Adenovirus Entry From the Apical Surface of Polarized Epithelia Is Facilitated by the Host Innate Immune Response

Abstract

Prevention of viral-induced respiratory disease begins with an understanding of the factors that increase or decrease susceptibility to viral infection. The primary receptor for most adenoviruses is the coxsackievirus and adenovirus receptor (CAR), a cell-cell adhesion protein normally localized at the basolateral surface of polarized epithelia and involved in neutrophil transepithelial migration. Recently, an alternate isoform of CAR, CAR ^Ex8, has been identified at the apical surface of polarized airway epithelia and is implicated in viral infection from the apical surface. We hypothesized that the endogenous role of CAR ^Ex8 may be to facilitate host innate immunity. We show that IL-8, a proinflammatory cytokine and a neutrophil chemoattractant, stimulates the protein expression and apical localization of CAR ^Ex8 via activation of AKT/S6K and inhibition of GSK3β. Apical CAR ^Ex8 tethers infiltrating neutrophils at the apical surface of a polarized epithelium. Moreover, neutrophils present on the apical-epithelial surface enhance adenovirus entry into the epithelium. These findings suggest that adenovirus evolved to co-opt an innate immune response pathway that stimulates the expression of its primary receptor, apical CAR ^Ex8, to allow the initial infection the intact epithelium. In addition, CAR ^Ex8 is a new target for the development of novel therapeutics for both respiratory inflammatory disease and adenoviral infection.

Author Summary

Respiratory viral infection is one of the leading causes of morbidity and mortality worldwide. Interventions that are able to limit viral infection will enhance human health and productivity. However, the mechanisms that control our susceptibility to viral infection and the factors that allow viral pathogens to breach the exterior epithelial barrier to initiate infection are not well understood. Here we find that adenovirus, a common cold virus and a potential gene therapy vector, uses a cellular receptor that is induced by the host innate immune response. Moreover, neutrophils, cells that are meant to protect the host in the early phase of an innate immune response, instead facilitate adenovirus infection. It has been known for over 15 years that adenovirus itself can induce an innate immune response and specifically induce host cell secretion of IL-8, a critical chemokine that attracts neutrophils to sites of infection. However, until now, it has been unclear how IL-8 induction might benefit the virus. Our data indicate that adenovirus evolved to use our innate defense system to enhance entry into the epithelium and identifies the apical adenovirus receptor as a new target that may modulate inflammatory disease.