The long term objective of this proposal is to gain insight into mechanisms of innate immunity to infectious agents in humans. Our discovery that TLR2 mediates the innate immune response to microbial lipoproteins, prompted us to investigate the regulation of innate immune response, finding that the selective induction of IL- 10 and IL 15, differentially programs macrophages for phagocytosis vs. antimicrobial responses in leprosy. The differential regulation of these pathways optimizes antimicrobial efficiency required for host defense against microbial pathogens, yet the divergence of these programs can also contribute to the pathogenesis of infectious disease. By investigating leprosy as a model, and its causative pathogen, Mycobacterium leprae (mLEP), we hope to gain insight into the innate immune mechanisms that instruct the macrophage functional programs that contribute to pathogenesis and host resistance. We therefore propose to: 1) determine the mechanisms by which mLEP, through distinct ligands, triggers innate immune receptors to differentially induce macrophage phagocytic and antimicrobial programs, 2) elucidate the mechanisms by which the local cytokine environment contributes to divergence of the macrophage functional programs in leprosy;and 3) investigate the mechanisms by which specific miRNAs regulate the phagocytic vs. antimicrobial innate immune responses in leprosy. Together these aims target an integrated understanding by which the innate immune response is programmed with relevance to host defense against microbial infection in humans, starting with the trigger (Aim 1), mechanisms of cytokine amplification (Aim 2) and molecular regulation (Aim 3) leading to the final functional programs at the site of infection in leprosy.
Our immune system rapidly recognizes and responds to microbes to combat infection. By studying leprosy, we propose to identify the parts of microbes that are recognized by the immune system, the types of immune responses that are generated, and the mechanism by which these immune responses are regulated. Insights into the host response to infection will provide new avenues for therapeutic intervention in infectious disease.
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|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|
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|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|
|Modlin, Robert L (2010) The innate immune response in leprosy. Curr Opin Immunol 22:48-54|
|Teles, Rosane M B; Krutzik, Stephan R; Ochoa, Maria T et al. (2010) Interleukin-4 regulates the expression of CD209 and subsequent uptake of Mycobacterium leprae by Schwann cells in human leprosy. Infect Immun 78:4634-43|
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