The Nipah virus (NiV) is an emerging viral pathogen, classified as a Category C pathogen of the NIAID Biodefense Research Agenda. NiV infects agricultural livestock and humans; in 1999, NiV infection among agricultural workers in Malaysia and Singapore resulted in a 40% mortality rate and loss of livestock worth over $100 million. NiV is a member of a new genus of paramyxoviruses, and little is known about NiV biology or the immune response to NiV. However, autopsy studies of NiV victims found that the virus targets lymph nodes and endothelial cells with endothelial syncytia formation being the pathologic hallmark of NiV infection. Cell fusion and syncytia formation depend on expression of the NiV F and G envelope glycoproteins. We have found that syncytia formation is regulated by glycosylation of these envelope glycoproteins, with specific N-glycans on NiV F and G playing important roles in cell fusion. Importantly, we have also found that cell fusion can be blocked by galectin-1, an endogenous lectin of the innate immune system that is expressed by endothelial cells and dendritic cells. In addition, we have made the novel observation that galectin-1 induces robust pro-inflammatory cytokine secretion by monocyte derived dendritic cells, an effect that may augment an antiviral immune response. Our driving hypothesis for this proposal is that glycan structures on the NiV F and G glycoproteins. and the innate immune lectin galectin-1 that recognizes these structures, are critical determinants in the pathogenesis of this viral disease.
Our Specific Aims are: (1) Determine structural features of oligosaccharides on the F and G env glycoproteins that are critical for glycoprotein expression and syncytia formation, (2) Elucidate the mechanism by which galectin-1 regulates NiV envelope glycoprotein-mediated cell fusion, (3) Characterize the structural features involved in binding to and fusion of target cells, (4) Examine the effects of galectin-1 on soluble mediators of the innate and adaptive immune response. This work will address critical issues for rapid development of strategies to enhance innate immune responses to this emerging viral pathogen. The co-investigators have a unique combination of expertise, and propose an innovative set of studies into the glycobiology of NiV pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI060694-01A1
Application #
6915278
Study Section
Special Emphasis Panel (ZRG1-IHD (01))
Program Officer
Cassetti, Cristina
Project Start
2005-03-15
Project End
2010-02-28
Budget Start
2005-03-15
Budget End
2006-02-28
Support Year
1
Fiscal Year
2005
Total Cost
$385,417
Indirect Cost
Name
University of California Los Angeles
Department
Pathology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Vigant, Frederic; Lee, Benhur (2011) Hendra and nipah infection: pathology, models and potential therapies. Infect Disord Drug Targets 11:315-36
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Bi, Shuguang; Hong, Patrick W; Lee, Benhur et al. (2011) Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry. Proc Natl Acad Sci U S A 108:10650-5
Aguilar, Hector C; Aspericueta, Vanessa; Robinson, Lindsey R et al. (2010) A quantitative and kinetic fusion protein-triggering assay can discern distinct steps in the nipah virus membrane fusion cascade. J Virol 84:8033-41
Garner, Omai B; Aguilar, Hector C; Fulcher, Jennifer A et al. (2010) Endothelial galectin-1 binds to specific glycans on nipah virus fusion protein and inhibits maturation, mobility, and function to block syncytia formation. PLoS Pathog 6:e1000993
Fulcher, Jennifer A; Chang, Margaret H; Wang, Shuo et al. (2009) Galectin-1 co-clusters CD43/CD45 on dendritic cells and induces cell activation and migration through Syk and protein kinase C signaling. J Biol Chem 284:26860-70
Aguilar, Hector C; Ataman, Zeynep Akyol; Aspericueta, Vanessa et al. (2009) A novel receptor-induced activation site in the Nipah virus attachment glycoprotein (G) involved in triggering the fusion glycoprotein (F). J Biol Chem 284:1628-35

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