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Adenovirus entry from the apical surface of polarized epithelia is facilitated by the host innate immune response.

Kotha PL, Sharma P, Kolawole AO, Yan R, Alghamri MS, Brockman TL, Gomez-Cambronero J, Excoffon KJ - PLoS Pathog. (2015)

Bottom Line: Prevention of viral-induced respiratory disease begins with an understanding of the factors that increase or decrease susceptibility to viral infection.We hypothesized that the endogenous role of CAREx8 may be to facilitate host innate immunity.In addition, CAREx8 is a new target for the development of novel therapeutics for both respiratory inflammatory disease and adenoviral infection.

View Article: PubMed Central - PubMed

Affiliation: Departments of Biological Sciences, Wright State University, Dayton, Ohio, United States of America.

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, CAREx8, 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 CAREx8 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 CAREx8 via activation of AKT/S6K and inhibition of GSK3β. Apical CAREx8 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 CAREx8, to allow the initial infection the intact epithelium. In addition, CAREx8 is a new target for the development of novel therapeutics for both respiratory inflammatory disease and adenoviral infection.

No MeSH data available.


Related in: MedlinePlus

Schematic of IL-8-mediated enhancement of AdV entry into polarized epithelia.1) Pathogenic microbes that invade the airway 2) cause both the resident macrophages and the epithelial cells to secrete IL-8. 3) IL-8 exposure causes intracellular signaling within the epithelial cells that augments de novo protein synthesis and apical localization of CAREx8. 4) IL-8 simultaneously recruits neutrophils that transmigrate through the epithelium from the basal surface to the apical surface and 5) bind to CAREx8 at the apical surface of the epithelium. 6) AdV entering the airway hijacks the host innate immune response and apical CAREx8 to gain entry into the host cell.
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ppat.1004696.g007: Schematic of IL-8-mediated enhancement of AdV entry into polarized epithelia.1) Pathogenic microbes that invade the airway 2) cause both the resident macrophages and the epithelial cells to secrete IL-8. 3) IL-8 exposure causes intracellular signaling within the epithelial cells that augments de novo protein synthesis and apical localization of CAREx8. 4) IL-8 simultaneously recruits neutrophils that transmigrate through the epithelium from the basal surface to the apical surface and 5) bind to CAREx8 at the apical surface of the epithelium. 6) AdV entering the airway hijacks the host innate immune response and apical CAREx8 to gain entry into the host cell.

Mentions: Taken together (Fig. 7), these data indicate that IL-8, potentially derived from stimulated resident macrophages or the epithelium itself, activates specific signaling pathways within polarized epithelial cells (Fig. 6L) that lead to increased apical CAREx8 and retention of transmigrating neutrophils at the apical surface. AdV has likely evolved to hijack this innate pathway and induced apical CAREx8 expression for entry into a polarized epithelium from the apical surface. Previously, it was assumed that AdV must breach the tight junction barrier to access its primary receptor. This study provides a novel mechanism and an explanation as to how the virus can infect the intact epithelium without breaching the barrier. Further elucidating these mechanisms in both healthy and diseased individuals will yield a greater understanding of the susceptibility of the airway epithelium to invading viral pathogens and interventions that reverse this effect. Moreover, if CAREx8 is upregulated in diseased conditions, novel therapies that target the CAR-neutrophil interaction may present a new anti-inflammatory treatment for inflammatory airway disease.


Adenovirus entry from the apical surface of polarized epithelia is facilitated by the host innate immune response.

Kotha PL, Sharma P, Kolawole AO, Yan R, Alghamri MS, Brockman TL, Gomez-Cambronero J, Excoffon KJ - PLoS Pathog. (2015)

Schematic of IL-8-mediated enhancement of AdV entry into polarized epithelia.1) Pathogenic microbes that invade the airway 2) cause both the resident macrophages and the epithelial cells to secrete IL-8. 3) IL-8 exposure causes intracellular signaling within the epithelial cells that augments de novo protein synthesis and apical localization of CAREx8. 4) IL-8 simultaneously recruits neutrophils that transmigrate through the epithelium from the basal surface to the apical surface and 5) bind to CAREx8 at the apical surface of the epithelium. 6) AdV entering the airway hijacks the host innate immune response and apical CAREx8 to gain entry into the host cell.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4358923&req=5

ppat.1004696.g007: Schematic of IL-8-mediated enhancement of AdV entry into polarized epithelia.1) Pathogenic microbes that invade the airway 2) cause both the resident macrophages and the epithelial cells to secrete IL-8. 3) IL-8 exposure causes intracellular signaling within the epithelial cells that augments de novo protein synthesis and apical localization of CAREx8. 4) IL-8 simultaneously recruits neutrophils that transmigrate through the epithelium from the basal surface to the apical surface and 5) bind to CAREx8 at the apical surface of the epithelium. 6) AdV entering the airway hijacks the host innate immune response and apical CAREx8 to gain entry into the host cell.
Mentions: Taken together (Fig. 7), these data indicate that IL-8, potentially derived from stimulated resident macrophages or the epithelium itself, activates specific signaling pathways within polarized epithelial cells (Fig. 6L) that lead to increased apical CAREx8 and retention of transmigrating neutrophils at the apical surface. AdV has likely evolved to hijack this innate pathway and induced apical CAREx8 expression for entry into a polarized epithelium from the apical surface. Previously, it was assumed that AdV must breach the tight junction barrier to access its primary receptor. This study provides a novel mechanism and an explanation as to how the virus can infect the intact epithelium without breaching the barrier. Further elucidating these mechanisms in both healthy and diseased individuals will yield a greater understanding of the susceptibility of the airway epithelium to invading viral pathogens and interventions that reverse this effect. Moreover, if CAREx8 is upregulated in diseased conditions, novel therapies that target the CAR-neutrophil interaction may present a new anti-inflammatory treatment for inflammatory airway disease.

Bottom Line: Prevention of viral-induced respiratory disease begins with an understanding of the factors that increase or decrease susceptibility to viral infection.We hypothesized that the endogenous role of CAREx8 may be to facilitate host innate immunity.In addition, CAREx8 is a new target for the development of novel therapeutics for both respiratory inflammatory disease and adenoviral infection.

View Article: PubMed Central - PubMed

Affiliation: Departments of Biological Sciences, Wright State University, Dayton, Ohio, United States of America.

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, CAREx8, 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 CAREx8 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 CAREx8 via activation of AKT/S6K and inhibition of GSK3β. Apical CAREx8 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 CAREx8, to allow the initial infection the intact epithelium. In addition, CAREx8 is a new target for the development of novel therapeutics for both respiratory inflammatory disease and adenoviral infection.

No MeSH data available.


Related in: MedlinePlus