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.
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.
|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|
|Walton, Andrew H; Muenzer, Jared T; Rasche, David et al. (2014) Reactivation of multiple viruses in patients with sepsis. PLoS One 9:e98819|
|Boomer, Jonathan S; Green, Jonathan M; Hotchkiss, Richard S (2014) The changing immune system in sepsis: is individualized immuno-modulatory therapy the answer? Virulence 5:45-56|
|Bo, Lulong; Li, Jinbao; Tao, Tianzhu et al. (2014) Probiotics for preventing ventilator-associated pneumonia. Cochrane Database Syst Rev :CD009066|
|Hutchins, Noelle A; Unsinger, Jacqueline; Hotchkiss, Richard S et al. (2014) The new normal: immunomodulatory agents against sepsis immune suppression. Trends Mol Med 20:224-33|
|Chang, Katherine C; Burnham, Carey-Ann; Compton, Stephanie M et al. (2013) Blockade ofthe negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis. Crit Care 17:R85|
|Hotchkiss, Richard S; Monneret, Guillaume; Payen, Didier (2013) Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 13:862-74|
|Takasu, Osamu; Gaut, Joseph P; Watanabe, Eizo et al. (2013) Mechanisms of cardiac and renal dysfunction in patients dying of sepsis. Am J Respir Crit Care Med 187:509-17|
|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|
|Hotchkiss, Richard S; Monneret, Guillaume; Payen, Didier (2013) Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis 13:260-8|
Showing the most recent 10 out of 12 publications