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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IDM-S (03))
Program Officer
Chin, Jean
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Medicine
United States
Zip Code
Wen, Xiaolin; Mousa, Jarrod J; Bates, John T et al. (2017) Structural basis for antibody cross-neutralization of respiratory syncytial virus and human metapneumovirus. Nat Microbiol 2:16272
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
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
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
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
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
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
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

Showing the most recent 10 out of 32 publications