Priya S. Prakash
University of Cincinnati
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Featured researches published by Priya S. Prakash.
Infection and Immunity | 2010
Kevin R. Kasten; Priya S. Prakash; Jacqueline Unsinger; Holly S. Goetzman; Lisa G. England; Cindy M. Cave; Aaron P. Seitz; Cristina N. Mazuski; Tony T. Zhou; Michel Morre; Richard S. Hotchkiss; David A. Hildeman; Charles C. Caldwell
ABSTRACT The sepsis syndrome represents an improper immune response to infection and is associated with unacceptably high rates of mortality and morbidity. The interactions between T cells and the innate immune system while combating sepsis are poorly understood. In this report, we observed that treatment with the potent, antiapoptotic cytokine interleukin-7 (IL-7) accelerated neutrophil recruitment and improved bacterial clearance. We first determined that T cells were necessary for the previously observed IL-7-mediated enhanced survival. Next, IL-7 increased Bcl-2 expression in T cells isolated from septic mice as early as 3 h following treatment. This treatment resulted in increased gamma interferon (IFN-γ) and IP-10 production within the septic peritoneum together with local and systemic increases of IL-17 in IL-7-treated mice. We further demonstrate that the increase in IL-17 was largely due to increased recruitment and production by γδ T cells, which express CXCR3. Consistent with increased IL-17 production, IL-7 treatment increased CXCL1/KC production, neutrophil recruitment, and bacterial clearance. Significantly, end-organ tissue injury was not significantly different between vehicle- and IL-7-treated mice. Collectively, these data illustrate that IL-7 can mediate the cross talk between Th1 and Th17 lymphocytes during sepsis such that neutrophil recruitment and bacterial clearance is improved while early tissue injury is not increased. All together, these observations may underlay novel potential therapeutic targets to improve the host immune response to sepsis.
The Journal of Infectious Diseases | 2012
Jacqueline Unsinger; Carey-Ann D. Burnham; Jacquelyn S. McDonough; Michel Morre; Priya S. Prakash; Charles C. Caldwell; W. Michael Dunne; Richard S. Hotchkiss
BACKGROUND Secondary hospital-acquired fungal infections are common in critically-ill patients and mortality remains high despite antimicrobial therapy. Interleukin-7 (IL-7) is a potent immunotherapeutic agent that improves host immunity and has shown efficacy in bacterial and viral models of infection. This study examined the ability of IL-7, which is currently in multiple clinical trials (including hepatitis and human immunodeficiency virus), to improve survival in a clinically relevant 2-hit model of fungal sepsis. METHODS Mice underwent cecal ligation and puncture to induce peritonitis. Four days later, surviving mice had intravenous injection with Candida albicans. Following Candida infection, mice were treated with IL-7 or saline control. The effect of IL-7 on host immunity and survival was recorded. RESULTS IL-7 ameliorated the loss of immune effector cells and increased lymphocyte functions, including activation, proliferation, expression of adhesion molecules, and interferon-γ production. These beneficial effects of IL-7 were associated with an increase in global immunity as reflected by an enhanced delayed type hypersensitivity response and a 1.7-fold improvement in survival. CONCLUSIONS The present findings showing that IL-7 improves survival in fungal sepsis, together with its previously reported efficacy in bacterial and viral infectious models, further supports its use as a novel immunotherapeutic in sepsis.
Journal of The American College of Surgeons | 2012
Ritha M. Belizaire; Priya S. Prakash; Jillian R. Richter; Bryce R.H. Robinson; Michael J. Edwards; Charles C. Caldwell; Alex B. Lentsch; Timothy A. Pritts
BACKGROUND Transfusion of stored blood is associated with increased complications. Microparticles (MPs) are small vesicles released from RBCs that can induce cellular dysfunction, but the role of RBC-derived MPs in resuscitation from hemorrhagic shock is unknown. In the current study, we examined the effects of RBC-derived MPs on the host response to hemorrhage and resuscitation. STUDY DESIGN MPs were isolated from murine packed RBC units, quantified using flow cytometry, and injected into healthy mice. Separate groups of mice underwent hemorrhage and resuscitation with and without packed RBC-derived MPs. Lungs were harvested for histology and neutrophil accumulation and assessed by myeloperoxidase content. Human neutrophils were treated with human RBC-derived MPs and CD11b expression, superoxide production, and phagocytic activity were determined. RESULTS Stored murine packed RBC units contained increased numbers of RBC-derived MPs compared with fresh units. Hemorrhaged mice resuscitated with MPs demonstrated substantially increased pulmonary neutrophil accumulation and altered lung histology compared with mice resuscitated without MPs. Intravenous injection of MPs into normal mice resulted in neutrophil priming, evidenced by increased neutrophil CD11b expression. Human neutrophils treated with RBC-derived MPs demonstrated increased CD11b expression, increased superoxide production, and enhanced phagocytic ability compared with untreated neutrophils. CONCLUSIONS Stored packed RBC units contain increased numbers of RBC-derived MPs. These MPs appear to contribute to neutrophil priming and activation. The presence of MPs in stored units can be associated with adverse effects, including lung injury, after transfusion.
