During the current funding period, we made significant progress defining the role of CXC chemokine receptor 3 (CXCR3) in the pathogenesis of septic shock. Our results show that CXCR3 is an important regulator of natural killer cell trafficking during septic shock caused by cecal ligation and puncture (CLP). Furthermore, CXCR3 deficiency or blockade causes significant attenuation of sepsis-induced physiologic dysfunction, systemic cytokine production and survival. Deficiency or blockade of the CXCR3 ligand CXCL10 also conferred protection from CLP-induced septic shock. Survival benefit was achievable when anti-CXCR3 IgG or anti- CXCL10 IgG was administered with fluids and antibiotics at 6 hours after CLP. Therefore, CXCR3 blockade was effective when initiated after the onset of sepsis and may represent a viable addition to a multi-modal approach for the treatment of septic shock. Yet, several questions remain regarding the efficacy of CXCR3 blockade in clinically relevant models of sepsis and the mechanisms by which the CXCR3 axis is activated during sepsis. The goals of this research project are two-fold: 1) To evaluate clinically relevant approaches for CXCR3 blockade with the goal of bringing this approach closer to application in the clinical setting and 2) To define the mechanisms by which CXCR3 activation facilitates the pathogenesis of septic shock and determine the cellular and molecular mechanisms by which the CXCR3 axis is activated during sepsis.
Specific Aim 1 : To define the efficacy of CXCR3 blockade in clinically relevant models of sepsis. In this aim, we will evaluate the efficacy of CXCR3 blockade when initiated after the onset of severe sepsis as indicated by the development of hypoperfusion and organ injury. The CLP model will be utilized as well as our well-developed models of Pseudomonas aeruginosa and Staphylococcus aureus burn wound sepsis. The efficacy of the small molecular weight CXCR3 inhibitor AMG487 will be determined in addition to immunoglobulin-based strategies.
Specific Aim 2 : To determine the role of the CXCR3 axis in the host response to infection. Some recent studies indicate that CXCL10 plays a role in facilitating effective bacterial clearance mechanisms in less severe models of systemic infection. Studies proposed in this aim will determine whether CXCR3 axis blockade will impair the host response to local infection and whether blockade of the CXCR3 axis during the acute phase of severe sepsis will predispose the host to secondary infections.
Specific Aim 3 : To define the mechanisms by which the CXCR3 axis is activated during septic shock and define the cell populations responsible for CXCR3- mediated pathobiology. These studies will define the mechanisms that regulate CXCL10 production in vivo. Emphasis will be placed on evaluating the importance of interferon signaling pathways. Further studies are proposed to determine the functional importance of CXCR3-mediated lymphocyte trafficking during severe sepsis and whether CXCR3 serves as an activating factor for non-migratory lymphocyte populations.

Public Health Relevance

Sepsis is a major cause of death in critically ill patients. The information gained from this project will advance our ability to treat severe sepsis and fill important gaps in knowledge by advancing our understanding of how the CXCR3 axis contributes to sepsis-induced pathobiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066885-12
Application #
8692836
Study Section
Special Emphasis Panel (ZRG1-SBIB-X (02))
Program Officer
Dunsmore, Sarah
Project Start
2003-07-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
12
Fiscal Year
2014
Total Cost
$388,575
Indirect Cost
$141,075
Name
Vanderbilt University Medical Center
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Patil, Naeem K; Bohannon, Julia K; Sherwood, Edward R (2016) Immunotherapy: A promising approach to reverse sepsis-induced immunosuppression. Pharmacol Res 111:688-702
Patil, Naeem K; Luan, Liming; Bohannon, Julia K et al. (2016) IL-15 Superagonist Expands mCD8+ T, NK and NKT Cells after Burn Injury but Fails to Improve Outcome during Burn Wound Infection. PLoS One 11:e0148452
Guo, Yin; Luan, Liming; Rabacal, Whitney et al. (2015) IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-γ. J Immunol 195:2353-64
Hotchkiss, Richard S; Sherwood, Edward R (2015) Immunology. Getting sepsis therapy right. Science 347:1201-2
Herzig, Daniela S; Luan, Liming; Bohannon, Julia K et al. (2014) The role of CXCL10 in the pathogenesis of experimental septic shock. Crit Care 18:R113
Bohannon, Julia K; Hernandez, Antonio; Enkhbaatar, Perenlei et al. (2013) The immunobiology of toll-like receptor 4 agonists: from endotoxin tolerance to immunoadjuvants. Shock 40:451-62
Herzig, Daniela S; Driver, Brandon R; Fang, Geping et al. (2012) Regulation of lymphocyte trafficking by CXC chemokine receptor 3 during septic shock. Am J Respir Crit Care Med 185:291-300
Herzig, Daniela S; Guo, Yin; Fang, Geping et al. (2012) Therapeutic efficacy of CXCR3 blockade in an experimental model of severe sepsis. Crit Care 16:R168
Bohannon, Julia; Guo, Yin; Sherwood, Edward R (2012) The role of natural killer cells in the pathogenesis of sepsis: the ongoing enigma. Crit Care 16:185
Herzig, Daniela; Fang, Geping; Toliver-Kinsky, Tracy E et al. (2012) STAT1-deficient mice are resistant to cecal ligation and puncture-induced septic shock. Shock 38:395-402

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