Bacterial infections are still a major cause of morbidity and mortality, especially in immunocompromised individuals. Peptidoglycan and endotoxin can reproduce most of the major signs and symptoms of infections, including production of cytokines and induction of septic shock. The prerequisite for release of cytokines is interaction of peptidoglycan and endotoxin with their specific receptors on host cells, which results in triggering of signal transduction pathways that culminate in induction of transcription of cytokine genes and secretion of cytokines. The overall goal of this project is to identify peptidoglycan receptor and peptidoglycan-activated signal transduction pathways. This will enable rational development of new therapeutic agents that can block the consequences of peptidoglycan-induced cell activation (sepsis syndrome, arthritis, etc.). The applicant proposes to test three hypotheses to determine if CD14, a macrophage endotoxin receptor, also serves as a receptor for peptidoglycan. Hypothesis I: Peptidoglycan binds to membrane CD14 and soluble CD14, which function as cell-activating receptors for PGN. The applicant proposes to test this hypothesis by i) demonstrating binding of peptidoglycan to membrane CD14 and soluble CD14; ii) determining if CD14-negative cells are activated by soluble CD14:peptidoglycan complexes; and iii) defining structural requirements of membrane and soluble CD14 for peptidoglycan binding and cell activation. Hypothesis II: Interaction of peptidoglycan with CD14 induces a cascade of phosphorylation events that starts with activation of Lyn and results in activation of MAP kinases. The applicant proposes to test this hypothesis by: i) defining the pathway through which Lyn transmits the activation signal into the cell; ii) identifying the pathways of activation of MAP kinases by peptidoglycan; and iii) determining if peptidoglycan-induced activation of MAP kinases is Lyn-dependent. Hypothesis III: Interaction of peptidoglycan with CD14 induces signal transduction pathways that culminate in activation of transcription factors that induce transcription of cytokine genes and secretion of cytokines. The applicant will test this hypothesis by: i) determining if peptidoglycan induces transcription of transcription factor and cytokine genes; ii) identifying transcription factors activated by peptidoglycan; iii) determining if peptidoglycan-induced transcription factors are required and sufficient for activation of cytokine genes; and iv) determining if Lyn and MAP kinases induce activation of transcription factors and cytokine genes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI028797-05A1
Application #
2003575
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1992-07-01
Project End
2002-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
5
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Kashyap, Des R; Kuzma, Marcin; Kowalczyk, Dominik A et al. (2017) Bactericidal peptidoglycan recognition protein induces oxidative stress in Escherichia coli through a block in respiratory chain and increase in central carbon catabolism. Mol Microbiol 105:755-776
Dziarski, Roman; Park, Shin Yong; Kashyap, Des Raj et al. (2016) Pglyrp-Regulated Gut Microflora Prevotella falsenii, Parabacteroides distasonis and Bacteroides eggerthii Enhance and Alistipes finegoldii Attenuates Colitis in Mice. PLoS One 11:e0146162
Jing, Xuefang; Zulfiqar, Fareeha; Park, Shin Yong et al. (2014) Peptidoglycan recognition protein 3 and Nod2 synergistically protect mice from dextran sodium sulfate-induced colitis. J Immunol 193:3055-69
Kashyap, Des Raj; Rompca, Annemarie; Gaballa, Ahmed et al. (2014) Peptidoglycan recognition proteins kill bacteria by inducing oxidative, thiol, and metal stress. PLoS Pathog 10:e1004280
Park, Shin Yong; Jing, Xuefang; Gupta, Dipika et al. (2013) Peptidoglycan recognition protein 1 enhances experimental asthma by promoting Th2 and Th17 and limiting regulatory T cell and plasmacytoid dendritic cell responses. J Immunol 190:3480-92
Dziarski, Roman; Kashyap, Des Raj; Gupta, Dipika (2012) Mammalian peptidoglycan recognition proteins kill bacteria by activating two-component systems and modulate microbiome and inflammation. Microb Drug Resist 18:280-5
Park, Shin Yong; Gupta, Dipika; Kim, Chang H et al. (2011) Differential effects of peptidoglycan recognition proteins on experimental atopic and contact dermatitis mediated by Treg and Th17 cells. PLoS One 6:e24961
Park, Shin Yong; Gupta, Dipika; Hurwich, Risa et al. (2011) Peptidoglycan recognition protein Pglyrp2 protects mice from psoriasis-like skin inflammation by promoting regulatory T cells and limiting Th17 responses. J Immunol 187:5813-23
Kashyap, Des Raj; Wang, Minhui; Liu, Li-Hui et al. (2011) Peptidoglycan recognition proteins kill bacteria by activating protein-sensing two-component systems. Nat Med 17:676-83
Saha, Sukumar; Jing, Xuefang; Park, Shin Yong et al. (2010) Peptidoglycan recognition proteins protect mice from experimental colitis by promoting normal gut flora and preventing induction of interferon-gamma. Cell Host Microbe 8:147-62

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