The focus of the proposed studies in the Project 3 of this Program Project is to provide high-resolution structural information, using X-ray crystallographic techniques, on both human and animal caliciviruses including the non-structural proteins to identify structural targets for the design and development of antiviral and diagnostic strategies.
In aim 1, we propose to determine crystallographic structures of (1) San Miguel sea lion virus, as a representative example of an animal calicivirus in the Vesivirus genus in which the viruses show a broad host range including a potential ability to infect humans, and cause a variety of illnesses; (2) recombinant Grimsby virus capsid (rGrV), as a representative of human calicivirus in the genogroup 2 of the Norovirus genus which shows contrasting carbohydrate binding properties, and (3) recombinant Sapporo virus capsid as a representative human calicivirus in the Sapovirus genus, in which the viruses are morphologically more similar to animal caliciviruses than to human noroviruses. These studies should provide an atomic level description of the structural variations in calicivirus capsids that may form a basis for host-specificity, tissue tropism, and contrasting receptor-binding activities. These studies are particularly relevant considering the recent findings that suggest zoonotic potential and inter-species transmission of caliciviruses.
In aim 2, we propose to determine the crystallographic structure of recombinant Norwalk virus (rNV) complexed with histo-blood group carbohydrates. Recently, Dr. Estes and others have shown that carbohydrates are cell-binding ligands for NV. These studies together with comparative structural analysis of rNV and rGrV should provide insights into the specificity of carbohydrate binding. The structural information learned should be useful for both the design of oligosaccharide mimics that could prevent or ameliorate infection by inhibiting virus binding to cells, and for developing carbohydrate-based diagnostic assays for human caliciviruses (Project 1 of this Program).
In aim 3, we propose crystallographic studies on VP2, encoded by the third ORF of the NV genome, and two enzymes, a 3C-like protease and an NTPase encoded by the first ORF. The minor capsid protein VP2 is suggested to be involved in enhanced capsid expression and stability and genome packaging (Project 2 of this Program). Because of their specific activities during virus infection, these proteins are promising targets for antiviral drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI057788-04
Application #
7447852
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
4
Fiscal Year
2007
Total Cost
$216,738
Indirect Cost
Name
Baylor College of Medicine
Department
Type
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Alvarado, Gabriela; Ettayebi, Khalil; Atmar, Robert L et al. (2018) Human Monoclonal Antibodies That Neutralize Pandemic GII.4 Noroviruses. Gastroenterology 155:1898-1907
Costantini, Veronica; Morantz, Esther K; Browne, Hannah et al. (2018) Human Norovirus Replication in Human Intestinal Enteroids as Model to Evaluate Virus Inactivation. Emerg Infect Dis 24:1453-1464
Bányai, Krisztián; Estes, Mary K; Martella, Vito et al. (2018) Viral gastroenteritis. Lancet 392:175-186
Cortes-Penfield, Nicolas W; Ramani, Sasirekha; Estes, Mary K et al. (2017) Prospects and Challenges in the Development of a Norovirus Vaccine. Clin Ther 39:1537-1549
Ramani, Sasirekha; Neill, Frederick H; Ferreira, Jennifer et al. (2017) B-Cell Responses to Intramuscular Administration of a Bivalent Virus-Like Particle Human Norovirus Vaccine. Clin Vaccine Immunol 24:
Hurwitz, Amy M; Huang, Wanzhi; Estes, Mary K et al. (2017) Deep sequencing of phage-displayed peptide libraries reveals sequence motif that detects norovirus. Protein Eng Des Sel 30:129-139
Sharma, Sumit; Carlsson, Beatrice; Czakó, Rita et al. (2017) Human Sera Collected between 1979 and 2010 Possess Blocking-Antibody Titers to Pandemic GII.4 Noroviruses Isolated over Three Decades. J Virol 91:
Shanker, Sreejesh; Hu, Liya; Ramani, Sasirekha et al. (2017) Structural features of glycan recognition among viral pathogens. Curr Opin Struct Biol 44:211-218
Zou, Winnie Y; Blutt, Sarah E; Crawford, Sue E et al. (2017) Human Intestinal Enteroids: New Models to Study Gastrointestinal Virus Infections. Methods Mol Biol :
Yu, Huimin; Hasan, Nesrin M; In, Julie G et al. (2017) The Contributions of Human Mini-Intestines to the Study of Intestinal Physiology and Pathophysiology. Annu Rev Physiol 79:291-312

Showing the most recent 10 out of 98 publications