JVI Accepts, published online ahead of print on 20 May 2009

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J. Virol. doi:10.1128/JVI.00535-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Ocular infection of mice with influenza A (H7) viruses: A site of primary replication and spread to the respiratory tract

Jessica A. Belser, Debra A. Wadford, Jianguo Xu, Jacqueline M. Katz, and Terrence M. Tumpey^*

Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333; Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322

^* To whom correspondence should be addressed. Email: tft9{at}cdc.gov.

Avian H7 influenza viruses have been responsible for poultry outbreaks worldwide and have resulted in numerous cases of human infection in recent years. The high rate of conjunctivitis associated with avian H7 subtype virus infections may represent a portal of entry for avian influenza viruses and highlights the need to better understand the apparent ocular tropism observed in humans. To study this, mice were inoculated by the ocular route with viruses of multiple subtypes and degrees of virulence. We found that in contrast to human (H3N2 and H1N1) viruses, H7N7 viruses isolated from the Netherlands in 2003 and H7N3 viruses isolated from British Columbia, Canada in 2004, two subtypes that were highly virulent for poultry, replicated to significant titer in the mouse eye. Remarkably, an H7N7 virus, as well as some avian H5N1 viruses, spread systemically following ocular inoculation, including to the brain, resulting in morbidity and mortality of mice. This correlated with efficient replication of highly pathogenic H7 and H5 subtypes in murine corneal epithelial sheets (ex vivo) and primary human corneal epithelial cells (in vitro). Influenza viruses were labeled to identify the virus attachment site in the mouse cornea. Although we found abundant H7 virus attachment to corneal epithelial tissue, this did not account for the differences in virus replication as multiple subtypes were able to attach to these cells. These findings demonstrate that avian influenza viruses within H7 and H5 subtypes are capable of using the eye as a portal of entry.