Methods: RSV clinical isolates were collected from the Vanderbilt Vaccine Clinic in 2001 (01/2-20) or from infants hospitalized with severe RSV illness as part of the Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure (INSPIRE) study in 2012 (12/11-19 and 12/12-6). Wild type mice were infected with individual RSV isolates and treated with either an anti-TSLP neutralizing antibody or an isotype control. On day 4 post-infection, lungs were collected for evaluation of ILC2 numbers. TSLPR-deficient mice were infected to evaluate pathophysiology. The appropriate institutional review boards approved all experiments.
Results: Neutralization of TSLP at 6 hours or 36 hours post-infection decreased the total number of IL-13-producing ILC2 on day 4 post-infection with RSV strain 01/2-20 compared to isotype treated mice. Similarly, TSLP neutralization attenuated IL-13-producing ILC2 on day 4 post-infection in mice inoculated with the INSPIRE strains. Deficiency of TSLPR in mice led to attenuated weight loss, decreased IL-13 production, and reduced airway mucus accumulation without a negative impact on viral load.
Conclusions: TSLP neutralization attenuated the IL-13-producing ILC2 response induced by multiple clinical isolates of RSV, including strains isolated as recently as 2012 that have known human pathogenic potential. These data suggest TSLP as an important therapeutic target during RSV infection.