Browsing by Subject "infection"
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Item FUNCTIONAL REGULATION OF PHAGOCYTIC CELLS BY IL-23 DURING LISTERIA MONOCYTOGENES INFECTION(2014-03) Indramohan, Mohanalaxmi; Break, Timothy J.; Witter, Alexandra R.; Berg, Rance E.Listeria monocytogenes (LM) is a Gram-positive intracellular pathogen that causes meningitis and septicemia in immunocompromised individuals, and spontaneous abortion in pregnant women. The versatility of LM makes it a useful tool for immunologists to understand how the immune system responds against harmful microorganisms. Cell recruitment mediated by the IL-23/IL-17 axis is important for protection against infectious diseases, but can cause damage during autoimmune disorders. By utilizing mice lacking IL-23 (IL-23p19 KO), our lab examines the role of this cytokine during a systemic bacterial infection. We have demonstrated that IL-23 promotes resistance against LM infection by increasing the recruitment of neutrophils to the liver, and monocytes to the spleen during LM infection. Interestingly, IL-23 or IL-17A is not required for enhancing phagocytic cell functions including phagocytosis, production of ROS, MPO, and pro-inflammatory mediators during LM infection. Understanding the significance of IL-23/IL-17axis in mediating the recruitment and function of immune cells will aid in the development of effective therapeutics depending on the disease condition. Purpose (a): Listeria monocytogenes (LM) is a Gram-positive intracellular foodborne pathogen that causes meningitis and septicemia in immunocompromised individuals, and spontaneous abortion in pregnant women. LM is widely used as a model pathogen to study host pathogen immune interactions. Cell recruitment mediated by the IL-23/IL-17 axis is necessary for protection against multiple infectious diseases, but can be detrimental during autoimmune disorders. We have previously shown utilizing mice lacking IL-23 (IL-23p19 KO) that IL-23 provides protection against LM infection by promoting the optimal recruitment of neutrophils to the liver, and monocytes to the spleen. The receptors for IL-23 and IL-17A are present on phagocytic cells including monocytes, neutrophils, and macrophages. However, it is not known whether IL-23 or IL-17A can impact the function of phagocytic cells during LM infection. Methods (b): Splenocytes and liver leukocytes were harvested from mice infected intravenously with ~10, 000 LM. Peritoneal wash was performed to isolate resident peritoneal macrophages. Flow cytometry was utilized to determine phagocytosis, production of reactive oxygen species (ROS), and myeloperoxidase (MPO). The concentrations of TNF-α, IL-1, IL-6, and nitric oxide (NO.) were measured by ELISAs/Griess assay. Results (c): Phagocytic cells isolated from control C57Bl/6 (B6) and IL-23p19 KO mice displayed equivalent phagocytic potential. There were no differences in the production of ROS or MPO from splenocytes isolated from both groups of mice. Furthermore, exogenous stimulation with rIL-23 or rIL-17A did not induce or enhance production of ROS or proinflammatory mediators from B6 splenocytes. Conclusions (d): IL-23 does not impact the function of phagocytic cells either by a direct or indirect mechanism during LM infection. Collectively, our data suggest that the lack of efficient recruitment of neutrophils to the liver, and monocytes to the spleen, results in a reduction in the overall levels of TNF-α and NO. and therefore, increases the susceptibility of IL-23p19 KO to LM infection.Item PREPATELLAR FAT THICKNESS RATIO AS AN INDICATOR OF INFECTION RISK FOLLOWING TOTAL KNEE ARTHROPLASTY(2013-04-12) McFarlin, JaredPurpose: Investigation of the correlation between obesity, as defined by BMI, and risk of infection following TKA has been met with mixed results. Several studies show an increased risk of infection in the obese, while others show an acceptable success rate. It is our belief that a specific study of the fat distribution surrounding the knee itself versus the general BMI measurement will yield a more precise corollary to the risk of infection. We plan to assess the fat distribution over the knee quantitatively by creating a "prepatellar fat thickness ratio", which would compare the soft tissue thickness anterior to the patella with the actual thickness of the patella. Methods: An alpha level of 0.05 was used to determine statistical significance. Descriptive statistics including means, standard deviations, frequencies and confidence intervals were computed for the variables of interest in the study. Chi-square tests were used to determine if a patient's development of an infection was associated with their gender, smoking or diabetes status. Linear regression were used to determine if the prepatellar ratio was significantly affected by a patient's BMI or age. Logistic regression and odds-ratios