| dc.description.abstract |
Airway epithelial cells pose a formidable barrier for the entry of pathogenic viruses. The epithelial tight junction proteins maintain the barrier integrity by sealing the space between the epithelial cells. Adenovirus, which commonly causes acute respiratory infections, uses CAR as its primary receptor for entry into the host cell. CAR is primarily expressed on the basolateral surface of the epithelial cell and thus is sequestered away from pathogen-exposed (apical) surface. However, despite the inaccessibility of CAR to invading adenoviruses, adenovirus infection is common. Many potential mechanisms have been proposed, for example: (A) A structural break in the epithelial barrier might expose the basolaterally expressed CAR to the invading pathogen. (B) The presence of CAREx8, an alternate splice form of CAR, at the apical surface of epithelial cells might serve as adenoviral receptor. Lutschg et al., 2011 demonstrated that apical treatment of airway epithelial cells with supernatant from activated macrophages, and more specifically interleukin-8 (IL-8), for 4h increased the apical localization of CAR and adenovirus infection. Thus, we hypothesized that additional cytokines released on the mucosal surface of the airway epithelial cells regulate the expression of CAR favoring adenoviral infection. To test this hypothesis, the apical surface of polarized Calu-3 cells was treated with 9 different cytokines for 4, 24 or 48h and analyzed for transduction with adenovirus carrying the β-galactosidase reporter gene. Amongst the cytokines tested, both IL-8 and MCP-1 (monocyte chemotactic protein-1) treated epithelia exhibited increased adenoviral infection at 4h and decreased adenoviral infection at 24 and 48h. Short time points (4h) correlated with increased apical CAR while longer time points (24 and 48h) did not. In summary, susceptibility to virus infection in the lung is modulated by the secreted molecules, and likely the cells, that are meant to protect it. |
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