Abstract Rationale The polymeric immunoglobulin receptor (PIGR) is expressed by epithelial cells and is responsible for the transport of IgA across the epithelium, where it coats the airway lumen and is broadly protective against pathogens. We and others have shown that PIGR expression is reduced in COPD and negatively correlates with exacerbation frequency. We hypothesized that restoration of PIGR expression using adeno-associated virus (AAV) will boost mucosal immunity in a broadly anti-pathogen manner. Methods To assess the feasibility and longevity of restoring PIGR expression with AAV, we used PIGR-deficient mice. We then used human nasal epithelial cells grown at air-liquid interface (ALI), which have low endogenous expression of PIGR, to assess whether PIGR-AAV was protective against influenza infection. Results PIGR-AAV was delivered intranasally to PIGR-deficient mice and resulted in long-lived expression of PIGR (up to d119). In addition, PIGR was functionally active, inducing transcytosis of IgA, which was detected in bronchoalveolar lavage fluid (157pg/ml with PIGR-AAV vs 15pg/ml with control AAV). In vitro, we used PIGR-AAV to infect nasal epithelial cells and showed that PIGR was expressed, IgA was transcytosed and, importantly, this resulted a significant decrease in viral infection when the cells were exposed to influenza virus, as demonstrated by a seven-fold decrease in viral mRNA expression. Conclusions Overall, we have demonstrated that PIGR expression can be restored by PIGR-AAV and that doing so is protective against viral infection. Our data support the concept of PIGR-AAV as a potential therapeutic for COPD. This abstract is funded by: AstraZeneca
Kearley et al. (Fri,) studied this question.