Browsing by Subject "Virus Diseases"
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Item Evaluation of NK Cell – Astrocyte Interactions: Potential Role in HIV-Associated Neurocognitive Disorders and HIV- Associated Dementia(2015-05-01) Bowen, Kelly E.; Mathew, Porunelloor A.; Mathew, Stephen O.; Hodge, Lisa M.NK cells play important roles in immunity against pathogens and cancer. NK cell functions are regulated by inhibitory and activating receptors binding corresponding ligands on the surface of target cells. During pathological conditions, NK cells were shown to be recruited to the CNS and could impact CNS physiology by killing glial cells and by secreting IFN-g. Astrocytes are intimately involved in immunological and inflammatory events occurring in the CNS and reactive astrogliosis is a key feature in HIV-associated neurocognitive disorders (HAND). There is little data on NK cell-astrocyte interactions and ligands expressed on astrocytes that could impact NK cell function. This study aimed to identify NK-associated ligands expressed by human astrocytes that confer this NK-directed cytotoxicity of astrocytes and assay the cytotoxicity differences in presence and absence of HIV 3S peptide. Using a fusion protein consisting of the extracellular domain of NKp44 fused to Fc portion of human IgG, we determined the expression of a novel ligand for NKp44 (NKp44L) on astrocytes. Incubation of astrocytes with 3S peptide downregulated NKp44L expression on astrocytes implicating protection from NK mediated killing. Thus, our study demonstrated that NKp44 has a protective effect on astrocytes from NK cell mediated killing during HIV infection. Astrocytes could also secrete cytokines that affect the expression of NK receptors on NK cells. We evaluated the expression of receptors on NK cells after co-culture with astrocytes. CD38 expression was increased on primary NK cells after incubation with astrocytes. CD38 is expressed on both NK cells and astrocytes and has an important implication in HIV-1 infection. Blocking CD38 signaling in our studies decreased astrocyte lysis, suggesting CD38 signaling has important implications in NK-astrocyte interactions. Future studies providing novel insights into the role of NK cells in the pathogenesis of HAND and other brain disorders might result in the development of NK cell based therapies for brain pathologies.Item HIV Related Risk Behaviors: A Comparitive Study of Urban, Suburban, and Rural U.S. Adolescents(2006-08-01) Patil, Godavari D.; Karan Singh; Sejong Bae; Francise Soto MasGodavari D. Patil, HIV Related Risk Behaviors: A Comparative Study of Urban, Suburban, and Rural U.S. Adolescents. Masters of Public Health (Biostatistics), August 2006, 120 pp., 29 tables, References, 209 titles. This explorative study YRBS 2003 data provides the prevalence of HIV-related risky sexual behaviors and predictors of such behaviors across gender, race/ethnicity, and metro status (N=15, 214) during 2003. Overall, more urban male adolescents engaged in health-compromising behaviors. A significant association was found between gender, race/ethnicity, and metro status and sexual behaviors and associated risk behaviors such as alcohol, drug use, and mental health indicators. These associated risk behaviors were not only associated among themselves and with sexual behaviors variables but also turned out to be responsible predictor variables for HIV related sexual risk behaviors. Minority groups especially black adolescents were at higher risk of contracting HIV infection as having multiple sexual partners was highest (8 fold) among black adolescents compared to mixed & other race, and Hispanic adolescents. Suburban adolescents were nearly two times more likely that rural and urban adolescents to having multiple partners. Results indicated that younger the age more the involvement in sexual and other risky behaviors.Item Intercellular Nef transfer and HIV-1 infection of astrocytes(2015-05-01) Luo, Xiaoyu; He, Johnny J.; Ghorpade, Anuja; Wordinger, Robert J.Acquired immune deficiency syndrome (AIDS) is a pandemic caused by human immunodeficiency virus type 1 (HIV-1). It is a major health issue in many parts of the world ever since its discovery in 1981. The most devastating effect of HIV-1 infection is the graduate loss of CD4+ T cells, which eventually leads to the dysfunction of the immune system, susceptibility to opportunistic infections and cancer. HIV-1 Nef protein is long known as an essential pathogenic factor for HIV-1/AIDS pathogenesis. A few recent studies including ours have demonstrated that Nef can be transferred to neighboring cells and alters the function of these cells. However, the underlying mechanism of intercellular Nef transfer is in dispute. In the first part of our study, we characterized two potential underlying mechanisms for intercellular Nef transfer: direct cell-cell contact and exosomes using several complementary strategies and a panel of exosomal markers. First, we showed that Nef was transferred from Nef-expressing or HIV-infected CD4+ T lymphocytes to CD4+ T lymphocytes and astrocytes, and that the transfer was mainly associated with tunneling nanotube formation. Then we determined that Nef enhanced virological synapse formation and induced cytoskeleton re-arrangement and cell surface protrusions, suggesting that Nef promotes the establishment of intercellular connection and communication between infected cells and uninfected cells. Thirdly, we examined the possibility of Nef transfer through exosomes. In the exosome uptake assay, Nef transfer was undetectable while exosome marker CD81 transferred rapidly. In contrast, Nef was detected in crude exosomes collected from Nef-transfected 293T. In addition, two different populations of exosomes were successfully separated by OptiPrep gradient fractionation and determined as AChE+/CD81low/TSG101low exosomes and AChE- /CD81high/TSG101high exosomes. We determined that Nef was selectively secreted into the AChE+/CD81low/TSG101low population. Lastly, microscopic imaging showed no significant Nef detection in exosomal vesicle-like structures in and out the cell. Taken together, this study shows that Nef transfer requires direct cell-cell contact such as tunneling nanotubes, not cell-free exosomes. In addition, this study reveals existence of two types of exosomes: AChE+/CD81low/TSG101low exosomes and AChE/CD81high/TSG101high exosomes. In the second part, we characterized HIV-1 infection of astrocytes. Astrocytes are the most abundant cells in the central nervous system (CNS) and play important roles in HIV-1/neuroAIDS. Detection of HIV-1 proviral DNA, RNA and early gene products but not late structural gene products in astrocytes in vivo and in vitro indicates that astrocytes are susceptible to HIV-1 infection albeit in a restricted manner. We, as well as others have shown that cell-free HIV-1 is capable of entering CD4- astrocytes through human mannose receptor-mediated endocytosis. In this study, we took advantage of several newly developed fluorescence protein-based HIV-1 reporter viruses and further characterized HIV-1 interaction with astrocytes. First, we found that HIV-1 was successfully transferred to astrocytes from HIV-infected CD4+ T cells in a cell-cell contact- and gp120-dependent manner. In addition, we demonstrated that compared to endocytosis-mediated cell-free HIV-1 entry and subsequent degradation of endocytosed virions, cell-cell contact between astrocytes and HIV-infected CD4+ T cells led to robust HIV-1 infection of astrocytes but retained the restricted nature of viral gene expression. Furthermore, we showed that HIV-1 latency was established in astrocytes. Lastly, we demonstrated that infectious progeny HIV-1 was readily recovered from latently infected astrocytes in a cell-cell contact-mediated manner. Taken together, our studies point to the importance of the cell-cell contact-mediated HIV-1 interaction with astrocytes and provide direct evidence to support the notion that astrocytes are HIV-1 latent reservoirs in the CNS.Item Interleukin-8: Baculovirus Expression and the Receptor Signal Transduction Pathway(1994-06-01) Kang, Xiaoqiang; Stephen R. Grant; Rafael Alvarez; Paula SumstomXiaoqiang, Kang., Interleukin-8: Baculovirus Expression and the Receptor Signal Transduction Pathway. Doctor of Philosophy (Biomedical Sciences), June, 1994, 150 pp., 4 tables, 36 illustrations, bibliography, 212 titles. The cDNA for human interleukin-8 (IL8) was subcloned from a bacterial source into the eukaryotic baculoviral vector expression system. Recombinant human IL-8 (rhIL-8) was