Bacterial infections are still the major cause of morbidity and mortality, and innate immunity is the first line of host defense against infections. The long-term objectives of this project are to elucidate how innate immunity protects the host from bacterial infections, how these infections can be prevented, how defects in innate immunity may result in pathologic conditions, and how development of these pathologic conditions can be prevented. This project will investigate a novel family of four pattern recognition molecules, peptidoglycan recognition proteins (PGLYRPs), that were discovered by this laboratory and recently identified as either hydrolytic for peptidoglycan (the major component of bacterial cell wall), or bactericidal for both Gram- positive and Gram-negative bacteria. Bactericidal PGLYRPs are expressed on the skin, in the eyes, on mucous membranes in the oral cavity and gastrointestinal tract, and in sweat, sebum, saliva, and polymorphonuclear leukocytes. The goal of this project is to determine the in vivo role ofmammalian PGLYRPs, and specifically, based on in vitro activities of these proteins, to test two hypotheses: (a) that bactericidal PGLYRPs play a role in protecting the host against infections, and (b) that bactericidal and peptidoglycan-hydrolytic PGLYRPsplay a scavenger role and protect the host from excessive inflammation induced by bacteria and their peptidoglycan component. These hypotheses will be tested byconstructing and using mice deficient in each of these four PGLYRPs, and also mice deficient in multiple PGLYRPs(two, three, or all four PGLYRPs).
The specific aims of this project will be to determine whether these mice have changed sensitivity to infections or changed responsiveness in the following inflammation or immune response models: (i) sensitivity to intestinal, eye, skin, intranasal lung, and systemic intraperitoneal infections;(ii) incidence and severity of experimentally-induced colitis, a model of inflammatory bowel disease caused by overgrowth of intestinal bacteria and increased inflammation induced by bacterial products;(iii)peptidoglycan-induced arthritis;(iv) peptidoglycan-induced experimental autoimmune encephalitis;and (v) adjuvant activity of peptidoglycan for antibody response. This project may discovernew mechanisms of resistance to infections, new susceptibility genes for inflammatory bowel disease, and new mechanisms of regulation of bacterially-induced arthritis, encephalitis, and antibody responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028797-19
Application #
8197143
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Korpela, Jukka K
Project Start
1992-07-01
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2014-11-30
Support Year
19
Fiscal Year
2012
Total Cost
$369,988
Indirect Cost
$124,963
Name
Indiana University-Purdue University at Indianapolis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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
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
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
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
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
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
Dziarski, Roman; Gupta, Dipika (2010) Review: Mammalian peptidoglycan recognition proteins (PGRPs) in innate immunity. Innate Immun 16:168-74
Saha, Sukumar; Qi, Jin; Wang, Shiyong et al. (2009) PGLYRP-2 and Nod2 are both required for peptidoglycan-induced arthritis and local inflammation. Cell Host Microbe 5:137-50

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