Submitted to: PLoS Pathogens
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/24/2012
Publication Date: 3/15/2012
Publication URL: http://handle.nal.usda.gov/10113/60115
Citation: Belser, J., Gustin, K.M., Maines, T.R., Pantin Jackwood, M.J., Katz, J.M., Tumpey, T.M. 2012. Influenza virus respiratory infection and transmission following ocular inoculation in ferrets. PLoS Pathogens. 8(3):e1002569. Interpretive Summary: Most infections with influenza virus result in respiratory disease. However, influenza viruses of the H7 subtype frequently cause ocular and not respiratory symptoms during human infection, demonstrating that the eye represents an alternate location for influenza viruses to infect humans. Using a ferret model, we studied the ability of influenza viruses to cause disease following ocular inoculation. We found that both human and avian influenza viruses could use the eye as a portal of entry to establish a respiratory infection in ferrets. Influenza viruses were also detected in ocular samples taken from ferrets during virus infection. We identified that influenza viruses spread to different tissues in ferrets when inoculated by ocular or respiratory routes, and that these differences affected the transmissibility of influenza viruses in this model. This study is the first to confirm that virus can spread from the eye to the respiratory tract in a replication-independent manner, and offers greater insight in understanding the ability of influenza viruses of all subtypes to cause human infection by the ocular route.
Technical Abstract: While influenza viruses are a common respiratory pathogen, sporadic reports of conjunctivitis following human infection demonstrates the ability of this virus to cause disease outside of the respiratory tract. The ocular surface represents both a potential site of virus replication and a portal of entry for establishment of a respiratory infection. However, the properties which govern ocular tropism of influenza viruses, the mechanisms of virus spread from ocular to respiratory tissue, and the potential differences in respiratory disease initiated from different exposure routes are poorly understood. Here, we established a ferret model of ocular inoculation to explore the development of virus pathogenicity and transmissibility following influenza virus exposure by the ocular route. We found that multiple subtypes of human and avian influenza viruses mounted a productive virus infection in the upper respiratory tract of ferrets following ocular inoculation, and were additionally detected in ocular tissue during the acute phase of infection. H5N1 viruses maintained their ability for systemic spread and lethal infection following inoculation by the ocular route. Replication-independent deposition of virus inoculum from ocular to respiratory tissue was limited to the nares and upper trachea, unlike traditional intranasal inoculation which results in virus deposition in both upper and lower respiratory tract tissues. Despite high titers of replicating transmissible seasonal viruses in the upper respiratory tract of ferrets inoculated by the ocular route, virus transmissibility to naïve contacts by respiratory droplets was reduced following ocular inoculation. These data improve our understanding of the mechanisms of virus spread following ocular exposure and highlight differences in the establishment of respiratory disease and virus transmissibility following use of different inoculation volumes and routes.