Age-dependent airway epithelial determinants of severe human respiratory viral
Prof. Dr. Dorothee Viemann & Dr. Simone Backes
Epidemiological data suggest that age-specific differences in the pathogenesis of respiratory viral infections (RVIs) arise from at least two critical key decisions: viral entry and/or spreading. Both are highly influenced by the age-specific programming of anti-viral immunity and inflammatory responsivity. However, the key cellular and molecular host factors that determine the outcome of RVIs at different age are ill defined and thus we lack preventive strategies or treatment alternative to vaccination. For the protection from increased infectious susceptibility and hyperinflammatory reactions, the airway epithelium must fulfil barrier functions and initiate regulated immune responses upon environmental challenges. The knowledge on the differentiation and function of airway epithelial cells (AECs) at different ages is quite fragmented. Our preliminary data point to profound differences in the transcriptional and epigenetic programming of AECs in preterm infants compared to term infants and adults. In this project, we will use 3D models of human neonatal and adult AECs and perform infections with three RNA viruses targeting preferential age groups (respiratory syncytial virus (RSV), influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to identify AEC-related age-dependent molecular decision points of severe RVIs. Hereby we will focus on (i) the link between age-specific cellular differentiation and immune function of the upper respiratory tract epithelium as well as viral entry, replication and spreading, (ii) the accessibility of candidate molecular decision points to modification and resulting consequences for the outcome of RVIs, and (iii) microbiota-derived environmental cues impacting on the programming of molecular decision points in RVIs.