Adaptive immunity to pathogens hinges upon separate processes for short- and long-term increases in the activity of antigen-specific B and T lymphocytes. Short-term multiplication and differentiation of plasma cells and cytotoxic T cells is critical for resolving an existing infection, but the strength of the immediate response needs to be balanced with the processes that establish long-term immunity such as affinity maturation, formation of memory B and T cells, and differentiation of long-lived bone marrow plasma cells. Much remains unknown about the genetic and systems-level decision-making that guides these short- and long-term processes. Without that understanding there are major gaps in strategies to establish and improve vaccines against many NIH Priority Pathogens, and to interpret patterns of human genetic, cellular, and serological variation to predict the efficacy and longevity of immunity in clinical settings and in the field. This project, in synergy with the Cores and other projects of this U19 program, will expand the community resource of mouse mutations and datasets that experimentally connect discrete genes with the cells and systems governing short- and long-term adaptive immunity. These resources and datasets will be distributed to the community via repositories and websites to enable researchers to test their own hypotheses about adaptive immunity. In addition, the project will focus on a subset of novel gene mutations affecting memory versus effector decisions or antibody affinity maturation in the context of immunity to NIH Priority Pathogens, and determine the cellular and molecular systems controlled by these genes.

Public Health Relevance

Immunity to viruses and bacteria, especially those representing potential bio-terrorism agents and emerging diseases, depends upon thousands of mostly unexplored genes that come together in sophisticated control systems coordinating the production of antibodies and T cells of the immune system. This project will define these genes and systems, and thereby open the way for new technologies to promote immunity against these agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI100627-03
Application #
8717570
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
Wang, Ying; Su, Lijing; Morin, Matthew D et al. (2016) TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS. Proc Natl Acad Sci U S A 113:E884-93
Shi, Hexin; Wang, Ying; Li, Xiaohong et al. (2016) NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nat Immunol 17:250-8
Siggs, Owen M; Stockenhuber, Alexander; Deobagkar-Lele, Mukta et al. (2016) Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity. Proc Natl Acad Sci U S A 113:E3706-15
Fragiadakis, Gabriela K; Baca, Quentin J; Gherardini, Pier Federico et al. (2016) Mapping the Fetomaternal Peripheral Immune System at Term Pregnancy. J Immunol 197:4482-4492
Wang, James Q; Beutler, Bruce; Goodnow, Christopher C et al. (2016) Inhibiting TLR9 and other UNC93B1-dependent TLRs paradoxically increases accumulation of MYD88L265P plasmablasts in vivo. Blood 128:1604-8
Andrews, T Daniel; Jeelall, Yogesh; Talaulikar, Dipti et al. (2016) DeepSNVMiner: a sequence analysis tool to detect emergent, rare mutations in subsets of cell populations. PeerJ 4:e2074
Angst, Martin S; Fragiadakis, Gabriela K; Gaudillière, Brice et al. (2016) In Reply. Anesthesiology 124:1414-5
Parish, Ian A; Stamp, Lincon A; Lorenzo, Ayla May D et al. (2016) A Novel Mutation in Nucleoporin 35 Causes Murine Degenerative Colonic Smooth Muscle Myopathy. Am J Pathol 186:2254-61
Frei, Andreas P; Bava, Felice-Alessio; Zunder, Eli R et al. (2016) Highly multiplexed simultaneous detection of RNAs and proteins in single cells. Nat Methods 13:269-75
Wu, Zuopeng; Liang, Rong; Ohnesorg, Thomas et al. (2016) Heterogeneity of Human Neutrophil CD177 Expression Results from CD177P1 Pseudogene Conversion. PLoS Genet 12:e1006067

Showing the most recent 10 out of 90 publications