Virus-host interactions that drive and control airway epithelial injury in coronavirus infections
Coronaviruses (CoV)9 are a major cause of respiratory tract infections in humans. Lung pathology varies greatly between infections caused by "common" human CoV (HCoV-229E, NL63, HKU1, OC43) and newly emerging (zoonotic) CoV (SARS-CoV and MERS-CoV). To date, the underlying mechanisms for strain-specific differences in human CoV-induced pathology have been poorly defined. To a large extent, this is due to a scarcity of experimental systems that appropriately reflect the complexity of CoV-host interactions occurring in different cell types and compartments of the lung.
Using a combination of advanced technologies available in the Clinical Research Unit KFO 309, including state-of-the-art human ex-vivo lung epithelial cell culture systems, CoV reverse genetics, and transcriptome and protein-protein interaction analysis at the single-cell level, the project aims to get insight into virus-encoded and cellular factors that drive human lung injury and host response in human respiratory infections caused by alpha- and beta-CoVs. A central hypothesis to be addressed in this project is that human CoVs encode a set of proteins that dampen or shape the epithelial cell immune response at the level of the ER stress response and the NF-κB pathway. The research program is mainly based on the use of differentiated human airway and alveolar epithelial cells and co-cultures with human alveolar macrophages/dendritic cells to study and compare the replication, gene expression and viral tropism of representative "common" and newly emerging CoV representing the genera Alpha- and Betacoronvirus. Furthermore, an extensive set of genetically engineered human CoV mutants will be generated and used to elucidate possible roles of defined viral proteins in human lung pathology. These mutants lack specific viral replicase gene-encoded enzymatic activities presumed to be involved in viral pathogenesis and express reporter genes to facilitate detection of virus-infected cells in complex culture systems.
The overall aim of the project is to define CoV-regulated pathways and molecules and their interactions with CoV-encoded effectors in the lung, which, in the long run, will provide a framework for developing novel diagnostic and therapeutic strategies to treat coronaviral infections more effectively