Long-lived B cell Immunity in the Respiratory Tract

Summary

Principal Investigator: Nicole Baumgarth
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2010-09-01 - 2014-08-31
more information: NIH RePORT

Top Publications

  1. pmc Protective B cell responses to flu--no fluke!
    Elizabeth E Waffarn
    Center for Comparative Medicine, University of California, Davis, Davis, CA 95616, USA
    J Immunol 186:3823-9. 2011
  2. pmc Single and coexpression of CXCR4 and CXCR5 identifies CD4 T helper cells in distinct lymph node niches during influenza virus infection
    Rebecca A Elsner
    Graduate Group in Microbiology, University of California, Davis, Davis, California, USA
    J Virol 86:7146-57. 2012
  3. pmc Predicting the outcome of infectious diseases: variability among inbred mice as a new and powerful tool for biomarker discovery
    Miriam E Martin
    The Center for Comparative Medicine, University of California, Davis, California, USA
    MBio 3:e00199-12. 2012
  4. ncbi The role of innate signals in B cell immunity to influenza virus
    Stephen O Priest
    Center for Comparative Medicine, University of California, Davis, Davis, CA 95616, USA
    Front Biosci (Schol Ed) 5:105-17. 2013
  5. ncbi Innate-like B cells and their rules of engagement
    Nicole Baumgarth
    Center for Comparative Medicine, University of California, Davis, CA 95616, USA
    Adv Exp Med Biol 785:57-66. 2013
  6. pmc How specific is too specific? B-cell responses to viral infections reveal the importance of breadth over depth
    Nicole Baumgarth
    Center for Comparative Medicine and the Department of Pathology, Microbiology and Immunology, University of California, Davis, Davis, CA 95616, USA
    Immunol Rev 255:82-94. 2013

Detail Information

Publications7

  1. pmc Protective B cell responses to flu--no fluke!
    Elizabeth E Waffarn
    Center for Comparative Medicine, University of California, Davis, Davis, CA 95616, USA
    J Immunol 186:3823-9. 2011
    ..Knowledge gained from the analysis of such highly protective humoral response might provide a blueprint for successful vaccines and vaccination approaches...
  2. pmc Single and coexpression of CXCR4 and CXCR5 identifies CD4 T helper cells in distinct lymph node niches during influenza virus infection
    Rebecca A Elsner
    Graduate Group in Microbiology, University of California, Davis, Davis, California, USA
    J Virol 86:7146-57. 2012
    ..The regulation of T cell localization, marked by the single and coexpression of CXCR4 and CXCR5, might be an important determinant of T(FH) function...
  3. pmc Predicting the outcome of infectious diseases: variability among inbred mice as a new and powerful tool for biomarker discovery
    Miriam E Martin
    The Center for Comparative Medicine, University of California, Davis, California, USA
    MBio 3:e00199-12. 2012
    ..We hypothesize that inbred mice represent a powerful new tool for the identification of biomarkers to predict the outcome of infectious diseases...
  4. ncbi The role of innate signals in B cell immunity to influenza virus
    Stephen O Priest
    Center for Comparative Medicine, University of California, Davis, Davis, CA 95616, USA
    Front Biosci (Schol Ed) 5:105-17. 2013
    ..Here we review the current understanding of early B cell responses to influenza virus infection and the role of innate signals (particularly IFN-I and TLR7) in shaping this response...
  5. ncbi Innate-like B cells and their rules of engagement
    Nicole Baumgarth
    Center for Comparative Medicine, University of California, Davis, CA 95616, USA
    Adv Exp Med Biol 785:57-66. 2013
    ....
  6. pmc How specific is too specific? B-cell responses to viral infections reveal the importance of breadth over depth
    Nicole Baumgarth
    Center for Comparative Medicine and the Department of Pathology, Microbiology and Immunology, University of California, Davis, Davis, CA 95616, USA
    Immunol Rev 255:82-94. 2013
    ..As outlined, the pathogenesis of influenza virus and the nature of the antiviral B-cell response seem to emphasize repertoire diversity over affinity maturation as driving forces behind the influenza-specific B-cell immunity. ..

