Sepsis is associated with aberrations in adaptive immunity that place the host at increased risk of secondary opportunistic infections. The overall goal of this proposal is to determine whether myeloid-derived suppressor cell populations (MDSC) contribute to outcome and the adaptive immune suppression seen in severe sepsis. MDSCs are a heterogeneous population of immature myeloid cells with suppressor cell activities. Understanding how these regulatory cells act during sepsis may permit the development of potential novel therapeutic avenues to ameliorate the immune suppression observed in severe sepsis. Therefore, three specific aims are proposed: 1. To determine which MDSC cell subpopulations possess these immunosuppressive properties, and through what mechanism(s) (NO, reactive oxygen species) are these immunosuppressive properties obtained. 2. To confirm and identify the MyD88 dependent cell processes that are required for the expansion of the MDSC populations in microbial sepsis, and whether these MyD88 dependent processes involve endogenous production of members of the CSF superfamily, and 3. To determine whether alterations in the MDSC population in response to sepsis modulates the acquired immune response, and can alter outcome to a secondary infectious challenge. Both MDSC numbers and function will be quantitated in septic mice, as will the degree of adaptive immunosuppression and susceptibility to a secondary bacterial challenge. MdSC numbers (CD31+CD11b+GR-1+) will be determined by flow cytometry, while suppressor cell activity will be evaluated functionally by co-culture with CD4+ and CD8+ splenocytes in response to antigen specific and nonspecific proliferative signals. Under in vivo conditions, the effect of these MDSC populations on T helper cell polarization (Th1 vs Th2) will also be determined. Finally, mice at the above time points post-CLP will be subjected to a secondary bacterial infection (Pseudomonas aeruginosa pneumonia, or Listeriosis) to determine their susceptibility. Thus, the proposed studies represent an innovative examination of a novel suppressor cell population as a potential mechanism for immune suppression during sepsis.
Sepsis is a life-threatening disease associated with significant immune suppression. Understanding the role that immature myeloid derived suppressor cells play in sepsis could lead to new therapeutic interventions. This program will explore the mechanisms responsible for the massive expansion of this cell population in the bone marrow, spleen and lymph nodes in sepsis, and the mechanisms behind its contribution to sepsis induced immune suppression.
| Mira, Juan C; Nacionales, Dina C; Loftus, Tyler J et al. (2018) Mouse Injury Model of Polytrauma and Shock. Methods Mol Biol 1717:1-15 |
| Mira, Juan C; Gentile, Lori F; Mathias, Brittany J et al. (2017) Sepsis Pathophysiology, Chronic Critical Illness, and Persistent Inflammation-Immunosuppression and Catabolism Syndrome. Crit Care Med 45:253-262 |
| Lopez, Maria-Cecilia; Efron, Philip A; Ozrazgat-Baslanti, Tezcan et al. (2016) Sex-based differences in the genomic response, innate immunity, organ dysfunction, and clinical outcomes after severe blunt traumatic injury and hemorrhagic shock. J Trauma Acute Care Surg 81:478-85 |
| Mira, Juan C; Szpila, Benjamin E; Nacionales, Dina C et al. (2016) Patterns of gene expression among murine models of hemorrhagic shock/trauma and sepsis. Physiol Genomics 48:135-44 |
| Loftus, Tyler J; Efron, Philip A; Moldawer, Lyle L et al. (2016) ?-Blockade use for Traumatic Injuries and Immunomodulation: A Review of Proposed Mechanisms and Clinical Evidence. Shock 46:341-51 |
| Mathias, Brittany; Lipori, Gigi; Moldawer, Lyle L et al. (2016) Integrating ""big data"" into surgical practice. Surgery 159:371-4 |
| Efron, Philip A; Mohr, Alicia M; Moore, Frederick A et al. (2015) The future of murine sepsis and trauma research models. J Leukoc Biol 98:945-52 |
| Efron, Philip A; Mohr, Alicia M (2015) The Monocyte That Wasn't. Crit Care Med 43:1532-4 |
| Cuenca, Alex G; Cuenca, Angela L; Gentile, Lori F et al. (2015) Delayed emergency myelopoiesis following polymicrobial sepsis in neonates. Innate Immun 21:386-91 |
| Cuenca, Alex G; Joiner, Dallas N; Gentile, Lori F et al. (2015) TRIF-dependent innate immune activation is critical for survival to neonatal gram-negative sepsis. J Immunol 194:1169-77 |
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