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)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
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
1991-01-01
Project End
2019-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
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
Keegan, Caroline; Krutzik, Stephan; Schenk, Mirjam et al. (2018) Mycobacterium tuberculosis Transfer RNA Induces IL-12p70 via Synergistic Activation of Pattern Recognition Receptors within a Cell Network. J Immunol 200:3244-3258
Madigan, Cressida A; Cambier, C J; Kelly-Scumpia, Kindra M et al. (2017) A Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosy. Cell 170:973-985.e10
Lopez, David; Montoya, Dennis; Ambrose, Michael et al. (2017) SaVanT: a web-based tool for the sample-level visualization of molecular signatures in gene expression profiles. BMC Genomics 18:824
Scumpia, Philip O; Botten, Giovanni A; Norman, Joshua S et al. (2017) Opposing roles of Toll-like receptor and cytosolic DNA-STING signaling pathways for Staphylococcus aureus cutaneous host defense. PLoS Pathog 13:e1006496
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
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
Realegeno, Susan; Kelly-Scumpia, Kindra M; Dang, Angeline Tilly et al. (2016) S100A12 Is Part of the Antimicrobial Network against Mycobacterium leprae in Human Macrophages. PLoS Pathog 12:e1005705
Kibbie, Jon; Teles, Rosane M B; Wang, Zhiming et al. (2016) Jagged1 Instructs Macrophage Differentiation in Leprosy. PLoS Pathog 12:e1005808
Schenk, Mirjam; Mahapatra, Sebabrata; Le, Phuonganh et al. (2016) Human NOD2 Recognizes Structurally Unique Muramyl Dipeptides from Mycobacterium leprae. Infect Immun 84:2429-38
Rotcheewaphan, Suwatchareeporn; Belisle, John T; Webb, Kristofor J et al. (2016) Diguanylate cyclase activity of the Mycobacterium leprae T cell antigen ML1419c. Microbiology 162:1651-1661

Showing the most recent 10 out of 42 publications