In recent years, Innate Immunity has gone from being the """"""""immunologists'dirty little secret"""""""" to being among the most active and exciting areas of immunology. Many recognition molecules of vertebrate innate immune cells have been defined and much is now known about their mechanisms of action. Nonetheless, much remains to be learned before we truly understand how to harness these mechanisms for vaccination and cancer immunotherapy or how to block them to treat autoimmune and inflammatory disease. This proposed Program Project combines 4 investigators with established expertise in the area of innate immunity to pursue related studies developing out of their independent research efforts, but containing numerous connections and great potential for combined effort. In Project #1, Dr. DeFranco will utilize his newly created conditional allele of myd88 to dissect the cellular basis of Toll-like receptor signaling for systemic and mucosal immune responses, with emphasis on airways and fungal infections. In Project #2, Dr. Ma will analyze the role of the ubiquitin-modifying regulator A20 in dendritic cells for restraining TLR responses and preventing inflammatory disease. In Project #3, Dr. Lowell will determine the mechanism by which myeloid cells contribute to lupus-like autoimmunity in the Lyn-deficient mouse model. Finally, in Project #4, Dr. Locksley will determine how chitin, a polysaccharide found in fungi and invertebrates, promotes type 2 immunity and how it interacts with TLR signaling pathways to regulate the type of immune response. Lay Language: The immune system recognizes conserved elements of viruses, bacteria, fungi and multicellular invertebrates to allow it to detect infections and fight them. Immunologists are defining a number of the molecular mechanisms by which this is done, but much remains to be learned, particularly to understand how these reactions are controlled to avoid excessive inflammation and tissue injury, while directing the immune system toward the type of immune response most beneficial for fighting the infectious agent that is present. Better understanding of these issues will lead to improved vaccination procedures and better ability to control excessive inflammatory conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI078869-04
Application #
8105430
Study Section
Special Emphasis Panel (ZAI1-MP-I (M1))
Program Officer
Davidson, Wendy F
Project Start
2008-07-15
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$1,733,579
Indirect Cost
Name
University of California San Francisco
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Costa, Sara; Marini, Olivia; Bevilacqua, Dalila et al. (2017) Role of MyD88 signaling in the imiquimod-induced mouse model of psoriasis: focus on innate myeloid cells. J Leukoc Biol 102:791-803
Molofsky, Ari B; Van Gool, Frédéric; Liang, Hong-Erh et al. (2015) Interleukin-33 and Interferon-? Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation. Immunity 43:161-74
Mayadas, Tanya N; Cullere, Xavier; Lowell, Clifford A (2014) The multifaceted functions of neutrophils. Annu Rev Pathol 9:181-218
Lamagna, Chrystelle; Hu, Yongmei; DeFranco, Anthony L et al. (2014) B cell-specific loss of Lyn kinase leads to autoimmunity. J Immunol 192:919-28
Abram, Clare L; Roberge, Gray L; Hu, Yongmei et al. (2014) Comparative analysis of the efficiency and specificity of myeloid-Cre deleting strains using ROSA-EYFP reporter mice. J Immunol Methods 408:89-100
Van Gool, Frédéric; Molofsky, Ari B; Morar, Malika M et al. (2014) Interleukin-5-producing group 2 innate lymphoid cells control eosinophilia induced by interleukin-2 therapy. Blood 124:3572-6
Hua, Zhaolin; Gross, Andrew J; Lamagna, Chrystelle et al. (2014) Requirement for MyD88 signaling in B cells and dendritic cells for germinal center anti-nuclear antibody production in Lyn-deficient mice. J Immunol 192:875-85
Molofsky, Ari B; Nussbaum, Jesse C; Liang, Hong-Erh et al. (2013) Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med 210:535-49
Hammer, Gianna Elena; Ma, Averil (2013) Molecular control of steady-state dendritic cell maturation and immune homeostasis. Annu Rev Immunol 31:743-91
Lamagna, Chrystelle; Scapini, Patrizia; van Ziffle, Jessica A et al. (2013) Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation. Proc Natl Acad Sci U S A 110:E3311-20

Showing the most recent 10 out of 30 publications