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Data from: Human parainfluenza virus 3 fusion protein cleavage: A key determinant of infection and spread

Stearns, Kyle1; Marcink, Tara1; Pawlack, Emily2; Sobolik, Elizabeth3; Porotto, Matteo1; Greninger, Alexander3; Niewiesk, Stefan2; Moscona, Anne1

Published May 09, 2026 on Dryad. https://doi.org/10.5061/dryad.xd2547dwk

Data files

May 09, 2026 version files 11.96 MB

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Abstract

Human parainfluenza virus 3 (HPIV3) entry into target cells depends on a viral fusion complex composed of hemagglutinin-neuraminidase (HN) and fusion protein (F). In addition to attachment, HN activates F to mediate membrane fusion, while its neuraminidase activity promotes viral release. This creates a biological paradox: virions must repeatedly engage sialic acid-rich substrates in the airway without prematurely triggering F, until they reach the target cell sialic acid receptor. Unlike the F proteins of laboratory strains that are cleaved intracellularly by furin to process F from its pro-protein to the active form that is essential for fusion, the F proteins of HPIV3 field strains lack a furin cleavage site and undergo partial cleavage mediated by extracellular serine proteases. We show that virions isolated directly from infected humans contain both cleaved and uncleaved F. In viral migration assays, reducing the proportion of cleaved F on virions increases the distance virions travel before infecting a cell. Even virions bearing only uncleaved F upon egress from infected cells can establish infection in vivo. These findings support a model in which uncleaved F on viral surfaces permits virions to engage and disengage sialylated substrates without undergoing premature fusion protein triggering, allowing virions to traverse the airway. Cleavage of F at the target cell then licenses membrane fusion, ensuring that virions initiate infection at the correct site. HPIV3 exploits host protease environments to produce virions with heterogeneity in F cleavage, equipped to either establish local infection or spread to distant target cells.