Exploring airway biological barriers: Implications for IgG-based therapeutics in respiratory infections

Despite the considerable value of prophylactic vaccines and post-exposure antimicrobials, respiratory infections represent a huge burden. The control of bacterial respiratory infections is compromised by the alarming rise in antibiotic resistance, which underscores the requirement for alternative or complementary interventions. Recent studies have demonstrated that anti-infective IgG-based therapeutics can have an important role in tackling pathogens, and that inhalation is a promising route to target respiratory infections in the lung. Here, we investigated the impact of physical and biological barriers encountered by inhaled IgG during respiratory infections. These include hyper-production and thickening of mucus, as well as bacteria embedded in biofilm. Experiments using artificial bronchiectasis-like mucus showed reduced mobility and pathogen-binding of IgG as compared to artificial mucus with healthy characteristics. Our findings highlight the reduced ability of IgG to effectively opsonize pathogens and trigger effector functions during respiratory infections, such as the ones associated to bronchiectasis. In parallel, IgG was able to disrupt P.aeruginosa biofilm integrity upon repeat administrations in vitro. These results support the use of locally applied human polyclonal IgG in infection-driven chronic lung diseases and highlight the challenges to consider for the development of inhaled IgG.