The role of respiratory syncytial virus in modulating early innate immune responses

Respiratory viruses are a common cause of disease and mortality across the globe. Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in young children worldwide and also represents a significant cause of mortality in adults over the age of 65. RSV is highly transmissible, and all children will become infected with RSV by the age of 3. Currently, there is currently no licensed RSV vaccine available.

Immune cells residing within the airways, known as alveolar macrophages (AM), are one of the first immune cells to encounter inhaled pathogens. However, all of the critical roles AMs play early after a respiratory virus infection remain unclear. Utilizing various genetic techniques, I generated virus strains expressing fluorescent reporters and tracked them early post-infection. I found that distinct respiratory viruses all abundantly infected AMs early post-infection. However, AMs did not support productive viral replication and served as a ‘viral sponge’ limiting access to the more susceptible lung cells. These infected AMs self-restricted viral replication and were not eliminated by the immune system. Long after RSV clearance, the previously infected AMs displayed enhanced functional capacity when re-infected. Together, this work provides valuable insight into a previously undefined role of AMs in the restriction of early viral replication and innate memory responses.

RSV strains are known to cause differential disease suggesting genetic variation influences disease severity. I generated recombinant RSV strains expressing proteins from strains that cause severe disease to elucidate the mechanism by which RSV induces disease. My data suggests that a single amino acid change in a major RSV surface protein can induce increased inflammation and severe disease. I identified the specific immune cell receptors that this amino acid binds to causing inflammation that results in severe disease. These studies will have important implications in the screening of RSV strains to predict upcoming disease severity during RSV season as well as influence the development of future therapeutic targets.