Human Pulmonary Microvascular Endothelial Cells Support Productive Replication of Highly Pathogenic Avian Influenza Viruses: Possible Involvement in the Pathogenesis of Human H5N1 Virus Infection

Zeng, Hui; Pappas, Claudia; Belser, Jessica A.; Houser, Katherine V.; Zhong, Weiming; Wadford, Debra A.; Stevens, Troy; Balczon, Ron; Katz, Jacqueline M.; Tumpey, Terrence M.

doi:10.1128/jvi.06348-11

Cited by 89 publications

(89 citation statements)

References 54 publications

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“…Given that both selectins and their ligands are evolutionary conserved molecules, one can predict expression of Su-SLe x on avian endothelial cells. Interestingly, three previous reports described a strong HA-dependent tropism of H5 and H7 poultry influenza viruses to endothelial cells of chicken embryo cells (13) and to cultured human pulmonary microvascular endothelial cells (45,69). Thus, enhanced binding of poultry influenza viruses to Su-SLe x and other sulfated and fucosylated sialyloligosaccharide sequences could have emerged as an adaptive change required for viral endotheliotropism in birds, a wellknown feature of highly pathogenic poultry influenza viruses with H5 and H7 HA (28).…”

Section: Discussionmentioning

confidence: 99%

Receptor-Binding Profiles of H7 Subtype Influenza Viruses in Different Host Species

Gambaryan

Matrosovich

Philipp

et al. 2012

J Virol

115

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Section: Discussionmentioning

confidence: 99%

Receptor-Binding Profiles of H7 Subtype Influenza Viruses in Different Host Species

Gambaryan

Matrosovich

Philipp

et al. 2012

J Virol

115

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“…2C), indicating that virus was present in this tissue. Therefore, OA inoculation of ferrets may represent an appropriate model for the study of the effects of vaccination and antiviral treatment in mitigating viral loads in ocular tissue following exposure to influenza viruses, especially strains that exhibit an ocular tropism in humans (27). Future study evaluating OA inoculation of respiratory viruses that do cause macroscopic ocular disease in mammalian models, such as RSV, is also warranted (1,23).…”

Section: Discussionmentioning

confidence: 99%

Influenza Virus Infectivity and Virulence following Ocular-Only Aerosol Inoculation of Ferrets

Belser

Gustin

Katz

et al. 2014

J Virol

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Respiratory pathogens have traditionally been studied by examining the exposure and infection of respiratory tract tissues. However, these studies typically overlook the role of ocular surfaces, which represent both a potential site of virus replication and a portal of entry for the establishment of a respiratory infection. To model transocular virus entry in a mammalian species, we established a novel inoculation method that delivers an aerosol inoculum exclusively to the ferret ocular surface. Using influenza virus as a representative respiratory pathogen, we found that both human and avian viruses mounted productive respiratory infections in ferrets following ocular-only aerosol inoculation, and we demonstrated that H5N1 virus can result in a fatal infection at doses below 10 PFU or with exposure times as short as 2 min. Ferrets inoculated by the ocular aerosol route with an avian (H7N7, H7N9) or human (H1N1, H3N2v) virus were capable of transmitting the virus to naïve animals in direct-contact or respiratory-droplet models, respectively. Our results reveal that ocular-only exposure to virus-containing aerosols constitutes a valid exposure route for a potentially fatal respiratory infection, even for viruses that do not demonstrate an ocular tropism, underscoring the public health implications of ocular exposure in clinical or occupational settings. IMPORTANCEIn the absence of eye protection, the human ocular surface remains vulnerable to infection with aerosolized respiratory viruses. In this study, we present a way to inoculate laboratory mammals that excludes respiratory exposure, infecting ferrets only by ocular exposure to influenza virus-containing aerosols. This study demonstrates that the use of respiratory protection alone does not fully protect against influenza virus exposure, infection, and severe disease.

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“…We found that H5N1 virus predominantly infected nonciliated cells and resulted in significantly more necrosis and substantial damage to the epithelial layer, which may contribute to the loss of cell integrity and diffusion of virus to the basolateral surface of tracheal epithelium. In vivo, recovery of virus from the epithelial basolateral side would contribute to infection of other cell types, including endothelial cells which possess ␣2,3-linked SA receptors (48), and virus spread to tissues outside of respiratory tract, potentially contributing to disease progression in mammals.…”

Section: Discussionmentioning

confidence: 99%

Tropism and Infectivity of Influenza Virus, Including Highly Pathogenic Avian H5N1 Virus, in Ferret Tracheal Differentiated Primary Epithelial Cell Cultures

Zeng

Goldsmith

Maines

et al. 2013

J Virol

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Tropism and adaptation of influenza viruses to new hosts is partly dependent on the distribution of the sialic acid (SA) receptors to which the viral hemagglutinin (HA) binds. Ferrets have been established as a valuable in vivo model of influenza virus pathogenesis and transmission because of similarities to humans in the distribution of HA receptors and in clinical signs of infection. In this study, we developed a ferret tracheal differentiated primary epithelial cell culture model that consisted of a layered epithelium structure with ciliated and nonciliated cells on its apical surface. We found that human-like (␣2,6-linked) receptors predominated on ciliated cells, whereas avian-like (␣2,3-linked) receptors, which were less abundant, were presented on nonciliated cells. When we compared the tropism and infectivity of three human (H1 and H3) and two avian (H1 and H5) influenza viruses, we observed that the human influenza viruses primarily infected ciliated cells and replicated efficiently, whereas a highly pathogenic avian H5N1 virus (A/Vietnam/1203/2004) replicated efficiently within nonciliated cells despite a low initial infection rate. Furthermore, compared to other influenza viruses tested, VN/1203 virus replicated more efficiently in cells isolated from the lower trachea and at a higher temperature (37°C) compared to a lower temperature (33°C). VN/1203 virus infection also induced higher levels of immune mediator genes and cell death, and virus was recovered from the basolateral side of the cell monolayer. This ferret tracheal differentiated primary epithelial cell culture system provides a valuable in vitro model for studying cellular tropism, infectivity, and the pathogenesis of influenza viruses.

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Human Pulmonary Microvascular Endothelial Cells Support Productive Replication of Highly Pathogenic Avian Influenza Viruses: Possible Involvement in the Pathogenesis of Human H5N1 Virus Infection

Cited by 89 publications

References 54 publications

Receptor-Binding Profiles of H7 Subtype Influenza Viruses in Different Host Species

Receptor-Binding Profiles of H7 Subtype Influenza Viruses in Different Host Species

Influenza Virus Infectivity and Virulence following Ocular-Only Aerosol Inoculation of Ferrets

Tropism and Infectivity of Influenza Virus, Including Highly Pathogenic Avian H5N1 Virus, in Ferret Tracheal Differentiated Primary Epithelial Cell Cultures

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