The goal of this research project is to understand the molecular mechanisms responsible for the opposing functions of Type I versus Type II interferon (IFN) in controlling the replication of and the pathogenesis associated with the intracellular pathogen Mycobacterium leprae (mLEP) in skin. The disease associated with mLEP varies in different patients with a large spectrum from self-limited, tuberculoid (T-lep) patients with expression of the Th1 cytokine IFN-gamma (Type II) in lesions to disseminated lepromatous (L-lep) patients with expression of immunosuppressive cytokines such as IL-10 in lesions. We were among the first groups made the initial discovery that, while Type II IFN is required for, Type I IFN (mainly IFN-alpha-s and IFN-Beta) plays a detrimental role in host defense against bacterial infections. However, the molecular mechanisms responsible for the effects of Type I and Type II IFNs on mLEP infection and disease development remain to be elucidated. Through close collaboration with Dr. Robert Modlin's group over the past ten years, it became clear that Type I IFN inducible genes are preferentially upregulated in L-lep lesions whereas Type II IFN inducible genes are preferentially upregulated in T-lep lesions. More importantly, we have identified a subset of Type II IFN inducible genes in T-lep lesions that have potential antimicrobial activities and a subset of Type I IFN inducible genes in L-lep lesions that may not only suppress immune responses but also promote pathogenesis of leprosy. We hypothesize that Type ll and Type I IFNs play opposite roles in controlling the mLEP infection and associated diseases by differentially inducing antimicrobial and immunosuppressive gene programs, respectively. We propose to : 1) identify the Type I vs. Type II IFN gene programs in leprosy lesions;2) determine the anti-mLEP activities of type II interferon inducible genes upregulated in T-lep;3) define type I IFN inducible gene programs in suppressing host immunity against mLEP and promoting pathogenesis. We believe our proposed studies will not only help us understand the molecular mechanisms responsible for the opposing functions of Type I and II IFN in controlling mLEP but also provide insight for novel therapeutic tools for skin and systemic inflammatory associated diseases.

Public Health Relevance

The goal of this research project is to understand the molecular mechanisms responsible for the opposing functions of Type I versus Type II interferons in controlling the growth of the bacteria that causes the skin disease leprosy. We found that the expression of Type I and Type II interferons in leprosy skin lesions correlates with the clinical presentation of the disease. Our proposed studies should provide insight for novel therapeutic tools for skin and systemic inflammatory associated 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 #
8531868
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
$315,890
Indirect Cost
$111,116
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