Influenza A penetrates host mucus by cleaving sialic acids with neuraminidase
Open accessAbstract
BACKGROUND: Influenza A virus (IAV) neuraminidase (NA) cleaves sialic acids (Sias) from glycans. Inhibiting NA with oseltamivir suppresses both viral infection, and viral release from cultured human airway epithelial cells. The role of NA in viral exit is well established: it releases budding virions by cleaving Sias from glycoconjugates on infected cells and progeny virions. The role of NA in viral entry remains unclear. Host respiratory epithelia secrete a mucus layer rich in heavily sialylated glycoproteins; these could inhibit viral entry by mimicking sialylated receptors on the cell surface. It has been suggested that NA allows influenza to penetrate the mucus by cleaving these sialylated decoys, but the exact mechanism is not yet established. METHODS: We tested IAV interaction with secreted mucus using frozen human trachea/bronchus tissue sections, and bead-bound purified human salivary mucins (HSM) and purified porcine submaxillary mucins (PSM). The protective effect of mucus was analyzed using MDCK cells coated with purified HSM and PSM with known Sia content. Oseltamivir was used to inhibit NA activity, and the fluorescent reporter substrate, 4MU-Neu5Ac, was used to quantify NA activity. RESULTS: IAV binds to the secreted mucus layer of frozen human trachea/bronchus tissues in a Sia dependent manner. HSM inhibition of IAV infection is Sia dose-dependent, but PSM cannot inhibit infection of underlying cells. HSM competitively inhibits NA cleavage of 4MU-Neu5Ac, reporter substrate. Human IAV effectively cleaves Sias from HSM but not from PSM, and binds to HSM but not to PSM. CONCLUSION: IAV interacts with human mucus on frozen tissue sections and mucus-coated beads. Inhibition of IAV infection by sialylated human mucus is dose-dependent, and enhanced when NA is inhibited with oseltamivir. Thus NA cleaves sialylated decoys during initial stages of infection. Understanding IAV interactions with host mucins is a promising new avenue for drug development.
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- Authors
- Cohen, M., Zhang, X.-Q., Senaati, H. P., Chen, H.-W., Varki, N. M., Schooley, R. T., & Gagneux, P.
- Affiliations
- University of California San Diego (US)
- National Taiwan University (TW)
- Corresponding author
- Gagneux, Pascal
- Venue
- Virology Journal
- Published
- 2013-11-22
- Volume
- 10
- Issue
- 1
- Pages
- 321-321
- ISSN
- 1743-422X (ISSN-L)
- PMC
- PMC3842836
- OpenAlex
- W2119621200
- Cited by
- 288
- References
- 56
- Citations by year
- 2026: 12 · 2025: 25 · 2024: 23 · 2023: 27 · 2022: 23 · 2021: 26 · 2020: 26 · 2019: 31 · 2018: 21 · 2017: 21 · 2016: 25 · 2015: 17 · 2014: 11
- FWCI
- 13.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Virology Journal (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- University of California, San Diego (#NS047101, P30 CA23100, P30 NS047101)
- National Cancer Institute (P30-CA-23100, P30CA023100)
- National Institute of Allergy and Infectious Diseases (U01AI074521)
- National Institute of Neurological Disorders and Stroke (NS047101, P30NS047101)
- Topics
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
- Keywords
- influenza A virus, neuraminidase, sialic acid, mucus, viral entry, salivary mucins, submaxillary mucin, oseltamivir, respiratory epithelium
- MeSH terms
- Animals, Bronchi, Cell Line, Dogs, Humans, Mucus, Neuraminidase, Influenza A virus, Saliva, Sialic Acids, Trachea, Viral Proteins, Virus Internalization
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