Lung infections and sepsis caused by P.aeruginosa are a leading cause of death in the intensive care unit. The failure rate for antibiotic treatment for P. aeruginosa pneumonia is high and antibiotic resistance that develops during therapy is associated with persistent pneumonia and development of multi-organ dysfunction syndrome. Therefore there is an urgent need to develop immunomodulatory strategies for P.aeruginosa lung infections. It is becoming evident that immunoglobulin receptors and intracellular proteins such as nucleotide oligomerization domains co-operate with TLRs and are critical in defining the innate host response to bacteria. Triggering receptor expressed on myeloid cells 1 (TREM-1) is a member of the super immunoglobulin family expressed on macrophage and neutrophils. Blockade of TREM-1 improves survival in lethal animal models of sepsis. These receptors are thus emerging as potent amplifiers of TLR initiated inflammatory responses however there is limited data on the mechanisms by which TREM-1 expression is regulated in response to bacteria and there is little to no information about how these receptors modulate host response to invading pathogens. We were the first to show that TREM-1 activation in response to LPS is transcriptionally controlled (1). While NF-?B activates the TREM-1 gene, PU.1 inhibits the expression of TREM-1 in response to LPS. Second, we have shown that MyD88 dependent and independent signaling determines the expression of TREM-1 in response to specific TLR ligands (2). We have also defined the functional consequences of silencing TREM-1 gene in macrophages which include altered availability of key signaling molecules downstream of TLR4 activation (3). Our new data shows that TREM-1 is induced in vivo in mice in response to P.aeruginosa and in human lungs with septic lung injury. TREM-1 activation in macrophages provides a positive feedback to the TLR induced inflammation by upregulating key biomolecules such as IL-6 and IL-23 thus exaggerating inflammation and impeding the immune capacity of macrophages to kill bacteria in vitro. Together these data indicate a significant crosstalk between TLR and TREM-1 signaling and suggest a key role for TREM-1 in defining the host immune response. Most importantly by using novel nanomicellar preparation we have shown that blockade of TREM-1 attenuates lung inflammation in mice in vivo. As a whole our published and preliminary studies suggest two fundamentally new mechanisms to be pursued in this application: (1) TREM-1 expression by transcriptional control and epigenetic modification in response to bacteria (2) mechanisms by which TREM-1 signaling exaggerates inflammation and inhibits host protective response to invading bacteria using genetic and novel nanomedicine approach. Our findings have led to the hypothesis that activation of TREM-1 in response to P.aeruginosa is regulated by NF-?B and PU.1. TREM-1 activation in macrophages plays a pivotal role in defining the host response to bacteria. Thus blockade of TREM-1 will enhance host immune capacity to P.aeruginosa lung infections. We propose three interrelated specific aims:1) Define the molecular mechanisms by which TREM-1 expression is regulated by p65 and PU.1 in vitro in macrophages in response to P.aeruginosa. 2) Elucidate the role of TREM-1 signaling in macrophages and in vivo in host immune response to P. aeruginosa infection. 3) Develop novel TREM-1 blocking nanomicelles for immunomodulatory therapies for P.aeruginosa pneumonia. Nosocomial pneumonia caused by P.aeruginosa is a leading cause of morbidity and mortality in critically ill patients and the Department of Veterans Affairs is the largest worldwide single provider of critical care services. Completion of these studies will provide an in depth understanding of the contribution of TREM-1 in lung immune response and will lay the ground work for developing immunomodulatory therapies that will have a significant impact on treatment of life threatening infections such as P.aeruginosa.

Public Health Relevance

The overall goal of this project is to in depth investigate the role of TREM-1 in the pathogenesis of P. aeruginosa lung infections. Host defense mechanisms involved in P.aeruginosa are extremely complex. Despite of the extensive work in this field effective immunomodulatory strategies to enhance host defense against P.aeruginosa infection have yet to be developed. To this end, we have identified TREM-1 as a potential molecular target and developed a novel therapeutic strategy to block TREM-1 using long-acting nanocarrier formulation. This approach exploits the pathophysiological characteristics of lung microenvironment in pneumonia along with the unique attributes of nanomedicine to curtail intense pulmonary inflammation. Completion of these studies will develop new immunomodulatory strategies for this devastating infection.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX001786-01
Application #
8334170
Study Section
Respiration (PULM)
Project Start
2013-07-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
Indirect Cost
Name
Jesse Brown VA Medical Center
Department
Type
DUNS #
010299204
City
Chicago
State
IL
Country
United States
Zip Code
60612
Bedi, Brahmchetna; Maurice, Nicholas M; Ciavatta, Vincent T et al. (2017) Peroxisome proliferator-activated receptor-? agonists attenuate biofilm formation by Pseudomonas aeruginosa. FASEB J 31:3608-3621
Kim, Kyun Ha; Sadikot, Ruxana T; Joo, Myungsoo (2016) Therapeutic effect of ent-kaur-16-en-19-oic acid on neutrophilic lung inflammation and sepsis is mediated by Nrf2. Biochem Biophys Res Commun 474:534-540
Yuan, Zhihong; Syed, Mansoor; Panchal, Dipti et al. (2016) TREM-1-accentuated lung injury via miR-155 is inhibited by LP17 nanomedicine. Am J Physiol Lung Cell Mol Physiol 310:L426-38
Bedi, Brahmchetna; Yuan, Zhihong; Joo, Myungsoo et al. (2016) Enhanced Clearance of Pseudomonas aeruginosa by Peroxisome Proliferator-Activated Receptor Gamma. Infect Immun 84:1975-1985
Kim, Kyun Ha; Song, Hyuk-Hwan; Ahn, Kyung-Seop et al. (2016) Ethanol extract of the tuber of Alisma orientale reduces the pathologic features in a chronic obstructive pulmonary disease mouse model. J Ethnopharmacol 188:21-30
Festic, Emir; Bansal, Vikas; Kor, Daryl J et al. (2015) SpO2/FiO2 ratio on hospital admission is an indicator of early acute respiratory distress syndrome development among patients at risk. J Intensive Care Med 30:209-16
Swenson, Colin E; Sadikot, Ruxana T (2015) Achromobacter respiratory infections. Ann Am Thorac Soc 12:252-8
Mirsaeidi, Mehdi; Farnia, Parissa; Sadikot, Ruxana et al. (2015) Nontuberculous Mycobacteria: Epidemiologic, Mycobacteriologic, and Clinical Aspects. Biomed Res Int 2015:523697
Sevransky, Jonathan E; Checkley, William; Herrera, Phabiola et al. (2015) Protocols and Hospital Mortality in Critically Ill Patients: The United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study. Crit Care Med 43:2076-84
de Paula Rogerio, Alexandre; Sorgi, Carlos Artério; Sadikot, Ruxana et al. (2015) The role of lipids mediators in inflammation and resolution. Biomed Res Int 2015:605959

Showing the most recent 10 out of 42 publications