Research Grants30

  1. VACCINE INDUCED IMMUNITY IN THE YOUNG AND AGED
    Rafi Ahmed; Fiscal Year: 2013
    ....
  2. T follicular helper cells: Role in generation of anti-HIV antibody responses
    Hendrik Streeck; Fiscal Year: 2013
    ..Thus in this proposal we aim to define the role of HIV-1-specific TFH cells in the control of HIV-1 infection and their ability to induce protective immunity on mucosal surfaces. ..
  3. Systems Biological Analysis of Innate and Adaptive Responses to Vaccination
    Bali Pulendran; Fiscal Year: 2013
    ..The successful completion of this program may provide insights into the defects that underlie poor vaccine efficacy in the elderly, and establish the broad utility of systems biology in predicting vaccine immunogenicity. ..
  4. Defining signatures for immune responsiveness by functional systems immunology
    David A Hafler; Fiscal Year: 2013
    ..abstract_text> ..
  5. Optimization of HIV vaccines for the induction of cross-reactive antibodies
    Shan Lu; Fiscal Year: 2013
    ..RELEVANCE: To optimize the next generation polyvalent Env HIV vaccine formulations using the multi-gene, polyvalent DNA prime - protein boost technology platform. ..
  6. Pathophysiologic and therapeutic mechanisms of aspirin exacerbated respiratory d*
    Joshua A Boyce; Fiscal Year: 2013
    ..The coordination of the AADCRC is enhanced by an administrative Core. ..
  7. Influenza Immunity: Protective Mechanisms Against Pandemic Respiratory Virus
    MARK MORRIS DAVIS; Fiscal Year: 2013
    ..It will also provide important information regarding the mechanisms responsible for the generation of protective B cell immunity against a wide array of other important human pathogens and bioterrorism agents. ..
  8. Shaping Antiviral Immunity by the Inflammatory, Regulatory and Tissue Environment
    E John Wherry; Fiscal Year: 2013
    ..Our goal is to define how unrelated infections impact immunological memory in hopes to improve vaccines. ..
  9. Host-pathogen competition in IFN mediated antiviral defense
    Jae U Jung; Fiscal Year: 2013
    ....
  10. Mentoring Research Excellence in Aging and Regenerative Medicine
    S Michal Jazwinski; Fiscal Year: 2013
    ..This COBRE will represent the centerpiece of the Tulane Center for Aging, and it will contribute strongly to our building of an exceptional biomedical aging research enterprise in Louisiana. ..
  11. Novel Ad/MVA and Ad/Protein HIV-1 Vaccines
    Dan H Barouch; Fiscal Year: 2013
    ..To define the mechanism of blocking acquisition of stringent SIV challenges by conducting antigen formulation and adoptive transfer studies in rhesus monkeys. ..
  12. Mucosal Immunity, Vaccines and Microbiota Interplay in Humans and Animal
    Marcelo B Sztein; Fiscal Year: 2013
    ..Given the shortcomings of available measures to successfully control this infection, and its bioterrorism potential, to develop a S. dysenteriae type 1 vaccine is of great importance. ..
  13. Immune Regulation of Virus Clearance and Tissue Injury at Sites of Infection
    Thomas J Braciale; Fiscal Year: 2013
    ..To determine the impact of viral infection on the production of Te-derived IL- 10. The proposed studies are designed to complement ongoing related studies in Projects 2, 3 and 4. ..
  14. Oxidation in Inflammation and Cardiovascular Disease
    Stanley L Hazen; Fiscal Year: 2013
    ..It may also lead to important insights for atherosclerosis risk assessment, diagnosis and therapy. ..
  15. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..
  16. Pulmonary Immunity To Pathogens In Neonates
    Troy D Randall; Fiscal Year: 2013
    ..abstract_text> ..
  17. International Comparisons of Well-Being, Health and Retirement
    ARIE KAPTEYN; Fiscal Year: 2013
    ..unreadable] Make harmonized institutional information available to the wider research community. ..
  18. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  19. Cellular Immunity to Category A-C Viruses in Humans
    ROBERT WILLIAM FINBERG; Fiscal Year: 2013
    ....
  20. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  21. Harnessing Human DC Subsets for Improved Muscosal Vaccines
    Gerard Zurawski; Fiscal Year: 2013
    ..We propose four projects and two technical development components which will be supported by six cores. ..
  22. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  23. Central and Effector B cells in the Lung
    Troy D Randall; Fiscal Year: 2013
    ..Thus, these results will inform the rational design of vaccines that protect the respiratory tract and lead to therapies that enhance or curtail the generation and maintenance of memory B cells in the lung. ..
  24. VIRAL INFECTION INFLUENCE ON TRANSPLANTATION TOLERANCE
    DALE LESLIE GREINER; Fiscal Year: 2013
    ..This work will identify how infection during transplantation may affect the host immune system and ultimate fate of the graft. ..