Journal of Trauma-injury Infection and Critical Care | 2012
Priya S. Prakash; Charles C. Caldwell; Alex B. Lentsch; Timothy A. Pritts; Bryce R.H. Robinson
BACKGROUND Microparticles (MPs) are 0.3 &mgr;m to 1.0 &mgr;m vesicles generated after cell activation or apoptosis that may play a role in the pathophysiology of sepsis. We sought to elucidate the role of MPs in patients with critical illness and hypothesized that MPs are generated at the site of inflammation and can modulate the immune response. METHODS Surgical patients with critical illness with ongoing sepsis were enrolled from the intensive care unit of an urban, Level I trauma center from March to June 2011. Abdominal washings and bronchoalveolar lavage fluid were collected from sites of inflammation. MPs were isolated using differential centrifugation, then characterized by flow cytometry. Immunologic assays were conducted by incubating neutrophil-derived MPs (NDMPs) with a human monocytic cell line (THP-1). A p value ⩽0.05 was considered significant. RESULTS MPs were absent in noninflamed foci in patients, whereas NDMPs were present in locations of inflammation. NDMPs were added to cultured THP-1 cells to quantify immunomodulatory effects. THP-1 cells were able to phagocytose NDMPs. Cells that ingested NDMPs demonstrated increased activation. In contrast, bystander THP-1 cells without ingested NDMPs demonstrated decreased activation. CONCLUSION NDMPs are generated at the site of inflammation in patients with critical illness during sepsis. They have a divergent effect on the immune response by activating phagocytic cells and deactivating bystander cells. NDMPs may play an important role in regulating the inflammatory response to sepsis in patients with critical illness. LEVEL OF EVIDENCE Prognostic/epidemiologic study, level III.
Biochemical and Biophysical Research Communications | 2013
Bobby L. Johnson; Holly S. Goetzman; Priya S. Prakash; Charles C. Caldwell
Despite advances in understanding and treatment of sepsis, it remains a disease with high mortality. Neutrophil Derived Microparticles (NDMPs) are present during sepsis and can modulate the immune system. As TNF-α is a cytokine that predominates in the initial stages of sepsis, we evaluated whether and how TNF-α can induce NDMPs in mice. We observed that TNF-α treatment results in increased NDMP numbers. We also determined that the activation of either TNF receptor 1 (TNFr1) or TNF receptor 2 (TNFr2) resulted in increased NDMP numbers and that activation of both resulted in an additive increase. Inhibition of Caspase 8 diminishes NDMPs generated through TNFr1 activation and inhibition of NF-κB abrogates NDMPs generated through activation of both TNFr1 and TNFr2. We conclude that the early production of TNF-α during sepsis can increase NDMP numbers through activation of the Caspase 8 pathway or NF-κB.
Endocrine‚ Metabolic & Immune Disorders-Drug Targets | 2010
Johannes Tschöp; Jonathan Dattilo; Priya S. Prakash; Kevin R. Kasten; Matthias H. Tschöp; Charles C. Caldwell
Sepsis, which is defined as a systemic inflammatory response syndrome that occurs during infection, is associated with several clinical conditions and high mortality rates. As sepsis progresses immune paralysis can become severe, leaving an already vulnerable patient ill equipped to eradicate primary or secondary infections. At present the predominant treatments for sepsis have not demonstrated convincing efficacy of decreased mortality. During sepsis, it has been observed that leptin levels initially increase but subsequently decline. A body of evidence has demonstrated that central or systemic leptin can beneficially regulate immune function. In this report expression of leptin and its receptor, signaling, and function on leukocytes will be reviewed. Furthermore, the effects mediated by central and systemic leptin during sepsis will be reviewed. Altogether, the ability of leptin to beneficially enhance inflammation and the host response during sepsis supports its use as a therapeutic agent, particularly during the latter phases of the syndrome.
Biochemical and Biophysical Research Communications | 2016
Emily F. Midura; Priya S. Prakash; Bobby L. Johnson; Teresa C. Rice; Natalia Kunz; Charles C. Caldwell
The morbidity and mortality from sepsis continues to remain high despite extensive research into understanding this complex immunologic process. Further, while source control and antibiotic therapy have improved patient outcomes, many immunologically based therapies have fallen short. Microparticles (MPs) are intact vesicles that serve as mediators of intercellular communication as well as markers of inflammation in various disease processes. We have previously demonstrated that MPs can be produced at the infected foci during sepsis, are predominantly of neutrophil derivation (NDMPs) and can modulate immune cells. In this study, we sought to elucidate the molecular mechanisms underlying NDMP generation. Using thioglycolate (TGA) to recruit and activate neutrophils, we first determined that intra-peritoneal TGA increase NDMP accumulation. We next utilized TGA-elicited neutrophils in vitro to investigate signaling intermediates involved in NDMP production, including the intrinsic and extrinsic caspase pathways, cAMP dependent PKA and Epac activation as well as the role myosin light chain kinase (MLCK) as a final mediator of NDMP release. We observed that NDMP generation was dependent on the extrinsic caspase apoptotic pathway (caspase 3 and caspase 8), cAMP activation of PKA but not of Epac, and on activation of MLCK. Altogether, these data contribute to an overall framework depicting the molecular mechanisms that regulate NDMP generation.
