The purpose of this Program Project is to enhance basic knowledge at the molecular level of host-pathogen relationships, focusing on macrophages, dendritic cells and their products, with respect to 3 bacterial pathogens, their products and their mechanisms of evasion or repair-- Mycobacterium tuberculosis (Mtb), Bacillus anthracis (Ba) and Yersinia pestis (Yp)-- and to use this knowledge to develop translational approaches to novel chemotherapeutics and vaccines. Mtb, Ba and Yp were chosen for study because (i) they allow us to compare and contrast different consequences of bacterial interaction with macrophages and DC; (ii) in each case, those interactionslwhether positive or negative---are critical to the pathogenesis of the disease; (iii) bronchopulmonary macrophages and DC often play a key role in the initial encounter of the host with these pathogens; and (iv) these pathogens use diverse mechanisms to evade or repair the antimicrobial lesions inflicted on them by host macrophages and DC. Specifically, this Program explores how human bronchopulmonary macrophages respond to Ba spores and toxins at the level of gene expression; how we can develop new inhibitors of enzymes within Mtb and Yp that are critical to the pathogenesis of their infections, namely, enzymes that degrade oxidized or nitrosated proteins and synthesize siderophores; and how we can use gene therapy vectors to target exogenous antigen into the appropriate compartments of DC to induce an effective vaccine against Yp while simultaneously providing for short term passive immunity. Cores provide for BSL3 wet lab and mouse work; microarray analysis of gene expression; computation and comparison of gene expression results; and high throughput screening of chemical libraries.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI056293-04
Application #
7028285
Study Section
Special Emphasis Panel (ZRG1-SSS-H (40))
Program Officer
Sizemore, Christine F
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
$1,384,909
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Lin, Gang; Li, Dongyang; Chidawanyika, Tamutenda et al. (2010) Fellutamide B is a potent inhibitor of the Mycobacterium tuberculosis proteasome. Arch Biochem Biophys 501:214-20
Lin, Gang; Li, Dongyang; de Carvalho, Luiz Pedro Sorio et al. (2009) Inhibitors selective for mycobacterial versus human proteasomes. Nature 461:621-6
Vandal, Omar H; Nathan, Carl F; Ehrt, Sabine (2009) Acid resistance in Mycobacterium tuberculosis. J Bacteriol 191:4714-21
Vandal, Omar H; Roberts, Julia A; Odaira, Toshiko et al. (2009) Acid-susceptible mutants of Mycobacterium tuberculosis share hypersusceptibility to cell wall and oxidative stress and to the host environment. J Bacteriol 191:625-31
Stirrett, Karen L; Ferreras, Julian A; Rossi, Sebastian M et al. (2008) A multicopy suppressor screening approach as a means to identify antibiotic resistance determinant candidates in Yersinia pestis. BMC Microbiol 8:122
Vandal, Omar H; Pierini, Lynda M; Schnappinger, Dirk et al. (2008) A membrane protein preserves intrabacterial pH in intraphagosomal Mycobacterium tuberculosis. Nat Med 14:849-54
Stirrett, Karen L; Ferreras, Julian A; Jayaprakash, Venkatesan et al. (2008) Small molecules with structural similarities to siderophores as novel antimicrobials against Mycobacterium tuberculosis and Yersinia pestis. Bioorg Med Chem Lett 18:2662-8
Cisar, Justin S; Ferreras, Julian A; Soni, Rajesh K et al. (2007) Exploiting ligand conformation in selective inhibition of non-ribosomal peptide synthetase amino acid adenylation with designed macrocyclic small molecules. J Am Chem Soc 129:7752-3
Quadri, Luis E N (2007) Strategic paradigm shifts in the antimicrobial drug discovery process of the 21st century. Infect Disord Drug Targets 7:230-7
Hu, Guiqing; Lin, Gang; Wang, Ming et al. (2006) Structure of the Mycobacterium tuberculosis proteasome and mechanism of inhibition by a peptidyl boronate. Mol Microbiol 59:1417-28

Showing the most recent 10 out of 16 publications