The overall theme of this grant is to understand mechanisms of acquired immunity to colonization by the encapsulated, extracellular bacterium Streptococcus pneumonias (pneumococcus), the cause of over 800,000 deaths from sepsis and pneumonia annually. Historically, antibody to the capsular polysaccharides has traditionally been viewed as the primary mechanism of immunity. In preliminary experiments, we found however that colonization with pneumococci could be prevented in the absence of antibody and that intranasal immunization by killed pneumococci protected antibody-deficient but not T-cell deficient mice, or mice that were congenitally deficient in CD4+ T cells or depleted of these cells at the time of challenge. In contrast, mice congenitally deficient in, or depleted of CD8+ T cells were fully protected. Adoptive transfer of CD4+ cells from immunized mice protected RAG-deficient mice from subsequent pneumococcal colonization. IFN-gamma deficient mice were protected by WCV;however, IL-17A receptor-deficient mice were not. Intranasal immunization with a combination of three pneumococcal proteins conferred antibody- independent immunity to pneumococcal colonization. Thus, our data suggest that immunity to pneumococcal colonization can be induced in the absence of antibody and requires the presence of acquired, antigen-specific IL-17A-producing CD4+ T cells at the time of challenge. The purpose of this proposal is to test the hypothesis that, under the initial influence of innate immune responses, these specific IL-17A T cell-mediated responses play a critical role in acquired resistance to pneumococcal colonization. The overall goals of this project are to study the mechanisms whereby cellular immune responses protect against pneumococcal colonization and/or disease and determine whether engagement of toll-like receptors (TLRs) determines the development of these T cell responses. Experimental approaches will include T cell adoptive transfer experiments, polarization of Th responses, immunization of cytokine- and TLR-deficient mice, and use of defined pneumococcal components as immunogens and TLR agonists. The results of our experiments will define a previously-unrecognized mechanism of protection against extracellular encapsulated bacteria and help in the development of novel vaccines against pneumococcus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI066013-04
Application #
7766974
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Khambaty, Farukh M
Project Start
2007-03-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$410,329
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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