Biochimica et Biophysica Acta | 2017
Bobby L. Johnson; Emily F. Midura; Priya S. Prakash; Teresa C. Rice; Natalia Kunz; Kathrin Kalies; Charles C. Caldwell
Although advances in medical care have significantly improved sepsis survival, sepsis remains the leading cause of death in the ICU. This is likely due to a lack of complete understanding of the pathophysiologic mechanisms that lead to dysfunctional immunity. Neutrophil derived microparticles (NDMPs) have been shown to be the predominant microparticle present at infectious and inflamed foci in human models, however their effect on the immune response to inflammation and infection is sepsis has not been fully elucidated. As NDMPs may be a potential diagnostic and therapeutic target, we sought to determine the impact NDMPs on the immune response to a murine polymicrobial sepsis. We found that peritoneal neutrophil numbers, bacterial loads, and NDMPs were increased in our abdominal sepsis model. When NDMPs were injected into septic mice, we observed increased bacterial load, decreased neutrophil recruitment, increased expression of IL-10 and worsened mortality. Furthermore, the NDMPs express phosphatidylserine and are ingested by F4/80 macrophages via a Tim-4 and MFG-E8 dependent mechanism. Finally, upon treatment, NDMPs decrease macrophage activation, increase IL-10 release and decrease macrophage numbers. Altogether, these data suggest that NDMPs enhance immune dysfunction in sepsis by blunting the function of neutrophils and macrophages, two key cell populations involved in the early immune response to infection. This article is part of a Special Issue entitled: Immune and Metabolic Alterations in Trauma and Sepsis edited by Dr. Raghavan Raju.
Journal of Trauma-injury Infection and Critical Care | 2017
Juan C. Duchesne; Danielle Tatum; Glenn Jones; Brandy Davis; Rosemarie Robledo; Marc DeMoya; Terence O'Keeffe; Paula Ferrada; Tomas Jacome; Rebecca Schroll; Jordan Wlodarczyk; Priya S. Prakash; Brian R. Smith; Kenji Inaba; Desmond Khor; Marquinn D. Duke; Mansoor Khan
BACKGROUND The neutrophil/lymphocyte ratio (NLR) has been associated as a predictor for increased mortality in critically ill patients. We sought to determine the relationship between NLR and outcomes in adult trauma patients with severe hemorrhage requiring the initiation of massive transfusion protocol (MTP). We hypothesized that the NLR would be a prognostic indicator of mortality in this population. METHODS This was a multi-institutional retrospective cohort study of adult trauma patients (≥18 years) with severe hemorrhage who received MTP between November 2014 and November 2015. Differentiated blood cell counts obtained at days 3 and 10 were used to obtain NLR. Receiver operating characteristic (ROC) curve analysis assessed the predictive capacity of NLR on mortality. To identify the effect of NLR on survival, Kaplan-Meier (KM) survival analysis and Cox regression models were used. RESULTS A total of 285 patients with severe hemorrhage managed with MTP were analyzed from six participating institutions. Most (80%) were men, 57.2% suffered blunt trauma. Median (IQR) age, Injury Severity Score, and Glasgow Coma Scale were 35 (25–47), 25 (16–36), and 9 (3–15), respectively. Using ROC curve analysis, optimal NLR cutoff values of 8.81 at day 3 and 13.68 at day 10 were calculated by maximizing the Youden index. KM curves at day 3 (p = 0.05) and day 10 (p = 0.02) revealed an NLR greater than or equal to these cutoff values as a marker for increased in-hospital mortality. Cox regression models failed to demonstrate an NLR over 8.81 as predictive of in-hospital mortality at day 3 (p = 0.056) but was predictive for mortality if NLR was greater than 13.68 at day 10 (p = 0.036). CONCLUSIONS NLR is strongly associated with early mortality in patients with severe hemorrhage managed with MTP. Further research is needed to focus on factors that can ameliorate NLR in this patient population. LEVEL OF EVIDENCE Prognostic study, level III.
Journal of Surgical Research | 2014
Joshua W. Kuethe; Priya S. Prakash; Emily F. Midura; Bobby L. Johnson; Kevin R. Kasten; Charles C. Caldwell