Respiratory Syncytial Virus (RSV) is a major public health problem in virtually all parts of the world, with significant morbidity, and mortality in the immunocompromised host. No effective vaccine is currently available for human use. Although the infection is exquisitely restricted to the respiratory epithelium, the role of mucosal tissues in the mechanism of pathogenesis or protective immunity remains to be determined. The nature of interaction between the respiratory epithelium and the virus appears to be an important determinant of the outcome of infection, based on studies carried out during the current funding period. This renewal proposal will focus on three important areas of mucosal immunity to RSV. These include: 1) Role of respiratory epithelium in the pathogenesis of, and mucosal immune response to infection with RSV. It is proposed to characterize the synthesis and release of immunoregulatory and proinflammatory cytokines by virus infected respiratory epithelial cells, the antigen presenting structures expressed by respiratory epithelium which influence T cell activation after exposure to RSV, and the functional effects of T cells and eosinophils following their interaction with virus infected respiratory epithelial cells. 2) Effects of secretory IgA (sIgA) RSV antibody on uptake of RSV antigen and subsequent development of T cell responses and elimination of the virus infected cells. Studies will be undertaken to evaluate the efficiency of antigen presentation by MHC molecules in respiratory epithelium after exposure to RSV. We will examine the neutralizing antibody activity in RSV specific secretory IgA and evaluate the uptake and secretion of SIgA, polymeric IgA and other RSV specific immunoglobulin by respiratory epithelial cells, employing monoclonal antibodies to the whole virus and to F or G viral proteins. 3) Outcome of differential selection of various RSV antigen epitopes for T cell presentation, based on the lineage of mucosal antigen presenting cells (APC). Comparative studies will be carried out to define the antigen presenting potential of respiratory epithelium (the site of primary disease of RSV), other mucosal epithelial cells and conventional APC. It is proposed to define immunodominant epitopes within F and G proteins of RSV capable of stimulating T cell activation with different MHC alleles. Finally, studies will be carried but to examine the kinetics and repertoire of T cell specific responses to different RSV peptide immunogens. We hope that the studies proposed in this application will show how different components of the immunopathological response to RSV infection are associated with recognition of particular viral proteins expressed on the airway epithelium by specific cytotoxic and helper T cell subsets and how protective immunity can be induced without harmful secondary responses to RSV infection, thereby enhancing the development of a safe, effective vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI015939-14A1
Application #
2060310
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1979-09-30
Project End
1999-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
14
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Haeberle, Helene A; Casola, Antonella; Gatalica, Zoran et al. (2004) IkappaB kinase is a critical regulator of chemokine expression and lung inflammation in respiratory syncytial virus infection. J Virol 78:2232-41
Tian, Bing; Brasier, Allan R (2003) Identification of a nuclear factor kappa B-dependent gene network. Recent Prog Horm Res 58:95-130
Zhang, Yuhong; Jamaluddin, Mohammad; Wang, Shaofei et al. (2003) Ribavirin treatment up-regulates antiviral gene expression via the interferon-stimulated response element in respiratory syncytial virus-infected epithelial cells. J Virol 77:5933-47
Haeberle, Helene A; Takizawa, Ryuta; Casola, Antonella et al. (2002) Respiratory syncytial virus-induced activation of nuclear factor-kappaB in the lung involves alveolar macrophages and toll-like receptor 4-dependent pathways. J Infect Dis 186:1199-206
Welliver, Robert C; Garofalo, Roberto P; Ogra, Pearay L (2002) Beta-chemokines, but neither T helper type 1 nor T helper type 2 cytokines, correlate with severity of illness during respiratory syncytial virus infection. Pediatr Infect Dis J 21:457-61
Jartti, Tuomas; van den Hoogen, Bernadette; Garofalo, Roberto P et al. (2002) Metapneumovirus and acute wheezing in children. Lancet 360:1393-4
Tian, Bing; Zhang, Yuhong; Luxon, Bruce A et al. (2002) Identification of NF-kappaB-dependent gene networks in respiratory syncytial virus-infected cells. J Virol 76:6800-14
Haeberle, Helene A; Nesti, Frances; Dieterich, Hans-Juergen et al. (2002) Perflubron reduces lung inflammation in respiratory syncytial virus infection by inhibiting chemokine expression and nuclear factor-kappa B activation. Am J Respir Crit Care Med 165:1433-8
Pazdrak, Konrad; Olszewska-Pazdrak, Barbara; Liu, Tianshuang et al. (2002) MAPK activation is involved in posttranscriptional regulation of RSV-induced RANTES gene expression. Am J Physiol Lung Cell Mol Physiol 283:L364-72
Casola, Antonella; Garofalo, Roberto P; Crawford, Sue E et al. (2002) Interleukin-8 gene regulation in intestinal epithelial cells infected with rotavirus: role of viral-induced IkappaB kinase activation. Virology 298:8-19

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