term impact. These potential advancements ultimately embody the goal of the team’s work, which is to prevent asthma and allergic disease development.