Sepsis is the leading cause of death in most intensive care units, and the death of septic patients usually does not result from the initial septic event but rather from subsequent nosocomial infections. Patients who survive severe sepsis often display severely compromised immune function. Not only is there significant apoptosis of lymphoid and myeloid cells that depletes critical components of the immune system during sepsis, there is also decreased function of the remaining immune cells. Studies in animals and humans suggest the immune defects that occur during sepsis may be critical to the pathogenesis and subsequent mortality. Using a cecal-ligation and puncture (CLP) model to induce intra-abdominal peritonitis, we recently established a mechanistic link between apoptotic cells generated during sepsis and the establishment of sepsis-induced immune suppression. We also found that the sepsis-induced immune suppression depends on generation of TNF-related apoptosis-inducing ligand (TRAIL)-expressing CD8 T cells. These results suggested TRAIL plays an important role in the induction of sepsis-induced immunosuppression, and we used this information to establish a clinically-relevant two-hit model of sepsis, which better reflects the delayed mortality seen during sepsis due to the second infection, to investigate sepsis-induced immune suppression of naove and memory Ag-specific CD8 T cell responses to an experimental secondary bacterial infection. Our proposed experiments will investigate the hypothesis that septic (CLP-treated) mice cannot clear a secondary infection because of the systemic suppression of the T cell compartment that is, in part, mediated by a TRAIL-dependent mechanism. Thus, the following distinct but complementary Specific Aims will be evaluated: 1 - Analyze primary CD8 T cell responses to secondary infection after sepsis and determine the role of TRAIL in sepsis- induced immunosuppression, 2 - Determine the extent to which sepsis influences the function of pre-existing memory CD8 T cells and investigate the role of TRAIL in that process, and 3 - Determine the long lasting consequences of sepsis-induced deletion of naove or memory CD8 T cells in vivo. Our experimental design will allow us to define the cellular and molecular mechanism(s) behind the induction and maintenance of sepsis-induced TRAIL-dependent suppression of T cell immunity. We also expect that the data we obtain from these studies will instrumental in the development of new TRAIL-based therapeutic approaches for counteracting the sepsis-induced immune suppression that leads to the high number of deaths seen during this uncontrolled inflammatory response.
The decision to generate protective immunity or tolerance often depends on the context in which T cells first encounter antigen. When examining sepsis-induced immunosuppression, we observed the distinct role for TNF-related apoptosis-inducing ligand (TRAIL) in the regulation of T cell-mediated immunity. The Potential Impact on Veterans Health Care is that our studies will increase our understanding of the failure to generate protective naove and memory T cell responses during sepsis, and define the regulatory role of TRAIL in this phenomenon.
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|Cabrera-Perez, Javier; Badovinac, Vladimir P; Griffith, Thomas S (2017) Enteric immunity, the gut microbiome, and sepsis: Rethinking the germ theory of disease. Exp Biol Med (Maywood) 242:127-139|
|Cabrera-Perez, Javier; Babcock, Jeffrey C; Dileepan, Thamotharampillai et al. (2016) Gut Microbial Membership Modulates CD4 T Cell Reconstitution and Function after Sepsis. J Immunol 197:1692-8|
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|Cabrera-Perez, Javier; Condotta, Stephanie A; James, Britnie R et al. (2015) Alterations in antigen-specific naive CD4 T cell precursors after sepsis impairs their responsiveness to pathogen challenge. J Immunol 194:1609-20|
|Condotta, Stephanie A; Khan, Shaniya H; Rai, Deepa et al. (2015) Polymicrobial Sepsis Increases Susceptibility to Chronic Viral Infection and Exacerbates CD8+ T Cell Exhaustion. J Immunol 195:116-25|
|Amarante-Mendes, Gustavo P; Griffith, Thomas S (2015) Therapeutic applications of TRAIL receptor agonists in cancer and beyond. Pharmacol Ther 155:117-31|
|Cabrera-Perez, Javier; Condotta, Stephanie A; Badovinac, Vladimir P et al. (2014) Impact of sepsis on CD4 T cell immunity. J Leukoc Biol 96:767-77|
|Markwart, Robby; Condotta, Stephanie A; Requardt, Robert P et al. (2014) Immunosuppression after sepsis: systemic inflammation and sepsis induce a loss of naïve T-cells but no enduring cell-autonomous defects in T-cell function. PLoS One 9:e115094|
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