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Description
Influenza A Virus (IAV) infections of the lower respiratory tract can induce viral pneumonia resulting in acute lung injury (ALI/ARDS) with fatal outcome. Characteristics of an IV-induced pneumonia are an alveolar epithelial cell (AEC) damage and accumulation of protein-rich edema fluid in the alveolar compartment impairing gas exchange. Depending on a sodium gradient established by the basolateral Na,K-ATPase (NKA) and the apical epithelial sodium channel (ENaC) edema fluid is removed from the alveolar space under normal conditions. However after IV-infection a decreased alveolar fluid clearance was observed.
In primary AEC it was shown that an IAV-infection leads to a mistargeting of the NKAα1-subunit to the apical cell membrane, but to a reduced NKA expression in the non-infected neighbouring cells. Co immunoprecipitation (co-IP) studies identified the viral M2 protein as a binding partner of NKAα1. To study the pathophysiological implications of this virus-host interaction we characterized the NKA binding site in the viral M2 protein. In a mutational approach we were able to identify three amino acids in the cytoplasmic tail abutting the transmembrane domain as critical for NKAα1 binding. Recombinant seasonal IAV with impaired NKAα1 binding was slightly attenuated for replication in vitro and ex vivo. It is currently investigated for mistargeting of the NKAα1 to the apical side of cell and the impact on edema clearance in a polarized Calu 3 cell model.
In addition to established roles in intracellular genome release and virus budding our data suggest a further function of the IV M2 protein in relocalizing the cellular NKAα1, which is likely to contribute to pathophysiological effects in IV infection. Investigating the impact of the M2/NKA interaction on the impaired edema clearance could help to better understand this outcome of an IV infection in the future.
| Choose primary session | Pathogenesis |
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| Choose secondary Session | Virus host cell interaction |
