The respiratory tract is one of the most important sites of entry for pathogens including many potential bioterrorism agents such as influenza virus. Although local innate and early adaptive immune defenses are known to be crucial for limiting initial pathogen spread, the mechanisms underlying mucosal immunity in the respiratory tract are still poorly defined. Lung tissue dendritic cells (DC) are key components of the innate immune system that regulate adaptive immunity by migrating to the regional lymph nodes to present antigens to T cells. Preliminary data suggest that contrary to current dogma, DC can also activate immune responses in the lung tissue itself. The objective of this application is to determine the mechanisms by which respiratory tract DC activated by influenza virus-infection regulate local virus-specific T and B cell responses and to test how application of inactivated virus (as a prototype vaccine) affects their functions. The central hypothesis underlying this study is that infection of lung tissue DC is critical for their ability to present antigen to B cells and to regulate virus-specific CD4 T cell responses. The following Specific Aims are proposed:
Specific Aim #1 is to fully characterize respiratory tract DC responses following sublethal infection of mice with influenza A/PR8, by studying the phenotype of DC and their viral- and host-gene expression ex vivo and to determine the mechanisms by which they regulate virus-specific T-dependent and/or T-independent B cell responses.
Specific Aim #2 will determine the ability of lung tissue and draining lymph node DC to regulate the induction and/or quality of virus-specific effector CD4 T cell responses, by measuring cytokine profiles and clonal burst sizes of naive and activated CD4+T cells in co-cultures with virus-stimulated respiratory tract DC and in vivo following adoptive transfer of DC.
Specific Aim #3 is to determine whether application of inactivated virus induces local DC populations that differ in phenotype, gene expression profile or effector function from those induced by live virus infection; thus whether differences in the quality of the DC responses induced to live and inactivated virus could underlie the often disappointing levels of protection achieved with inactivated virus vaccines compared to those obtained after active infection. In summary, this study will provide a detailed understanding of respiratory tract DC biology, particularly their role in regulating early local responses at the site of pathogen entry. This information could help the development of novel interventions that utilize early respiratory tract defenses for immune protection. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI055881-05
Application #
7195073
Study Section
Special Emphasis Panel (ZRG1-SSS-F (01))
Program Officer
Gondre-Lewis, Timothy A
Project Start
2003-09-15
Project End
2008-02-29
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
5
Fiscal Year
2007
Total Cost
$316,811
Indirect Cost
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Nguyen, Trang T T; Kläsener, Kathrin; Zürn, Christa et al. (2017) The IgM receptor Fc?R limits tonic BCR signaling by regulating expression of the IgM BCR. Nat Immunol 18:321-333
Savage, Hannah P; Baumgarth, Nicole (2015) Characteristics of natural antibody-secreting cells. Ann N Y Acad Sci 1362:132-42
Baumgarth, Nicole; Waffarn, Elizabeth E; Nguyen, Trang T T (2015) Natural and induced B-1 cell immunity to infections raises questions of nature versus nurture. Ann N Y Acad Sci 1362:188-99
Mooney, J P; Butler, B P; Lokken, K L et al. (2014) The mucosal inflammatory response to non-typhoidal Salmonella in the intestine is blunted by IL-10 during concurrent malaria parasite infection. Mucosal Immunol 7:1302-11
Baumgarth, Nicole (2013) How specific is too specific? B-cell responses to viral infections reveal the importance of breadth over depth. Immunol Rev 255:82-94
Rau, Friederike C; Dieter, Jacquelyn; Luo, Zhang et al. (2009) B7-1/2 (CD80/CD86) direct signaling to B cells enhances IgG secretion. J Immunol 183:7661-71
Chang, W L William; Barry, Peter A; Szubin, Richard et al. (2009) Human cytomegalovirus suppresses type I interferon secretion by plasmacytoid dendritic cells through its interleukin 10 homolog. Virology 390:330-7
Chang, W L William; Baumgarth, Nicole; Eberhardt, Meghan K et al. (2007) Exposure of myeloid dendritic cells to exogenous or endogenous IL-10 during maturation determines their longevity. J Immunol 178:7794-804