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Influenza A virus diffusion through mucus gel networks.

ABSTRACT: Mucus in the lung plays an essential role as a barrier to infection by viral pathogens such as influenza A virus (IAV). Previous work determined mucin-associated sialic acid acts as a decoy receptor for IAV hemagglutinin (HA) binding and the sialic-acid cleaving enzyme, neuraminidase (NA), facilitates virus passage through mucus. However, it has yet to be fully addressed how the physical structure of the mucus gel influences its barrier function and its ability to trap viruses via glycan mediated interactions to prevent infection. To address this, IAV and nanoparticle diffusion in human airway mucus and mucin-based hydrogels is quantified using fluorescence video microscopy. We find the mobility of IAV in mucus is significantly influenced by the mesh structure of the gel and in contrast to prior reports, these effects likely influence virus passage through mucus gels to a greater extent than HA and NA activity. In addition, an analytical approach is developed to estimate the binding affinity of IAV to the mucus meshwork, yielding dissociation constants in the mM range, indicative of weak IAV-mucus binding. Our results provide important insights on how the adhesive and physical barrier properties of mucus influence the dissemination of IAV within the lung microenvironment.

SUBMITTER: Kaler L

PROVIDER: S-EPMC8941132 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Influenza A virus diffusion through mucus gel networks.

Kaler Logan L Iverson Ethan E Bader Shahed S Song Daniel D Scull Margaret A MA Duncan Gregg A GA

Communications biology 20220322 1

Mucus in the lung plays an essential role as a barrier to infection by viral pathogens such as influenza A virus (IAV). Previous work determined mucin-associated sialic acid acts as a decoy receptor for IAV hemagglutinin (HA) binding and the sialic-acid cleaving enzyme, neuraminidase (NA), facilitates virus passage through mucus. However, it has yet to be fully addressed how the physical structure of the mucus gel influences its barrier function and its ability to trap viruses via glycan mediate ...[more]

PMID: 35318436

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Project description:Sialic acids (Sia) are the primary receptors for influenza viruses and are widely displayed on cell surfaces and in secreted mucus. Sia may be present in variant forms that include O-acetyl modifications at C-4, C-7, C-8, and C-9 positions and N-acetyl or N-glycolyl at C-5. They can also vary in their linkages, including α2-3 or α2-6 linkages. Here, we analyze the distribution of modified Sia in cells and tissues of wild-type mice or in mice lacking CMP-N-acetylneuraminic acid hydroxylase (CMAH) enzyme, which synthesizes N-glycolyl (Neu5Gc) modifications. We also examined the variation of Sia forms on erythrocytes and in saliva from different animals. To determine the effect of Sia modifications on influenza A virus (IAV) infection, we tested for effects on hemagglutinin (HA) binding and neuraminidase (NA) cleavage. We confirmed that 9-O-acetyl, 7,9-O-acetyl, 4-O-acetyl, and Neu5Gc modifications are widely but variably expressed in mouse tissues, with the highest levels detected in the respiratory and gastrointestinal (GI) tracts. Secreted mucins in saliva and surface proteins of erythrocytes showed a high degree of variability in display of modified Sia between different species. IAV HAs from different virus strains showed consistently reduced binding to both Neu5Gc- and O-acetyl-modified Sia; however, while IAV NAs were inhibited by Neu5Gc and O-acetyl modifications, there was significant variability between NA types. The modifications of Sia in mucus may therefore have potent effects on the functions of IAV and may affect both pathogens and the normal flora of different mucosal sites.IMPORTANCE Sialic acids (Sia) are involved in numerous different cellular functions and are receptors for many pathogens. Sia come in chemically modified forms, but we lack a clear understanding of how they alter interactions with microbes. Here, we examine the expression of modified Sia in mouse tissues, on secreted mucus in saliva, and on erythrocytes, including those from IAV host species and animals used in IAV research. These Sia forms varied considerably among different animals, and their inhibitory effects on IAV NA and HA activities and on bacterial sialidases (neuraminidases) suggest a host-variable protective role in secreted mucus.

Project description:Respiratory mucus lining the airway epithelium constitutes an important first line of defense against infection with influenza A virus (IAV). Previous studies suggested that the inhibitory potential of mucus relies not only on the presence of decoy receptors but also on the dense meshwork blocking virus access to the epithelium independent of sialic acid. Here, we report for a panel of human and avian IAV isolates that susceptibility to neutralization by respiratory mucus varies in a strain-dependent manner. Our data reveal that viral neuraminidase (NA) activity inversely correlates with the mucus sensitivity of a given strain. As NA cleaves sialic acid from glycan chains and thus releases IAV from decoy receptor binding, our results imply that virus inhibition by mucus is mainly driven by decoy receptor binding of IAV. Other inhibitory properties of mucus, such as size exclusion, non-covalent interactions with mucus components, or the presence of immunomodulatory molecules, likely play minor roles in neutralizing IAV. Inhibition of NA activity using oseltamivir was sufficient to increase the sensitivity of a seasonal IAV strain to mucus during infection in a cell-based neutralization assay and in differentiated primary human airway epithelial cultures. Overall, our data highlight the importance of NA for the initiation of virus infection besides its major function in release, especially in overcoming the host defense mechanism of mucociliary clearance in the airway epithelium. Furthermore, strain-specific differences in the ability to penetrate respiratory mucus may be the result of host adaptation and can have consequences for the transmissibility and infectivity of circulating viruses. IMPORTANCE The respiratory tract of humans is constantly exposed to potentially harmful agents, such as small particles or pathogens, and thus requires protective measures. Respiratory mucus that lines the airway epithelia plays a major role in the prevention of viral infections by limiting the mobility of viruses, allowing subsequent mucociliary clearance. Understanding the interplay between respiratory mucus and viruses can help elucidate host and virus characteristics that enable the initiation of infection. Here, we tested a panel of primary influenza A viruses of avian or human origin for their sensitivity to mucus derived from primary human airway cultures and found that differences between virus strains can be mapped to viral neuraminidase activity. We also show that binding of influenza A viruses to decoy receptors on highly glycosylated mucus components constitutes the major inhibitory function of mucus against influenza A viruses.

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Influenza A virus diffusion through mucus gel networks.

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Influenza A virus diffusion through mucus gel networks.

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