were computed to examine the effect that BMI, smoking, diabetes, gender or the prepatellar ratio had on developing an infection post total knee arthroplasty. Results: There were no significant associations detected between developing an infection and the patient's gender, age, BMI, smoking or diabetes status. Using logistic regression, it was determined that for every 0.925mm increase in the ratio between the thickness of the patella and the thickness of the prepatellar soft tissue, a patient's risk of developing an infection post-surgery increased approximately 2.523 times. Conclusions: Many authors believe obesity plays a significant part in increasing infection risks, and used BMI to verify this risk; however, the prepatellar fat thickness ratio proved to be the most accurate predictor of infection in our study. BMI is a not a composition specific measurement, and has met mixed results when used to predict infection risks in some studies. In contrast, the prepatellar ratio is both composition and site specific for TKA. Further investigation is warranted, but it is our belief that this measurement holds promise as a pre-operative indicator of infection riskItem RISK FACTORS FOR INFECTION IN TOTAL JOINT ARTHROPLASTY(2013-04-12) Heim, KathrynPurpose: Infections can be a serious complication following total joint arthroplasty. Several risk factors for increased incidence of infection have been previously reported. The purpose of this study is to evaluate the patient population at JPS for risk factors that may be associated with higher rates of infection. Our hypothesis is that patients with a BMI>30 and other comorbidities are more likely to have a post-surgical complication following total joint arthroplasty when compared to non-obese, healthy patients. Methods: Retrospective chart review of approximately 261 patients from 2008-2012. Charts were analyzed for general demographics, complications, age/gender, health status, prophylactic antibiotics, and surgery time. Patients who were receiving either knee or hip surgery were documented. Each patient was assessed for their degree of general health using BMI, ASA and CCI scores. These categories were compared between patients with complication and those without complications. Results: From the criteria gathered, a nonparametric logistic regression was utilized in order to determine the extent of correlation regarding risk factors for infection. The objective was to determine if there were any risk factors that were recorded that coincided with infection status of patients that have received total joint arthroplasty. After adjusting for confounders, the resulting p-value (0.869) from the sample suggested that there was no significance of risk factors in regards to infection status within the study. In addition, the deep infection rate (15.3 per 1000 cases) exhibits superior performance in regards to surgery and the afflictions that can influence patients. Along with this, the infection rate of the study (84.3 per 1000 cases) may suggest that in the future, the quality of care may be perceived in a more important manner. Conclusions: Although this study didn't yield the results we were looking for, we still have hope for our hypothesis both in the hip subsection and total joints overall as this study continues. One limitation on our study was a smaller than expected patient enrollment. This being a retrospective study, some of the older charts were not available for review, which limited our numbers. That being so, our total enrollment for hips and knees were reduced from approximately 400 patients to 261; with this smaller sample size our data may not truly represent the population from which it is derived.Item THE ROLE OF CRH IN THE LUNG DURING PNEUMOCOCCAL INFECTION(2014-03) Burnley, Brittney N.; Burnley, Preston I.; Su, Dong Ming; Jones, Harlan P.This research aims to identify a better approach in the treatment of bacterial pneumonia. Current treatment uses steroids to decrease tissue damage, however evidence has yet to determine if this treatment leads to increased survival. Our studies uses the stress hormone CRH to enhance this therapeutic approach. Purpose (a): Complications from respiratory pneumonia, mainly caused by Streptococcus pneumoniae (S. pneumoniae), account for the majority of deaths due to respiratory disease worldwide. Treatment with antibiotics is the standard protocol in eliminating S. pneumoniae during infection. However, suppression of inflammatory responses, through glucocorticoids, is also used as an adjunctive therapy during severe infection. Glucocorticoids (GCs) are central mediators of immune suppression and are the primary pharmacologic treatment used to reduce inflammatory responses (IR) in patients with severe bacterial pneumonia. GC treatment however, remains controversial due to inconclusive evidence in reducing mortality amongst at