The goals of this research are to elucidate transcriptional networks that participate in the immune response to infection by Mycobacterium leprae (mLEP) and to devise therapeutic strategies that enhance the immune response by manipulating these networks. Many mLEP patients develop a self-limiting tuberculoid form of the disease (T-lep), in which an effective immune response is dependent on transcriptional networks in macrophages activated by Toll-like receptor ligands. Type II interferon (IFN-gamma), and IL-15. These stimuli drive the transcriptional activation of genes encoding key antimicrobial peptides and cytokines that promote a robust T helper 1 response. Vitamin D plays a major role in enhancing this response, as demonstrated by the increased susceptibility of vitamin D-deficient individuals to bacterial infection. In other patients, disseminated lepromatous (L-lep) lesions develop that appear to be caused, in part, by immune suppression by the Type I IFN, IFN-Beta. Projects 1, 2, and 4 of this application will focus on microbial stimuli that drive the mLEP response, proteins induced by IFN-gamma and IFN-Beta that either enhance or suppress the antimicrobial response, and vitamin D metabolic pathways as they pertain to antimicrobial immunity. In this Project, we hypothesize that elucidation and dissection of transcriptional networks activated by stimuli that either catalyze or suppress the immune response to mLEP infection will lead to key regulatory nodes and mechanisms that can be targeted by novel therapeutics strategies. This hypothesis is based on emerging excitement about the potential of chromatin and epigenetic regulators as therapeutic targets. We propose to: 1) use high-throughput sequencing analysis of transcriptional networks (RNAseq) to understand how multiple stimuli help shape the effective and ineffective immune responses that characterize T-lep and L-lep lesions;2) elucidate the mechanism by which vitamin D suppresses the expression of important cytokines like IL-12 while promoting the expression of key antimicrobial peptides, towards the goal of uncoupling these activities in a therapeutic setting;3) elucidate the mechanisms that distinguish the Type I and Type II IFN responses, towards the translational goal of converting the suppressive Type I response into an effective Type II response. These studies have considerable potential to translate basic knowledge of gene regulation circuitry into disease therapies and will provide knowledge of transcriptional networks that will be of great value to the goals of the entire CORT team and to other basic and translational researchers studying antimicrobial immunity.

Public Health Relevance

The immune response to microbial infection is activated by interactions between the microbe and cells of the host immune system. These interactions drive the activation of hundreds of genes that orchestrate the response. Elucidation of key regulatory networks and mechanisms that participate in the response to a well-studied human pathogen, using recently developed genomics techniques, will provide a new perspective to the study of antimicrobial immunity and suggest novel strategies for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center (P50)
Project #
5P50AR063020-02
Application #
8531869
Study Section
Special Emphasis Panel (ZAR1-KM)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$307,767
Indirect Cost
$102,993
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Inkeles, Megan S; Scumpia, Philip O; Swindell, William R et al. (2015) Comparison of molecular signatures from multiple skin diseases identifies mechanisms of immunopathogenesis. J Invest Dermatol 135:151-9
Smale, Stephen T (2014) Transcriptional regulation in the immune system: a status report. Trends Immunol 35:190-4
Montoya, Dennis; Inkeles, Megan S; Liu, Phillip T et al. (2014) IL-32 is a molecular marker of a host defense network in human tuberculosis. Sci Transl Med 6:250ra114
Adams, John S; Rafison, Brandon; Witzel, Sten et al. (2014) Regulation of the extrarenal CYP27B1-hydroxylase. J Steroid Biochem Mol Biol 144 Pt A:22-7
Chun, Rene F; Liu, Philip T; Modlin, Robert L et al. (2014) Impact of vitamin D on immune function: lessons learned from genome-wide analysis. Front Physiol 5:151
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