Influenza virus remains a major public health concern for the USA and the world. To best insure that a pandemic like the 1918-1919 episode does not reoccur, national and international surveillance, effective vaccine and novel and effective antiviral therapy are required. Here we propose a multi-institute cooperative research project focused on discovery and use of novel chemicals that selectively manipulate the immunologic response in the lung as a therapeutic approach to better control influenza viral infection. We and others have evidence in animal models that the immune response (immunopathology) to influenza contributes significantly to morbidity and mortality. We have preliminary but impressive data that low doses of sphingosine analogs administered as a single dose intratracheally but not systemically acts locally in the lung to specifically suppress antiviral T cell proliferative responses. We propose that: 1) single aerosol exposure of the lungs to a sphingosine analog will inhibit antiviral proliferation thus modulating the resultant immunopathologic injury; 2) this mechanism will synergize with classic antiviral protective therapy; 3) combination of these therapeutic approaches will protect the host during H5N1 infection. To test this proposal Hugh Rosen, with expertise in immunology, medicinal chemistry and human therapeutics, will continue the development of sphingosine compounds and their testing with Michael Oldstone, experienced in viral-immunobiology and use of the WSN recombinant virus expressing immunodominant CDS and CD4 T cell epitopes of LCMV. WSN recombinant infection is preceded with transfer of GFP, RFP or Th1.1 congenically labeled CD4 and CDS T cells to these LCMV epitopes allowing quantitation of flu-specific T cells in the lung. The LCMV recombinant as well as GFP-labeled WSN virus used has been prepared by the third partner in this enterprise, Yoshihiro Kawaoka, an expert in influenza viruses. Kawaoka will test novel sphingosine analogs against H5N1 influenza virus. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AI074564-01
Application #
7288013
Study Section
Special Emphasis Panel (ZAI1-CCH-M (M2))
Program Officer
Krafft, Amy
Project Start
2007-06-01
Project End
2012-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$1,606,853
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Sarkisyan, Gor; Gay, Laurie J; Nguyen, Nhan et al. (2014) Host endothelial S1PR1 regulation of vascular permeability modulates tumor growth. Am J Physiol Cell Physiol 307:C14-24
Teijaro, John R; Walsh, Kevin B; Long, James P et al. (2014) Protection of ferrets from pulmonary injury due to H1N1 2009 influenza virus infection: immunopathology tractable by sphingosine-1-phosphate 1 receptor agonist therapy. Virology 452-453:152-7
Oldstone, Michael B A; Rosen, Hugh (2014) Cytokine storm plays a direct role in the morbidity and mortality from influenza virus infection and is chemically treatable with a single sphingosine-1-phosphate agonist molecule. Curr Top Microbiol Immunol 378:129-47
Walsh, Kevin B; Teijaro, John R; Brock, Linda G et al. (2014) Animal model of respiratory syncytial virus: CD8+ T cells cause a cytokine storm that is chemically tractable by sphingosine-1-phosphate 1 receptor agonist therapy. J Virol 88:6281-93
Oldstone, Michael B A; Teijaro, John R; Walsh, Kevin B et al. (2013) Dissecting influenza virus pathogenesis uncovers a novel chemical approach to combat the infection. Virology 435:92-101
Matheu, Melanie P; Teijaro, John R; Walsh, Kevin B et al. (2013) Three phases of CD8 T cell response in the lung following H1N1 influenza infection and sphingosine 1 phosphate agonist therapy. PLoS One 8:e58033
Walsh, Kevin B; Sidney, John; Welch, Megan et al. (2013) CD8+ T-cell epitope mapping for pneumonia virus of mice in H-2b mice. J Virol 87:9949-52
Guerrero, Miguel; Poddutoori, Ramulu; Urbano, Mariangela et al. (2013) Discovery, design and synthesis of a selective S1P(3) receptor allosteric agonist. Bioorg Med Chem Lett 23:6346-9
Rosen, Hugh; Stevens, Raymond C; Hanson, Michael et al. (2013) Sphingosine-1-phosphate and its receptors: structure, signaling, and influence. Annu Rev Biochem 82:637-62
Oldstone, Michael B A (2013) Lessons learned and concepts formed from study of the pathogenesis of the two negative-strand viruses lymphocytic choriomeningitis and influenza. Proc Natl Acad Sci U S A 110:4180-3

Showing the most recent 10 out of 32 publications