Sepsis is a systemic response to severe infection with an associated mortality of approximately 30%. Although many sepsis-induced deaths take place during the initial hyperinflammatory phase, those patients that survive often develop and may succumb to secondary infections. These infections are frequently caused by organisms not typically pathogenic in immunocompetent hosts, suggesting that this later phase of sepsis is characterized by clinically important immunosuppression. Although a number of mechanisms of immunosuppression have been identified in animal models of sepsis, few systematic studies have been conducted in patients. In addition, relatively new and potent mechanisms involving expression of inhibitory receptors such as PD-1, BTLA and CTLA4, as well as regulatory cell populations have been identified. Of particular interest, patients with chronic viral infection hav been demonstrated to develop a phenomenon termed immune cell exhaustion. Characterized by persistent, elevated expression of inhibitory receptors, exhausted T cells manifest severe functional defects. Supported by our preliminary data, we hypothesize that the immunosuppression in sepsis results from the combined consequences of an expansion of suppressive cells and a state of immune cell exhaustion that develops progressively over time, such that at early stages it is both identifiable and reversible. The goals of this project are to ) determine the mechanism of immunosuppression in patients that die of sepsis, and 2) identify clinically relevant markers that identify those patients with sepsis that are immunosuppressed and for which immunomodulating therapies may be of benefit. To achieve these goals, we will perform a detailed functional, phenotypic and mechanistic analysis of immune cells isolated following a novel, rapid bedside autopsy of patients that die of sepsis. This will be coupled with a prospective study of patients hospitalized in the intensive care units with sepsis, to determine clinically useful markers that can identify patients that are more severely immune compromised and therefore at increased risk for secondary infection. Together, these studies will substantially advance our understanding of the pathogenesis of this disease and directly impact the care of patients with sepsis.

Public Health Relevance

This study will examine the reasons why patients with sepsis die. In particular, the study will examine mechanisms for the impaired immune system that occurs in patients with prolonged sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM098391-01A1
Application #
8297918
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2012-05-07
Project End
2016-02-28
Budget Start
2012-05-07
Budget End
2013-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$573,579
Indirect Cost
$193,606
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Shindo, Yuichiro; Unsinger, Jacqueline; Burnham, Cary-Ann et al. (2015) Interleukin-7 and anti-programmed cell death 1 antibody have differing effects to reverse sepsis-induced immunosuppression. Shock 43:334-43
Chang, Katherine; Svabek, Catherine; Vazquez-Guillamet, Cristina et al. (2014) Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis. Crit Care 18:R3
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Venet, Fabienne; Lukaszewicz, Anne-Claire; Payen, Didier et al. (2013) Monitoring the immune response in sepsis: a rational approach to administration of immunoadjuvant therapies. Curr Opin Immunol 25:477-83

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