Respiratory tract infections induce strong and long-lasting humoral immune responses locally at the site, contributing significantly to immune protection from challenge infection. The mechanisms that induce and control protective local immune responses are currently not fully understood. The study is based on preliminary data in mice that implicate the rapidly induced extrafollicular foci B cell response as source for long-lived humoral immunity in the respiratory tract following influenza virus infection. The objective for this proposal is to identify the mechanisms that regulate this long-term local antibody response to influenza virus in the respiratory tract.
In Specific Aim #1 the differentiation pathways and protective capacity of lung antibody-secreting cells following influenza virus infection will be measured in wildtype mice and in mice that lack formation of germinal centers (SAP-/- mice) or strong extrafollicular foci responses (following inactivated virus delivery) using BLIMP-1 reporter mice and a newly developed system for tracking of influenza hemagglutinin-specific, C12Id-expressing B cells ex vivo.
Specific Aim #2 will study the mechanisms regulating the migration/retention of lung plasma cell precursors to the respiratory tract. They will assess the extent to which migration of virus-specific B cells/plasma cells from regional lymph nodes is required for the establishment of lung tissue plasma cell pools, and using genetic screening and a custom microfluidics device, will identify the integrins and chemokines/receptors responsible for the selective accumulation and/or retention of plasma cells the lung tissue under shear stress.
Specific Aim #3 will use gene expression studies to determine the differentiation stage of plasma cells/precursors in the lung tissue and BrDU labeling studies to identify the mechanisms underlying the longevity of the antibody-secreting cells in the lung. Adoptive transfer studies will assess the requirements for antigen and/or infection-induced inflammatory signals for their maintenance. These studies will provide novel information on the characteristics and the B cell developmental pathways that generate the long-lived humoral immune responses in the respiratory tract, basic knowledge on B cell response regulation that can aid rationale vaccine design.

Public Health Relevance

Protection from infections with influenza virus is contributed at least in part by antibody-secreting cells that establish in the lung following influenza virus infection. This study aims to understand how these cells are generated and what regulates their migration/maintenance in the lung. This basic information will provide potential avenues for rational vaccine design that aims to boost local/mucosal immune responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI085568-04
Application #
8521064
Study Section
Special Emphasis Panel (ZRG1-IMM-E (02))
Program Officer
Hauguel, Teresa M
Project Start
2010-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$352,371
Indirect Cost
$119,721
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
Yenson, Vanessa; Baumgarth, Nicole (2014) Purification and immune phenotyping of B-1 cells from body cavities of mice. Methods Mol Biol 1190:17-34
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
Baumgarth, Nicole (2013) Innate-like B cells and their rules of engagement. Adv Exp Med Biol 785:57-66
Priest, Stephen O; Baumgarth, Nicole (2013) The role of innate signals in B cell immunity to influenza virus. Front Biosci (Schol Ed) 5:105-17
Elsner, Rebecca A; Ernst, David N; Baumgarth, Nicole (2012) Single and coexpression of CXCR4 and CXCR5 identifies CD4 T helper cells in distinct lymph node niches during influenza virus infection. J Virol 86:7146-57
Waffarn, Elizabeth E; Baumgarth, Nicole (2011) Protective B cell responses to flu--no fluke! J Immunol 186:3823-9
Oslund, Karen L; Baumgarth, Nicole (2011) Influenza-induced innate immunity: regulators of viral replication, respiratory tract pathology & adaptive immunity. Future Virol 6:951-962