NS1 of H5N1 interacts with SAP-97 in a PDZ-dependent manner to disrupt epithelial barrier integrity

The ability of influenza A virus to cause global pandemics has been a great concern throughout history and poses a serious health risk worldwide. Pandemic outbreaks throughout history, such as the Spanish flu of 1918, have claimed the lives of millions of people worldwide. The current outbreak of avian influenza (H5N1) that began in 1997 is still claiming lives, and therefore efforts to understand the mechanisms of pathogenesis in this highly virulent virus are of the utmost importance. According to the World Health Organization, there have been 447 reported H5N1 human cases, resulting in 263 deaths. The pathology of H5N1 infection includes pulmonary edema and diarrhea. Large scale sequencing of influenza A viruses revealed that nonstructural protein 1 (NS1) contains a class I PDZ motif. The NS1 proteins of avian origin contain the PDZ motif ESEV, which has been found to bind several cellular PDZ domain proteins. The interaction of NS1 and host proteins via the PDZ motif is a determinant in the virulence of influenza viruses of avian origin. Consistent with the clinical symptoms, this study is the first to show that the NS1 protein of A/chicken/Vietnam/C58/04 binds synapse-associated protein-97 (SAP-97), an adherens junction protein, in a PDZ motif-dependent manner. In H5N1 infected tissues, the SAP-97 distribution is reorganized. Functionally, the interaction of NS1 and SAP-97 results in the loss of epithelial barrier function. This mechanism helps to explain why the two disease states, pulmonary edema and diarrhea, in which epithelial barrier is compromised, are both common in human H5N1 infection.