The Paramyxoviruses infect human and animal hosts and are responsible for causing major human illnesses, as well as animal infections of significant economic consequence. The entry into cells of most Paramyxoviruses requires an attachment protein, HN, H or G, depending on the virus, and a fusion (F) glycoprotein. In this proposal will study the structure and function of the HN protein to better understand how its stalk region controls the specificity of F protein activation, thereby triggering membrane fusion. We will determine why a subset of HN proteins require a proteolytic activation step to enable receptor binding, receptor destroying and fusion promoting activities. This proposal will also focus on the study of the F glycoproteins, to gain insight into potential structural differences in the prefusion conformations across the paramyxovirus family and to better understand how neutralizing antibodies engage and inhibit F protein functions. The proposed research will provide significant new insights into how these paramyxovirus entry glycoproteins mediate infection and potentially provide new avenues for the development of antiviral therapeutics.

Public Health Relevance

The Paramyxoviruses are a large virus family whose members are the cause of significant human morbidity and mortality. The entry of paramyxoviruses into a cell requires the fusion of viral and cellular lipid membranes. This process is carried out by the viral fusion glycoprotein (F), typically after it is activated by a viral attachment protein (HN, H or G), which binds to a host cell receptor. This research proposal focuses on furthering our understanding of both F and HN proteins and how these communicate and function in viral entry and infection. In addition, the proposed research will investigate how antibodies directed against the F protein neutralize the virus. The results of this research will have potential significance in developing novel antiviral therapeutics and vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061050-10
Application #
8450699
Study Section
Special Emphasis Panel (ZRG1-IDM-S (03))
Program Officer
Sakalian, Michael
Project Start
2000-04-01
Project End
2016-02-29
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$290,890
Indirect Cost
$105,610
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Adu-Gyamfi, Emmanuel; Kim, Lori S; Jardetzky, Theodore S et al. (2016) Mutagenesis of Paramyxovirus Hemagglutinin-Neuraminidase Membrane-Proximal Stalk Region Influences Stability, Receptor Binding, and Neuraminidase Activity. J Virol 90:7778-88
Wong, Joyce J W; Paterson, Reay G; Lamb, Robert A et al. (2016) Structure and stabilization of the Hendra virus F glycoprotein in its prefusion form. Proc Natl Acad Sci U S A 113:1056-61
Adu-Gyamfi, Emmanuel; Kim, Lori S; Jardetzky, Theodore S et al. (2016) Flexibility of the Head-Stalk Linker Domain of Paramyxovirus HN Glycoprotein Is Essential for Triggering Virus Fusion. J Virol 90:9172-81
Song, Albert S; Poor, Taylor A; Abriata, Luciano A et al. (2016) Immobilization of the N-terminal helix stabilizes prefusion paramyxovirus fusion proteins. Proc Natl Acad Sci U S A 113:E3844-51
Poor, Taylor A; Song, Albert S; Welch, Brett D et al. (2015) On the stability of parainfluenza virus 5 F proteins. J Virol 89:3438-41
Bose, Sayantan; Jardetzky, Theodore S; Lamb, Robert A (2015) Timing is everything: Fine-tuned molecular machines orchestrate paramyxovirus entry. Virology 479-480:518-31
Poor, Taylor A; Jones, Lisa M; Sood, Amika et al. (2014) Probing the paramyxovirus fusion (F) protein-refolding event from pre- to postfusion by oxidative footprinting. Proc Natl Acad Sci U S A 111:E2596-605
Bose, Sayantan; Song, Albert S; Jardetzky, Theodore S et al. (2014) Fusion activation through attachment protein stalk domains indicates a conserved core mechanism of paramyxovirus entry into cells. J Virol 88:3925-41
Jardetzky, Theodore S; Lamb, Robert A (2014) Activation of paramyxovirus membrane fusion and virus entry. Curr Opin Virol 5:24-33
Welch, Brett D; Paduch, Marcin; Leser, George P et al. (2014) Probing the functions of the paramyxovirus glycoproteins F and HN with a panel of synthetic antibodies. J Virol 88:11713-25

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