Influenza virus and endothelial cells: a species specific relationship

Abstract

Influenza A virus (IAV) infection is an important cause of respiratory disease in humans. The original reservoirs of IAV are wild waterfowl and shorebirds, where virus infection causes limited, if any, disease. Both in humans and in wild waterbirds, epithelial cells are the main target of infection. However, influenza virus can spread from wild bird species to terrestrial poultry. Here, the virus can evolve into highly pathogenic avian influenza (HPAI). Part of this evolution involves increased viral tropism for endothelial cells. HPAI virus infections not only cause severe disease in chickens and other terrestrial poultry species but can also spread to humans and back to wild bird populations. Here, we review the role of the endothelium in the pathogenesis of influenza virus infection in wild birds, terrestrial poultry and humans with a particular focus on HPAI viruses. We demonstrate that whilst the endothelium is an important target of virus infection in terrestrial poultry and some wild bird species, in humans the endothelium is more important in controlling the local inflammatory milieu. Thus, the endothelium plays an important, but species-specific, role in the pathogenesis of influenza virus infection.

Keywords: endothelial cells; highly pathogenic avian influenza; influenza virus; poultry; zoonotic infection.

Figure 1

Endotheliotropism and epitheliotropism of IAVs in chickens. Virus distribution in: (A) endothelial cells of the wattle of a chicken naturally infected with HPAI H7N7 virus. Brown-reddish staining antigen indicative of viral replication is present in many endothelial cell nuclei (arrows) and cytoplasm lining the small blood vessels. The dermis is expanded by edema (asterisk). (original magnification 200×, in van Riel et al. (2009) (B) Epithelial cell nuclei (arrowheads) and in endothelial cells (arrows) of the nasal mucosa of a chicken 24 h after experimental intranasal infection with 10⁵ TCID₅₀ of HPAI H5N1 virus A/Indonesia/05/2005, illustrating both epitheliotropism and endotheliotropism of the virus (original magnification 200×). (C) Endothelial cell nuclei (arrows) of the lung interstitium 24 h after infection of the same chicken as in (B), the alveolar lining epithelial cells nuclei (arrowheads) do not stain positive for viral antigen (original magnification 400×). (Immunohistochemistry (IHC) for IAV-nucleoprotein (NP) with hematoxylin counterstain).

Figure 2

Epitheliotropism of IAVs in ferrets. IAV distribution in: (A) Epithelial cell nuclei and apical cytoplasm of the nasal respiratory mucosa of a ferret 24 h after experimental intranasal infection with 10⁶ TCID₅₀ of seasonal influenza H3N2 A/Netherlands/177/2008 (original magnification 800×). (B) Epithelial cells of a bronchiole (asterisk) and in few alveolar lining epithelial cell nuclei (arrows) of a ferret lung 24 h after experimental intratracheal infection with 10⁶ TCID₅₀ of influenza pH1N1 A/Netherlands/602/2009. The blood vessel lumen lining endothelial cell nuclei (arrowhead) do not stain positive for viral antigen (original magnification 200×). (C) Alveolar lining epithelial cell nuclei (arrows) of a ferret lung 24 h after experimental intratracheal infection with 10⁶ TCID₅₀ of HPAI H5N1 virus A/Indonesia/05/2005. The blood vessel lumen lining endothelial cell nuclei (arrowhead) do not stain positive for viral antigen (original magnification 400×). Brown-reddish staining antigen indicative of viral replication was present only in epithelial cells of ferret respiratory tract, not in ferret endothelial cells. (Immunohistochemistry (IHC) for IAV-nucleoprotein (NP) with hematoxylin counterstain).