This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Influenza virions target their hosts by first binding to nine-carbon backbone sugars (sialic acids, Sias) on host cells to initiate infection. After binding sialylated structures on the cell membrane, influenza viruses infect cells via endocytic pathways. The two major viral envelope proteins are hemagglutinin (HA), which binds to Sias, and neuraminidase (NA), which cleaves host Sias. All Influenza A virus subtypes have been isolated from wild bird species, which are considered the reservoir for infection. Influenza targets and binds sialylated glycans on the gastrointestinal (GI) tract and respiratory epithelia. The epithelium is covered with a thick mucus layer comprised of sialylated secreted-mucins, which can potentially act as a natural barrier for influenza infection by providing a """"""""decoy"""""""" for viruses HA binding. Mucins are complex and heavily glycosylated O-linked glycoproteins, which form the major component of the mucus layer. Binding to mucins will inhibit influenza viruses from reaching the underlying epithelial cells, however, influenza NA can potentially cleave the sialylated mucins and allow virus penetration toward the host cell. The relationship between mucin-binding by the viruses HA and cleaving by the viruses NA will determine whether the viruses will be able to escape from the """"""""decoy"""""""". Despite the substantial thickness of the mucin layer (10-200 ?m), and the potential role of mucins in influenza binding and infection, studies of influenza host tissues interactions are done on dehydrated tissues in which the mucus layer is destroyed. We propose to study the interplay between influenza virus and the secreted mucus, and to obtain molecular resolution information on influenza-mucin interaction, by cryo-electron microscopy.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR017573-10
Application #
8362478
Study Section
Special Emphasis Panel (ZRG1-CB-B (40))
Project Start
2011-05-01
Project End
2012-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
10
Fiscal Year
2011
Total Cost
$6,427
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Kulczyk, Arkadiusz W; Moeller, Arne; Meyer, Peter et al. (2017) Cryo-EM structure of the replisome reveals multiple interactions coordinating DNA synthesis. Proc Natl Acad Sci U S A 114:E1848-E1856
Sherman, Michael B; Kakani, Kishore; Rochon, D'Ann et al. (2017) Stability of Cucumber Necrosis Virus at the Quasi-6-Fold Axis Affects Zoospore Transmission. J Virol 91:
Short, James R; Speir, Jeffrey A; Gopal, Radhika et al. (2016) Role of Mitochondrial Membrane Spherules in Flock House Virus Replication. J Virol 90:3676-83
Razinkov, Ivan; Dandey, Venkat; Wei, Hui et al. (2016) A new method for vitrifying samples for cryoEM. J Struct Biol 195:190-198
Guenaga, Javier; de Val, Natalia; Tran, Karen et al. (2015) Well-ordered trimeric HIV-1 subtype B and C soluble spike mimetics generated by negative selection display native-like properties. PLoS Pathog 11:e1004570
McCullough, John; Clippinger, Amy K; Talledge, Nathaniel et al. (2015) Structure and membrane remodeling activity of ESCRT-III helical polymers. Science 350:1548-51
McNulty, Reginald; Lokareddy, Ravi Kumar; Roy, Ankoor et al. (2015) Architecture of the Complex Formed by Large and Small Terminase Subunits from Bacteriophage P22. J Mol Biol 427:3285-3299
Lee, Jeong Hyun; Leaman, Daniel P; Kim, Arthur S et al. (2015) Antibodies to a conformational epitope on gp41 neutralize HIV-1 by destabilizing the Env spike. Nat Commun 6:8167
Derking, Ronald; Ozorowski, Gabriel; Sliepen, Kwinten et al. (2015) Comprehensive antigenic map of a cleaved soluble HIV-1 envelope trimer. PLoS Pathog 11:e1004767
Grover, Rajesh K; Zhu, Xueyong; Nieusma, Travis et al. (2014) A structurally distinct human mycoplasma protein that generically blocks antigen-antibody union. Science 343:656-661

Showing the most recent 10 out of 187 publications