Sepsis accounts for 250,000 deaths annually in the United States alone. Unrestrained stimulation of phagocytes can induce Systemic Inflammatory Response Syndrome (SIRS) resulting in failure of multiple systemic organs. Prolonged SIRS leads to enhanced susceptibility to nosocomial infection. Phagocyte recognition of microbial products is mediated by Toll like receptors via activation of Toll/IL-1R (TIR) adaptor MyD88-dependent NF-kB activation. There are numerous endogenous brakes involved in TLR activation, including phosphatases SHIP-1 and DUSP. The role of the phosphatase and tensin homolog PTEN in controlling macrophage activation and its role in controlling polymicrobial sepsis is unknown. This project is based on preliminary data showing that PTEN inhibits MyD88 expression by controlling actions of specific microRNAs. Furthermore, while PTEN activation has protective effects in acute sepsis, enhanced and chronic PTEN expression produces deleterious effects favoring endotoxin tolerance and possibly secondary infection. The hypothesis to be tested is that although PTEN protects against overwhelming inflammatory responses early in acute sepsis, excessive PTEN expression is responsible for both the initiation and maintenance of sepsis-induced immunoparalysis states by impairing TLR activation in phagocytes. These studies will increase our overall understanding of how innate immunity works, and will produce insights regarding the pathogenesis of acute sepsis and enhanced susceptibility to secondary infection in deleterious conditions. We propose the following specific aims: 1 - Determine how PTEN controls transcriptional and post-transcriptional modifications involved in MyD88 expression;2- Determine how PTEN influences sepsis outcome and morbidities associated with secondary lung infection. The identification of specific components and their modes of action in maintenance of sepsis may identify targets for therapeutic intervention resulting in improved immune responsiveness in settings of host vulnerability, and may suggest strategies to dampen the immune response in settings of exaggerated inflammation.
Sepsis remains the leading cause of mortality in intensive care units, and is the most common cause of late organ injury after trauma and surgical intervention. Although sepsis starts with overwhelming inflammation and is followed by organ damage, it also produces a state of impaired immunity, which is often followed by nosocomial infection. This project seeks to investigate the role of a molecular brake in both homeostatic innate immune responses, as well as in deleterious conditions, to identify novel regulatory pathways involved in early events involved in sepsis, and elucidate pathways contributing to impaired immunity in later stages of sepsis involved in secondary infection.
|Sisti, Flavia; Wang, Soujuan; Brandt, Stephanie L et al. (2018) Nuclear PTEN enhances the maturation of a microRNA regulon to limit MyD88-dependent susceptibility to sepsis. Sci Signal 11:|
|Brandt, Stephanie L; Wang, Sue; Dejani, Naiara N et al. (2018) Excessive localized leukotriene B4 levels dictate poor skin host defense in diabetic mice. JCI Insight 3:|
|Brandt, Stephanie L; Putnam, Nicole E; Cassat, James E et al. (2018) Innate Immunity to Staphylococcus aureus: Evolving Paradigms in Soft Tissue and Invasive Infections. J Immunol 200:3871-3880|
|Brandt, Stephanie L; Serezani, C Henrique (2017) Too much of a good thing: How modulating LTB4 actions restore host defense in homeostasis or disease. Semin Immunol 33:37-43|
|Piñeros Alvarez, Annie Rocio; Glosson-Byers, Nicole; Brandt, Stephanie et al. (2017) SOCS1 is a negative regulator of metabolic reprogramming during sepsis. JCI Insight 2:|
|Filgueiras, Luciano Ribeiro; Brandt, Stephanie L; Ramalho, Theresa Raquel de Oliveira et al. (2017) Imbalance between HDAC and HAT activities drives aberrant STAT1/MyD88 expression in macrophages from type 1 diabetic mice. J Diabetes Complications 31:334-339|
|Zhang, Huajia; Rodriguez, Sonia; Wang, Lin et al. (2016) Sepsis Induces Hematopoietic Stem Cell Exhaustion and Myelosuppression through Distinct Contributions of TRIF and MYD88. Stem Cell Reports 6:940-956|
|Ishizuka, Edson K; Filgueiras, Luciano Ribeiro; Rios, Francisco J et al. (2016) PAFR activation of NF-?B p65 or p105 precursor dictates pro- and anti-inflammatory responses during TLR activation in murine macrophages. Sci Rep 6:32092|
|Zoccal, Karina F; Sorgi, Carlos A; Hori, Juliana I et al. (2016) Opposing roles of LTB4 and PGE2 in regulating the inflammasome-dependent scorpion venom-induced mortality. Nat Commun 7:10760|
|Dejani, Naiara N; Brandt, Stephanie L; Piñeros, Annie et al. (2016) Topical Prostaglandin E Analog Restores Defective Dendritic Cell-Mediated Th17 Host Defense Against Methicillin-Resistant Staphylococcus Aureus in the Skin of Diabetic Mice. Diabetes 65:3718-3729|
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