Toll-like receptors (TLRs) play a pivotal role in shaping then host immune response to a pathogen or a vaccine. Our understanding of the mechanisms by which this occurs, have arisen from explorations that probe the response of immune cells to a single TLR ligand. However, microbes and vaccines do not simply stimulate a single TLR, but rather stimulate combinations of different TLRs. Recent work by Lanzavecchia and others suggests that the combinatorial activation of multiple TLRs result in a synergistic activation of cytokine production by dendritic cells (DCs). The impact of this synergy on the adaptive immune response is poorly understood. In particular, there is little or no understanding of the innate immune mechanisms that affect critical variables of the B cell response, such as memory B cell generation, affinity maturation, and induction of neutralizing antibodies. Our preliminary data in mice, suggest that TLR ligands administered with an antigen, can elicit antigen-specific antibody responses. In particular, specific combinations of TLR ligands result in a synergistic induction of the antigen-specific antibody responses, and in the induction of high avidity antibodies. The precise mechanism by which this occurs is a mystery, and will be the major focus of this proposal, and will be achieved in the following aims:
Aim 1 : To determine whether combined stimulation with TLR4 + TLR7/8 ligands results in a synergistic activation of the germinal center pathway of memory B-cell differentiation Aim 2: To determine the cellular and molecular mechanism(s) by which TLR ligands act synergistically to stimulate antigen-specific B cell responses Aim 3: To determine the "quality" of antibody that is optimally suited for protection against specific category A-C agents The successful completion of these aims, will greatly facilitate the rational design of vaccines that stimulate optimally effective types of B cell responses against various pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057157-11
Application #
8437252
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
11
Fiscal Year
2013
Total Cost
$341,944
Indirect Cost
$55,607
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Guo, Haitao; Gao, Jianmei; Taxman, Debra J et al. (2014) HIV-1 infection induces interleukin-1? production via TLR8 protein-dependent and NLRP3 inflammasome mechanisms in human monocytes. J Biol Chem 289:21716-26
Emery, Felicia D; Stabenow, Jennifer M; Miller, Mark A (2014) Efficient inactivation of Burkholderia pseudomallei or Francisella tularensis in infected cells for safe removal from biosafety level 3 containment laboratories. Pathog Dis 71:276-81
Rice, Amanda D; Adams, Mathew M; Lindsey, Scott F et al. (2014) Protective properties of vaccinia virus-based vaccines: skin scarification promotes a nonspecific immune response that protects against orthopoxvirus disease. J Virol 88:7753-63
Pop, Laurentiu M; Barman, Stephen; Shao, Chunli et al. (2014) A reevaluation of CD22 expression in human lung cancer. Cancer Res 74:263-71
Agnihothram, Sudhakar; Yount Jr, Boyd L; Donaldson, Eric F et al. (2014) A mouse model for Betacoronavirus subgroup 2c using a bat coronavirus strain HKU5 variant. MBio 5:e00047-14
Zellweger, Raphaƫl M; Eddy, William E; Tang, William W et al. (2014) CD8+ T cells prevent antigen-induced antibody-dependent enhancement of dengue disease in mice. J Immunol 193:4117-24
Zhao, Jincun; Li, Kun; Wohlford-Lenane, Christine et al. (2014) Rapid generation of a mouse model for Middle East respiratory syndrome. Proc Natl Acad Sci U S A 111:4970-5
Krumm, Stefanie A; Yan, Dan; Hovingh, Elise S et al. (2014) An orally available, small-molecule polymerase inhibitor shows efficacy against a lethal morbillivirus infection in a large animal model. Sci Transl Med 6:232ra52
Blake, Lauren E; Garcia-Blanco, Mariano A (2014) Human genetic variation and yellow fever mortality during 19th century U.S. epidemics. MBio 5:e01253-14
de Alwis, Ruklanthi; de Silva, Aravinda M (2014) Measuring antibody neutralization of dengue virus (DENV) using a flow cytometry-based technique. Methods Mol Biol 1138:27-39

Showing the most recent 10 out of 288 publications