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The goal of this project is to establish a unique experimental system to study fundamental aspects of human respiratory virus replication and interactions with the innate immune system at the natural entry port of human respiratory viruses, namely the human airway epithelium (HAE). Specifically, we aim to make primary HAE cultures amenable to genetic modifications by applying lentivirus-based vectors to mediate trans-gene expression and knock-down of particular genes. The efficacy and biological effect of genetic modifications in HAE cultures will be assessed by analyzing infection of HAE cultures with human coronaviruses.