Induction of interleukin-8 by adenovirus serotype 7 via activation of extracellular -regulated kinase 1 /2 and the role of the fiber attachment receptor.

摘要

The hallmarks of Adenovirus Type 7 (Ad7) infection, particularly in comparison to other Ad serotypes, include a robust infiltration and activation of neutrophils within the lungs of the infected individual. The reasons for the enhanced inflammation and severity associated with Ad7 remain unclear. We demonstrate that Ad7 infection induces the production of the pro-inflammatory chemokine, IL-8, via capsid-mediated activation of a host signal transduction pathway that leads to phosphorylation and activation of Extracellular-regulated Kinase 1/2 (ERK1/2). Activation of the ERK1/2 pathway does not require viral expression, and appears to be initiated subsequent to internalization of the viral particles into acidified endosomes. Using both chemical and genetic inhibitors, we have shown that maximal induction of IL-8 by Ad7 requires activation of ERK1/2, although we have not ruled out the involvement of other pathways. We have purified a recombinant Ad7 fiber protein that effectively blocks infection with subgroup B Ads (Ad7 and Ad3), but has no effect on infection with non-subgroup B Ads such as Ad5 or Ad9 which utilize the Coxsackievirus and Adenovirus Receptor for fiber attachment. We provide evidence that the fiber protein is interacting with the unknown fiber receptor, and is capable of blocking both Ad7 induction of ERK and IL-8, but does not elicit such events on its own. Finally, we describe how this recombinant fiber protein has utility for identification of the unknown Ad7 fiber receptor.