Influenza A penetrates host mucus by cleaving sialic acids with neuraminidase

被引:222
作者
Cohen, Miriam [1 ]
Zhang, Xing-Quan [2 ]
Senaati, Hooman P. [1 ]
Chen, Hui-Wen [2 ]
Varki, Nissi M. [1 ]
Schooley, Robert T. [2 ]
Gagneux, Pascal [1 ]
机构
[1] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Div Infect Dis, La Jolla, CA 92093 USA
来源
VIROLOGY JOURNAL | 2013年 / 10卷
关键词
Influenza A; Sialic acids; Mucus; Neuraminidase; Infection; Saliva; HUMAN AIRWAY EPITHELIUM; HUMAN SALIVARY MUCINS; RECEPTOR-BINDING; VIRUS INFECTION; RESPIRATORY-TRACT; MEMBRANE-FUSION; SPECIFICITY; MICROARRAY; CONTRIBUTE; DEFENSE;
D O I
10.1186/1743-422X-10-321
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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.
引用
收藏
页数:13
相关论文
共 52 条
  • [31] PROBING OF THE RECEPTOR-BINDING SITES OF THE H1 AND H3 INFLUENZA-A AND INFLUENZA-B VIRUS HEMAGGLUTININS BY SYNTHETIC AND NATURAL SIALOSIDES
    MATROSOVICH, MN
    GAMBARYAN, AS
    TUZIKOV, AB
    BYRAMOVA, NE
    MOCHALOVA, LV
    GOLBRAIKH, AA
    SHENDEROVICH, MD
    FINNE, J
    BOVIN, NV
    [J]. VIROLOGY, 1993, 196 (01) : 111 - 121
  • [32] 2-DEOXY-2,3-DEHYDROSIALIC ACIDS, .2. COMPETIVE INHIBITION OF VIBRIO CHOLERAE NEURAMINIDASE BY 2-DEOXY-2,3-DEHYDRO-N-ACYLNEURAMINIC ACIDS
    MEINDL, P
    TUPPY, H
    [J]. HOPPE-SEYLERS ZEITSCHRIFT FUR PHYSIOLOGISCHE CHEMIE, 1969, 350 (09): : 1088 - &
  • [33] SIALIDASES IN VERTEBRATES: A FAMILY OF ENZYMES TAILORED FOR SEVERAL CELL FUNCTIONS
    Monti, Eugenio
    Bonten, Erik
    D'Azzo, Alessandra
    Bresciani, Roberto
    Venerando, Bruno
    Borsani, Giuseppe
    Schauer, Roland
    Tettamanti, Guido
    [J]. ADVANCES IN CARBOHYDRATE CHEMISTRY AND BIOCHEMISTRY, VOL 64, 2010, 64 : 403 - 479
  • [34] NADANO D, 1986, J BIOL CHEM, V261, P1550
  • [35] Neuraminidase activity assays for monitoring MDCK cell culture derived influenza virus
    Nayak, DP
    Reichl, U
    [J]. JOURNAL OF VIROLOGICAL METHODS, 2004, 122 (01) : 9 - 15
  • [36] Sialic acid receptor detection in the human respiratory tract: evidence for widespread distribution of potential binding sites for human and avian influenza viruses
    Nicholls, John M.
    Bourne, Anthony J.
    Chen, Honglin
    Guan, Yi
    Peiris, J. S. Malik
    [J]. RESPIRATORY RESEARCH, 2007, 8 (1):
  • [37] Cross Talk Between Animal and Human Influenza Viruses
    Ozawa, Makoto
    Kawaoka, Yoshihiro
    [J]. ANNUAL REVIEW OF ANIMAL BIOSCIENCES, VOL 1, 2013, 1 : 21 - 42
  • [38] N-ACETYL-9-O-L-LACTYLNEURAMINIC ACID, A NEW ACYLNEURAMINIC ACID FROM BOVINE SUBMANDIBULAR-GLAND
    SCHAUER, R
    HAVERKAMP, J
    WEMBER, M
    VLIEGENTHART, JFG
    KAMERLING, JP
    [J]. EUROPEAN JOURNAL OF BIOCHEMISTRY, 1976, 62 (02): : 237 - 242
  • [39] Antivirals for influenza: Strategies for use in pediatrics
    Smith S.M.
    Gums J.G.
    [J]. Pediatric Drugs, 2010, 12 (5) : 285 - 299
  • [40] Glycan microarray technologies: tools to survey host specificity of influenza viruses
    Stevens, James
    Blixt, Ola
    Paulson, James C.
    Wilson, Ian A.
    [J]. NATURE REVIEWS MICROBIOLOGY, 2006, 4 (11) : 857 - 864