The outcome of an infection with any given pathogen depends both upon the nature of the pathogen, and the response of the host. Controlling the host-pathogen interaction for the benefit of the host thus requires an understanding both of the pathogen and of the host immune response. Faculty in The Department of Immunology and Infectious Diseases at the Harvard University School of Public Health (HSPH) are uniquely equipped to collaborate to bring these components together. This Department consists of investigators who study the immune response (Glimcher: Project 1, Grusby: Project 2), the interaction of the host and pathogen in vivo (Kramnik: Project 3) and the pathogen itself (Rubin: Project 4). Dr. Glimcher, Project 1, has discovered two gene products that represent early molecular checkpoints in the development of each of these immune response types. T-bet is a transcription factor that dictates the Thl genetic program while the XBP-1 transcription factor controls the generation of plasma cells and hence antibodies. Dr. Grusby, Project 2 has studied the function and modulation of another set of transcription factors, the Stats, which are critical in regulating Type 1 and Type 2 immunity. An additional set of genetic loci that regulate the immune response to Mycobacterium tuberculosis and Francisella tularensis in vivo is the subject of Project 3, Kramnik. This Project also addresses the critical role of the innate rather than the adaptive immune response to the successful control of pathogens. Understanding the structure and function of the pathogen itself is a vital part of any effort to successfully combat pathogens. The genes responsible for virulence of Francisella tularensis will be studied taking advantage of new technologies in genomics and proteomics in Rubin, Project 4. In this proposal, these investigators join with a group specializing in protein structure determination (Petsko: Project 5), and a biotechnology company focused on the immune system with expertise in drug discovery (Allecure: subcontract), to develop a novel strategy for biodefense. In the first component, we recognize that structures of these potential drug targets will provide a framework for virtual screening of combinatorial libraries and for structure-guided drug design. The second component requires productive interaction of academia with industry, the appropriate site for efficient drug discovery. The overall objective of this interdependent, interdisciplinary team is to develop molecules that modulate the host immune system so as to augment the protective effects of vaccines against microbial pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI056296-04
Application #
7034660
Study Section
Special Emphasis Panel (ZAI1-NBS-I (M1))
Program Officer
Mallia, Conrad M
Project Start
2003-09-15
Project End
2008-02-29
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
4
Fiscal Year
2006
Total Cost
$4,457,415
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Liu, Ce Feng; Brandt, Gabriel S; Hoang, Quyen Q et al. (2016) Crystal structure of the DNA binding domain of the transcription factor T-bet suggests simultaneous recognition of distant genome sites. Proc Natl Acad Sci U S A 113:E6572-E6581
Martinon, Fabio; Glimcher, Laurie H (2011) Regulation of innate immunity by signaling pathways emerging from the endoplasmic reticulum. Curr Opin Immunol 23:35-40
Collins, Patrick L; Chang, Shaojing; Henderson, Melodie et al. (2010) Distal regions of the human IFNG locus direct cell type-specific expression. J Immunol 185:1492-501
Riol-Blanco, Lorena; Lazarevic, Vanja; Awasthi, Amit et al. (2010) IL-23 receptor regulates unconventional IL-17-producing T cells that control bacterial infections. J Immunol 184:1710-20
Martinon, Fabio; Chen, Xi; Lee, Ann-Hwee et al. (2010) TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol 11:411-8
Hett, Erik C; Chao, Michael C; Rubin, Eric J (2010) Interaction and modulation of two antagonistic cell wall enzymes of mycobacteria. PLoS Pathog 6:e1001020
Cai, Lei; Pan, Hui; Trzci?ski, Krzysztof et al. (2010) MYBBP1A: a new Ipr1's binding protein in mice. Mol Biol Rep 37:3863-8
Lee, Ann-Hwee; Glimcher, Laurie H (2009) Intersection of the unfolded protein response and hepatic lipid metabolism. Cell Mol Life Sci 66:2835-50
Glimcher, Laurie H; Lee, Ann-Hwee (2009) From sugar to fat: How the transcription factor XBP1 regulates hepatic lipogenesis. Ann N Y Acad Sci 1173 Suppl 1:E2-9
Pan, Hui; Mostoslavsky, Gustavo; Eruslanov, Evgeny et al. (2008) Dual-promoter lentiviral system allows inducible expression of noxious proteins in macrophages. J Immunol Methods 329:31-44

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