The long-term objective of this proposal is to gain insight into mechanisms of innate immunity to infectious agents in humans, with particular emphasis on the role of Toll-like receptors (TLRs) in cutaneous host defense. We recently reported a role for TLRs in the immune response to microbial pathogens, leading to the induction of IL-12, a powerful signal for the generation of Th1 cytokine responses, and inducible nitric oxide synthase (NOS), a direct microbicidal pathway. We propose experiments to investigate the role of TLRs in skin and the innate response to microbial infection. First, we hypothesize that different TLRs have distinct roles in host immunity. We will determine the role of specific TLRs in the cutaneous immune response by comparing the distribution of TLRs in skin lesions, analyzing the role of distinct TLRs in monocyte and keratinocyte responses to microbial ligands and determining the mechanism by which TLR activation leads to killing of intracellular bacteria. Second we hypothesize that distinct TLRs or TLR signaling pathways lead to immunostimulatory vs. down-modulatory events. We propose to determine the structural characteristics of TLRs that lead to distinct signaling specificities and the signal transduction pathway leading to induction of IL-12 and iNOS vs the induction of IL-10 and macrophage apoptosis. Third, we hypothesize that the expression of TLR on T cells allows these cells of the adaptive immune system to participate in the innate response. We propose to measure the T-cell receptor repertoire of TLR+ T cells and the response of TLR+ T cells to microbial ligands including the cytokine patterns induced and signal transduction pathways activated. We believe that the insights obtained form the study of TLRs in skin and their response to microbial lipoproteins will provide new knowledge about the innate immune response and suggest new avenues of immunologic intervention in human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI047868-05
Application #
6735691
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Plaut, Marshall
Project Start
2000-09-01
Project End
2005-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
5
Fiscal Year
2004
Total Cost
$266,875
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Schenk, Mirjam; Mahapatra, Sebabrata; Le, Phuonganh et al. (2016) Human NOD2 Recognizes Structurally Unique Muramyl Dipeptides from Mycobacterium leprae. Infect Immun 84:2429-38
Teles, Rosane M B; Kelly-Scumpia, Kindra M; Sarno, Euzenir N et al. (2015) IL-27 Suppresses Antimicrobial Activity in Human Leprosy. J Invest Dermatol 135:2410-2417
Ma, Feng; Liu, Su-Yang; Razani, Bahram et al. (2014) Retinoid X receptor ? attenuates host antiviral response by suppressing type I interferon. Nat Commun 5:5494
Schenk, Mirjam; Fabri, Mario; Krutzik, Stephan R et al. (2014) Interleukin-1? triggers the differentiation of macrophages with enhanced capacity to present mycobacterial antigen to T cells. Immunology 141:174-80
Teles, Rosane M B; Graeber, Thomas G; Krutzik, Stephan R et al. (2013) Type I interferon suppresses type II interferon-triggered human anti-mycobacterial responses. Science 339:1448-53
Klug-Micu, Georgiana M; Stenger, Steffen; Sommer, Andrea et al. (2013) CD40 ligand and interferon-? induce an antimicrobial response against Mycobacterium tuberculosis in human monocytes. Immunology 139:121-8
Schenk, Mirjam; Krutzik, Stephan R; Sieling, Peter A et al. (2012) NOD2 triggers an interleukin-32-dependent human dendritic cell program in leprosy. Nat Med 18:555-63
Liu, Philip T; Wheelwright, Matthew; Teles, Rosane et al. (2012) MicroRNA-21 targets the vitamin D-dependent antimicrobial pathway in leprosy. Nat Med 18:267-73
Parvatiyar, Kislay; Zhang, Zhiqiang; Teles, Rosane M et al. (2012) The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response. Nat Immunol 13:1155-61
Ouyang, Songying; Song, Xianqiang; Wang, Yaya et al. (2012) Structural analysis of the STING adaptor protein reveals a hydrophobic dimer interface and mode of cyclic di-GMP binding. Immunity 36:1073-86

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