The SARS Coronavirus E Protein Interacts with PALS1 and Alters Tight Junction Formation and Epithelial Morphogenesis

Teoh, Kim-Tat; Siu, Yu-Lam; Chan, Wing-Lim; Schlüter, Marc A.; Liu, Chia-Jen; Peiris, J. S. Malik; Bruzzone, Roberto; Margolis, Benjamin; Nal, Béatrice

The SARS coronavirus (SARS-CoV) is an enveloped virus with a positive single strand RNA genome, which has emerged in the human population during winter 2002–2003 causing an outbreak of severe acute respiratory infections with a 10% mortality rate (Peiris et al., 2004). The reasons for the severity of illness in SARS-CoV infected patients are still not clearly understood. The SARS-CoV mainly targets epithelial cells, the respiratory tract being the primary site of infection (Nicholls et al., 2003; Nicholls et al., 2006). One of the major pathological features of SARS-CoV infection is diffuse alveolar damage (DAD) of the human lung, more prominent in the terminal stage, with occasional extensive damage of the lung epithelium (Kuiken et al., 2003; Nicholls et al., 2003). Several hypotheses have been made to explain DAD, invoking either intrinsic cytopathic effect of the virus or dysfunction of the immune system (Chen and Subbarao, 2007; Perlman and Netland, 2009; Yoshikawa et al., 2009). Another clinical feature is the extrapulmonary dissemination of the virus with other organ dysfunction including lymphoid tissues, liver, intestine, and kidney (Farcas et al., 2005; Gu et al., 2005). One possibility is that viral proteins disrupt mucosal integrity by interfering with the regulation and maintenance of specialized epithelial functions, such as intercellular junctions and apicobasal polarity and, as a consequence, induce viral dissemination. In this line, recent studies using a recombinant virus lacking the SARS-Cov E gene suggest that E envelope protein is a virulence factor influencing replication level, virus dissemination, and pathogenicity of SARS-CoV in animal models (DeDiego et al., 2007; DeDiego et al., 2008). However, the molecular mechanism involving E in pathogenesis is not known. Interestingly, in vitro studies on monolayers of human airway epithelial cells have shown that morphology of cells was affected at late time points following infection (72 and 120 h) and suggested that cellular junctions and polarity were altered (Sims et al., 2005).