Leprosy, a human disease caused by the intracellular pathogen Mycobacterium leprae (mLEP), offers an attractive model for investigating immune responses to infection as the disease represents a spectrum, in which the clinical manifestations correlate with the immune response to the pathogen. By investigating leprosy, we discovered a novel pathway involving NOD2-mediated induction of IL-32, triggering the differentiation of monocytes into CD1+ DC with professional antigen presenting cell function. Although either IL-32 or GM-CSF derived DC efficiently take up, process and present exogenous antigen via MHC class II to CD4+ T cells, only IL-32 derived DC "cross-present" exogenous antigen via MHC class I to CD8+ T cells. Typically, MHC class I samples antigen in the cytoplasm, which in professional antigen presenting cells leads to activation of na?ve CD8+ T cells to become cytotoxic cells, required for host defense against infection. Therefore, "cross- presentation" is required to induce CD8+ cytotoxic T cell responses when antigen is located in the endocytic pathway of antigen presenting cells, i.e. when a pathogen resides in the endocytic pathway or antigen is acquired exogenously. We hypothesize that CD8+ T cells recognize mLEP antigens as a result of IL-32 induced cross-presentation, triggering an antimicrobial response in leprosy. We propose to: 1) elucidate the mechanism(s) by which IL-32 induces cross-presentation of mLEP antigen to CD8+ T cells;2) determine the mechanism of antigen presentation by which CD8+ T cells recognize mLEP infected monocytes/macrophages including the role of the vitamin D antimicrobial pathway in cross-presentation;and, 3) understand the mechanisms by which MHC class I-restricted CD8+ T cells contribute to host defense in leprosy. The studies we propose are intended to provide a comprehensive analysis of cross-presentation and induction of CD8+ T cells to gain insight into mechanisms of host defense against microbial pathogens that reside in the endocytic pathway. We would hope that the insights gained will identify new biomarkers for diagnosis, as well as targets for treatment of chronic human infectious diseases.

Public Health Relevance

We have chosen to study leprosy, because it remains a global health burden on developing countries, because it provides an extraordinary model to study human immune responses to a microbial pathogen and because the lesions are readily accessible for study of immune processes at the site of disease. The investigation of how T cells are activated in leprosy and how they contribute to host defense against the bacteria that causes leprosy will provide new insights into the human immune system as well as provide novel targets for therapeutic intervention against a wide range of infectious diseases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01AI022553-30A1
Application #
8761022
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Jacobs, Gail G
Project Start
Project End
Budget Start
Budget End
Support Year
30
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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
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
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
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
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
Modlin, Robert L (2012) Innate immunity: ignored for decades, but not forgotten. J Invest Dermatol 132:882-6
Fabri, Mario; Realegeno, Susan E; Jo, Eun-Kyeong et al. (2011) Role of autophagy in the host response to microbial infection and potential for therapy. Curr Opin Immunol 23:65-70
Fabri, Mario; Stenger, Steffen; Shin, Dong-Min et al. (2011) Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages. Sci Transl Med 3:104ra102
Cruz, Daniel; Wang, Zhiming; Kibbie, Jon et al. (2011) Diversity through phosphine catalysis identifies octahydro-1,6-naphthyridin-4-ones as activators of endothelium-driven immunity. Proc Natl Acad Sci U S A 108:6769-74
Lee, Delphine J; Li, Huiying; Ochoa, Maria T et al. (2010) Integrated pathways for neutrophil recruitment and inflammation in leprosy. J Infect Dis 201:558-69

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