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Infection and Replication of Influenza Virus at the Ocular Surface

Hannah M. Creager,a,b Amrita Kumar,a Hui Zeng,a Taronna R. Maines,a Terrence M. Tumpey,a Jessica A. Belsera aInfluenzaDivision,NationalCenterforImmunizationandRespiratoryDiseases,CentersforDiseaseControl andPrevention,Atlanta,Georgia,USA bEmoryUniversity,Atlanta,Georgia,USA
Abstract

Although influenza viruses typically cause respiratory tract disease, some viruses, particularly those with an H7 hemagglutinin, have been isolated from the eyes of conjunctivitis cases. Previous work has shown that isolates of multiple subtypes from both ocular and respiratory infections are capable of replication in human ex vivo ocular tissues and corneal or conjunctival cell monolayers, leaving the determinants of ocular tropism unclear. Here, we evaluated the effect of several variables on tropism for ocular cells cultured in vitro and examined the potential effect of the tear film on viral infectivity. All viruses tested were able to replicate in primary human corneal epithelial cell monolayers subjected to aerosol inoculation. The temperature at which cells were cultured postinoculation minimally affected infectivity. Replication efficiency, in contrast, was reduced at 33°C relative to that at 37°C, and this effect was slightly greater for the conjunctivitis isolates than for the respiratory ones. With the exception of a seasonal H3N2 virus, the subset of viruses studied in multilayer corneal tissue constructs also replicated productively after either aerosol or liquid inoculation. Human tears significantly inhibited the hemagglutination of both ocular and nonocular isolates, but the effect on viral infectivity was more variable, with tears reducing the infectivity of nonocular isolates more than ocular isolates. These data suggest that most influenza viruses may be capable of establishing infection if they reach the surface of ocular cells but that this is more likely for ocular-tropic viruses, as they are better able to maintain their infectivity during passage through the tear film.

Keywords

EpiCorneal (COR-100), influenza virus, infection, tight junction protein ZO-1, Mucin 1 (MUC1), Mucin 4 (MUC4), Mucin 16 (MUC16), α2,6- linked sialic acid, α2,3-linked sialic acid eye, viral replication, ocular infection, tropism, aerosol inoculation, tear film, conjunctivitis

Materials Tested

influenza A viruses (10), aerosols

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