risk populations. Cortisol is an important human GC, whose release is regulated by Corticotropin Releasing Hormone (CRH), a neuropeptide produced primarily by the hypothalamus that mediates adaptive physiological responses. Regulation by CRH is typically involved in controlling immune and IR through cortisol, but has been found to have direct impact within inflamed tissues through ligation with two cellular receptors, CRH-R1 and CRH-R2.Though they provide total immune suppression preventing extensive tissue damage, a problem arises with treatment because they leave the host prone to secondary infections which they are unable to combat due to the actions of the GCs. Therefore, a gap remains in the ability to maintain host immune defenses to facilitate clearance of the pathogen, particularly in instances of ineffective antibiotic treatment caused by bacterial resistance. Therefore, the development of approaches that dampen excessive inflammatory responses without jeopardizing the host may hold promise for reducing risk of mortality due to sepsis. Methods (b): The current study tested the effects of CRH and CRH-R1 antagonist, Antalarmin (ANT) administration, in ICR (CD1) mice subjected to 1 x105 colonies forming units (CFUs) of S. pneumoniae. All experimental groups were compared to the experimental group receiving Dexamethasone (DEX), which is the pharmacological glucocorticoid analogue currently used in clinical settings. Survival studies were conducted to determine the effect that treatment has on overall survival, after treatment at 18 hours. Lung tissue and total blood was analyzed by CFUs to determine bacterial load 24 hours after infection and treatment (18 hours). Additionally lung tissue was analyzed via H&E to determine changes in lung pathology. Results (c): Results of survival indicated that when mice were administered CRH, they had a significant increase in survival when compared to the infection only, ANT, and DEX groups. Conclusions (d): These findings suggest that CRHR1 plays a role in host defenses against pulmonary S. pneumoniae infection and may hold promise as a target to control disease mortality as an alternative approach to glucocorticoids.Item The Roles of IFN-y and IL-4 in the Upper and Lower Respiratory Tracts Immune Responses Toward Mycoplasma Infection(2003-12-01) Woolard, Matthew D.; Jerry SimeckaWoolard, Matthew D., The Roles of IFN-γ and IL-4 in the Upper and Lower Respiratory Tracts Immune Responses Toward Mycoplasma Infection. Doctor of Philosophy (Biomedical Sciences), December, 2003, 136 pp., 1 table, 16 illustrations, bibliography, 152 titles. The purpose of these studies was to evaluate the roles of IFN-γ and IL-4 during the development of immune responses of the upper and lower respiratory tracts, during mycoplasma respiratory disease. To study their roles, we took advantage of IFN-γ and IL-4 knockout (KO) mice. The loss of IL-4 did not impact the development of disease or the clearance of mycoplasma from either respiratory tracts during mycoplasma infection. However, IL-4 mediated responses dampen mycoplasma induced bronchial hyperresponsiveness (BHR), which are in direct contrast to theories that state that IL-4 is critical for the development of BHR. This suggests that mycoplasma exacerbation of asthma is a synergism between IL-4 and non-IL-4 mediated responses. Thus, IL-4 does not impact mycoplasma disease development, but dampens detrimental non-IL-4 mediated responses that exacerbate BHR during mycoplasma disease. The loss of IFN-γ did not affect disease or the number of mycoplasma organisms in the upper respiratory tract; this is in contrast to the lungs where the loss of IFN-γ led to a defect in innate immune responses. A significant increase in mycoplasma organisms were seen by day 3 post-infection which led to exacerbation of disease pathology. By three days after infection, only the number of IFN-γ+ NK cells increase in numbers in response to mycoplasma infection. However, the depletion NK cells by anti-asialo GM1 antibody treatment did not affect the clearance of mycoplasma from lungs of BALB/c mice, however, NK cell depletion from IFN-γ KO mice lead to increased clearance of mycoplasma organisms from the lung. Further studies demonstrated that NK cells in an IFN-γ deficient environment lead to increased secretion of IL-10, G-CSF, and TNF-α and increased numbers of cell infiltrated into the alveoli and airways. These results suggest that NK cells of the lung have anti-inflammatory roles that IFN-γ counteracts in BALB/c mice. Regardless, these studies demonstrate that NK cells in an IFN-γ deficient environment impair innate immune responses from clearing mycoplasma organisms from the lung. These studies demonstrated diverse but novel functions for IFN-γ and IL-4 during respiratory infections that will have significant impact on future studies of respiratory immunology.