This project will follow the observation of the second funding period that rare variants of the human, interferon-induced, antiviral restriction factor MxA increase the risk to contract zoonotic influenza A viruses (IAVs). C01 will continue to study genetic and immunological susceptibility factors for avian IAV infections by reanalyzing the genomic data of H7N9-infected patients and healthy controls from the second funding period to identify additional, rare genetic defects affecting H7N9 susceptibility and by investigating whether anti-interferon autoantibodies predispose humans to H7N9 infections. C01 will also explore the MxA interactome by incorporating cross-linkers into MxA using amber codon suppression – based on the hypothesis that cellular factors, which regulate MxA activity, are also determine susceptibility to avian IAV infections. Identified risk factors will be further characterized in an IAV infection model in human lung organoids. Moreover, they will investigate the role of the dominant-negative effect of inactive MxA variants on wild-type MxA in the emergence of IAV variants that are able to escape MxA restriction in a heterozygous, MxA transgenic mouse model.