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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|Cappuccio, Antonio; Zollinger, RaphaÃ«l; Schenk, Mirjam et al. (2015) Combinatorial code governing cellular responses to complex stimuli. Nat Commun 6:6847|
|Teles, Rosane M B; Kelly-Scumpia, Kindra M; Sarno, Euzenir N et al. (2015) IL-27 Suppresses Antimicrobial Activity in Human Leprosy. J Invest Dermatol 135:2410-7|
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|Meller, Stephan; Di Domizio, Jeremy; Voo, Kui S et al. (2015) T(H)17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26. Nat Immunol 16:970-9|
|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|
|Ma, Feng; Liu, Su-Yang; Razani, Bahram et al. (2014) Retinoid X receptor Î± attenuates host antiviral response by suppressing type I interferon. Nat Commun 5:5494|
|Wang, Yaya; Shaked, Iftach; Stanford, Stephanie M et al. (2013) The autoimmunity-associated gene PTPN22 potentiates toll-like receptor-driven, type 1 interferon-dependent immunity. Immunity 39:111-22|
|Chung, Andrew W; Sieling, Peter A; Schenk, Mirjam et al. (2013) Galectin-3 regulates the innate immune response of human monocytes. J Infect Dis 207:947-56|
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