Human metapneumovirus (HMPV), a recently discovered paramyxovirus, infects nearly 100% of the world population and causes severe respiratory disease in infants, the elderly, and immunocompromised patients. We previously showed that HMPV binds heparan sulfate proteoglycans (HSPGs) and that HMPV binding requires only the viral fusion (F) protein. To characterize the features of this interaction critical for HMPV binding and the role of this interaction in infection in relevant models, we utilized sulfated polysaccharides, heparan sulfate mimetics, and occluding compounds. Iota-carrageenan demonstrated potent anti-HMPV activity by inhibiting binding to lung cells mediated by the F protein. Furthermore, analysis of a minilibrary of variably sulfated derivatives of Escherichia coli K5 polysaccharide mimicking the HS structure revealed that the highly O-sulfated K5 polysaccharides inhibited HMPV infection, identifying a potential feature of HS critical for HMPV binding. The peptide dendrimer SB105-A10, which binds HS, reduced binding and infection in an F-dependent manner, suggesting that occlusion of HS at the target cell surface is sufficient to prevent infection. HMPV infection was also inhibited by these compounds during apical infection of polarized airway tissues, suggesting that these interactions take place during HMPV infection in a physiologically relevant model. These results reveal key features of the interaction between HMPV and HS, supporting the hypothesis that apical HS in the airway serves as a binding factor during infection, and HS modulating compounds may serve as a platform for potential antiviral development.
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Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) under award F30AI114194 to E.M.K. and NIH grants R01AI051517 and 2P20 RR020171 from the National Center for Research Resources to R.E.D. Funding was also provided by the CCTS TL1 training program (TL1TR000115) to E.M.K. and UK University Research Professor funds to R.E.D. The UK Flow Cytometry & Cell Sorting Core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center, and an NCI Center Core Support Grant (P30 CA177558) to the University of Kentucky Markey Cancer Center.
Klimyte, Edita M.; Smith, Stacy E.; Oreste, Pasqua; Lembo, David; and Dutch, Rebecca Ellis, "Inhibition of Human Metapneumovirus Binding to Heparan Sulfate Blocks Infection in Human Lung Cells and Airway Tissues" (2016). Molecular and Cellular Biochemistry Faculty Publication. 107.