Knocking Out Respiratory Viruses Before They Cause Damage

Viral pneumonias from influenza, respiratory syncytial virus (RSV), SARS-CoV-2 and other respiratory viruses are a major cause of morbidity and mortality. They can lead to long-term structural damage to the lungs and have systemic effects on the kidneys, heart and other organs. Also, RSV in childhood is associated with the development of asthma, a chronic lung disease.

Researchers at Brigham and Women’s Hospital seek to limit the severe effects of respiratory viruses by using new methods to reduce the viral load and excessive lung inflammation that are common with these lung infections. Bruce D. Levy, MD, chief of the Brigham’s Pulmonary and Critical Care Medicine Division and co-director of the Lung Center, recently published an article with his colleagues in the Airway Inflammation and Resolution Lab on their research in Frontiers in Immunology.

“The COVID-19 pandemic has shown us that respiratory viruses are a serious public health problem,” Dr. Levy says. “Many healthy adults have innate mechanisms that mitigate the severity of viral infection, making the experience akin to a simple cold. However, those mechanisms do not operate as effectively in the very young and the very old, leading them to be predisposed to more serious illness.”

Resolving the RSV Inflammatory Process

The study looked at the role of two specialized pro-resolving mediators (SPMs)—protectin conjugates in tissue regeneration 1 (PCTR1) and protectin D1 (PD1)—to see if they would decrease viral load in mice infected with a clinical strain of RSV. Such SPMs have been shown to drive the resolution of acute inflammatory processes to restore tissue homeostasis after sterile or infectious injury and to enhance bacterial pathogen clearance.

PCTR1 in lung tissue decreases neutrophil migration while increasing macrophage recruitment and efferocytosis. PD1 is present in exhaled breath and decreases T cell migration, promotes T cell apoptosis and reduces inflammatory cytokine production.

Dr. Levy and his colleagues hypothesized that by augmenting endogenous resolution circuits, those SPMs would provide a more holistic approach to improving RSV outcomes than therapeutic approaches that chemically inhibit the inflammatory response and increase immunosuppressive risks. As an aside, therapeutic monoclonal antibodies have been developed to prevent RSV infection in high-risk infants, but this approach has not yet proven useful as a therapeutic for active RSV infection.

“With active RSV infection in the lungs, levels of SPMs decreased, and as infection resolves, SPM levels increased back to pre-infection levels,” Dr. Levy says. “We wanted to see what happens when we introduce these mediators when the subject is in the early stages of active infection, before SPMs decrease.”

The researchers found that introducing PCTR1 and PD1 during early RSV infection induced lambda interferon expression in mouse and human airway epithelial cells, preventing disruption of the airway’s mucosal shield, decreasing the viral burden of RSV and decreasing inflammation. According to the study’s authors, these results suggest protective rather than immunosuppressive actions for these SPMs.

Translational Studies of RSV Infection Underway

While the mouse model in the study faithfully replicates aspects of human RSV infection, it does not incorporate all human infection features. Therefore, Dr. Levy and his colleagues are conducting ongoing translational research studies to determine the relationships between SPMs and protective mechanisms for respiratory viral infections in humans.

In one study, Dr. Levy is investigating why the resolution mechanisms for dampening lung inflammation in patients with chronic asthma appear not to function properly. The study, part of the Severe Asthma Research Program, involves immunophenotyping patients with severe asthma and tracking them for over a decade to determine the frequency of asthma exacerbations, which are typically driven by respiratory viruses, relating to resolution mechanisms.

In another study, Dr. Levy is examining the role of resolution mechanisms in regulating inflammatory response in patients with acute respiratory distress syndrome (ARDS), which causes “overly exuberant” lung inflammation. Although ARDS is associated with influenza, pneumonia and lung trauma, this work has taken on new urgency due to the association between ARDS and COVID-19.

Respiratory Viruses Require a Team Approach

The Brigham is a leading center for people with severe COVID-19, influenza, RSV, asthma, ARDS and other complex problems that typically respond poorly to available medications. It brings together state-of-the-art critical care medicine services, next-generation lung transplant support and one of the country’s largest research platforms driven by leading investigators in the field of pulmonary medicine.

“From clinicians to translational researchers to bench scientists, the Brigham is laser-focused on developing new insights and therapeutic approaches to acute and chronic respiratory diseases,” Dr. Levy says. “However, it is important to recognize that the clinical care and patient-oriented research for these conditions are a team sport. We are proud to play a central role in a national effort that involves multiple partner institutions and investigators working together synergistically to understand the pathophysiology of these diseases and provide the requisite insights to develop new therapeutics.”