Leprosy, a human disease caused by the intracellular pathogen Mycobacterium leprae (mLEP), offers an attractive model for investigating the regulation of innate and adaptive immune responses to infection in skin. The disease represents a spectrum, in which the clinical manifestations correlate with the immune response to the pathogen. By investigating the adaptive immune response in leprosy, we established that resistant, self-limited, tuberculoid (T-lep) patients express the Thi cytokine IFN-gamma in lesions, whereas disseminated lepromatous (L-lep) patients manifest Th2 cytokines IL-4 and IL-10 in lesions (1). Our new preliminary data indicates the differential expression of interferons (IFNs) and their downstream gene networks in leprosy skin esions. The striking finding was that expression ofthe Type II IFN, IFN-gamma, as well as IFN-gamma inducible genes including the antimicrobial gene program, were enriched in T-lep lesions. In contrast, expression ofthe Type IFN, IFN-Beta, as well as IFN-Beta inducible genes, predominated in L-lep lesions. We hypothesize that specific mLEP secreted proteins/ligands differentially trigger production of Type II vs. Type I IFNs in T-lep vs. L-lep patients, respectively. To test this hypothesis, we propose translational experiments to: 1) identify the T cell epitopes/antigens in the putative mLEP secretome which induce the Type II IFN, IFN-gamma, in leprosy patients and trigger an antimicrobial activity, 2) determine whether specific mLEP secreted proteins induce Type I IFNs and inhibit antimicrobial responses;and, 3) investigate the mechanism by which the secreted mLEP glycolipid, phenolic glycolipid-1 (PGL-1), triggers Type I IFN responses in monocytes/macrophages. The studies we propose are intended to provide a comprehensive analysis of the mechanisms that trigger Type I vs. Type II IFNs in leprosy, including the role of these pathways in host defense and pathogenesis. We would hope that insights would assist in the diagnosis and prevention of leprosy, as well as provide new avenues for development of immunomodulatory approaches for a variety of human skin diseases.

Public Health Relevance

We propose to study patients with the skin disease leprosy to gain insight into how immune proteins called interferons regulate host responses to infection in skin. The information gained can be applied to develop treatments for a variety of human skin diseases.

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 #
8531867
Study Section
Special Emphasis Panel (ZAR1-KM)
Project Start
2013-08-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$348,303
Indirect Cost
$122,518
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Nielson, Carrie M; Jones, Kerry S; Bouillon, Roger et al. (2016) Role of Assay Type in Determining Free 25-Hydroxyvitamin D Levels in Diverse Populations. N Engl J Med 374:1695-6
Nielson, Carrie M; Jones, Kerry S; Chun, Rene F et al. (2016) Free 25-Hydroxyvitamin D: Impact of Vitamin D Binding Protein Assays on Racial-Genotypic Associations. J Clin Endocrinol Metab 101:2226-34
Lam, Larry; Chin, Lydia; Halder, Ramesh C et al. (2016) Epigenetic changes in T-cell and monocyte signatures and production of neurotoxic cytokines in ALS patients. FASEB J 30:3461-3473
Tong, Ann-Jay; Liu, Xin; Thomas, Brandon J et al. (2016) A Stringent Systems Approach Uncovers Gene-Specific Mechanisms Regulating Inflammation. Cell 165:165-79
Srikanth, P; Chun, R F; Hewison, M et al. (2016) Associations of total and free 25OHD and 1,25(OH)2D with serum markers of inflammation in older men. Osteoporos Int 27:2291-300
Busch, Martin; Herzmann, Christian; Kallert, Stephanie et al. (2016) Lipoarabinomannan-Responsive Polycytotoxic T Cells Are Associated with Protection in Human Tuberculosis. Am J Respir Crit Care Med 194:345-55
Cunningham, Cameron R; Champhekar, Ameya; Tullius, Michael V et al. (2016) Type I and Type II Interferon Coordinately Regulate Suppressive Dendritic Cell Fate and Function during Viral Persistence. PLoS Pathog 12:e1005356
Inkeles, Megan S; Teles, Rosane M B; Pouldar, Delila et al. (2016) Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy. JCI Insight 1:e88843
Jenkinson, Carl; Taylor, Angela E; Hassan-Smith, Zaki K et al. (2016) High throughput LC-MS/MS method for the simultaneous analysis of multiple vitamin D analytes in serum. J Chromatogr B Analyt Technol Biomed Life Sci 1014:56-63
Cappuccio, Antonio; Zollinger, Raphaël; Schenk, Mirjam et al. (2015) Combinatorial code governing cellular responses to complex stimuli. Nat Commun 6:6847

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