synthesized and secreted from SF9 cells following infection of a recombinant virus harboring the full-length IL-8 structural gene. Recombinant human interleukin-8 was purified ([greater than] 600 fold) to homogeneity using preparative HPLC. The rhIL-8 preparation retained all of the physical, immunological, and biochemical properties of the natural product (monocyte-derived IL-8). Baculovirus vector expression coupled to preparative HPLC proved to be a very efficient method for large-scale recombinant interleukin production. Biochemical mechanisms that mediate IL-8 receptor-stimulated activities are poorly understood. In this study, I have explored the intracellular mechanism(s) induced by IL-8 in differentiated HL-60 cells. IL-8 induced a rapid and transient activation of phospholipase A2 in differentiated HL-60 cells. A consequence of phospholipase A2 activation was the release of arachidonic acid and the generation of lysophospholipids from membrane phospholipids. The IL-8 stimulated-arachidonic acid release was pertussis toxin and phospholipase A2 inhibitor sensitive, and protein kinase C independent. In contrast to another neutrophil chemotactic factor, fMLP, IL-8 did not stimulate the activation of phospholipase C and phospholipase D. When comparing the phosphorylation events induced by IL-8 and fMLP, I found that these two chemotactic factors triggered different protein phosphorylation profiles. Tyrosine phosphorylation of proteins was not detected following IL-8 stimulation in HL-60 cells. However, IL-8 stimulated the rapid autophosphorylation of calcium/calmodulin-dependent protein kinase II (CaM kinase II). These results strongly suggest that the IL-8 receptor is closely coupled to the activation of PLA2 and that CaM kinase II is an integral component of IL-8 receptor signal pathway.Item "Is it as Simple as ABC?" -- Applying Uganda's ABC Approach Amongst the Dinka Ethnic Group of Southern Sudan(2007-12-01) Madut, Nyebol B.; Peter Hilsenrath; Karan Singh; Jim StimpsonMadut, Nyebol B., “Is it as simple as ABC? – Applying Uganda’s ABC approach amongst the Dinka ethnic group of Southern Sudan. Master of Public Health (Health Management and Policy), December 2007, 127 pp, 23 figures, 23 tables, bibliography, 157 titles. The purpose of this thesis is to explore those activities than can potentially result in a constructive balance of A, B and C activities, which could translate into an effective HIV prevention strategy for Southern Sudan’s largest ethnic group, the Dinka. In other words, the objective of this paper is to examine the local cultural context of southern Sudan’s largest ethnic group, as well as the state of the AIDS epidemic in areas populated by the Dinka; and then determine which public health and/or health management and policy strategies will prove to be the most effective in tailoring an appropriate mix of ABC activities.Item Religiosity and Sexually Transmitted Diseases: How Past and Present Religiosity Affect the Odds of Having a Sexually Transmitted Diseases(2008-05-01) Jackson, Rachel; Lurie, Sue; Martin, Marcus; Cardarelli, KathrynJackson, Rachel S. Religiosity and Sexually Transmitted Diseases: How Past and Present Religiosity Affect the Odds of Having a Sexually Transmitted Disease among Young Adults. Master of Public Health (Community Health), May 2008, 73 pp., 7 tables, 2 figures, bibliography, 57 titles. The purpose of this study was to determine if and how religiosity among American adolescents affects their odds of developing an STD by young adulthood. Using the National Longitudinal Study of Adolescent Health, the odds of developing an STD were calculated based on past religiosity (religiosity score at Wave I), present religiosity (religiosity score at Wave III), and continued religiosity (religiosity score at Wave III adjusted for Wave I religiosity score). It was determined that religiosity, both past and present, impact the odds of developing an STD, but that the direction and magnitude of this relationship varies by race and religion.Item T-Helper Cell Responses in Lungs After Immunization and Chronic Respiratory Disease; And Their Association With Pulmonary Inflammation(2001-05-01) Jones, Harlan P.; Simecka, Jerry; Dimitrijevich, S. Dan; Goldfarb, Ronald H.The purpose of these studies was to characterize T helper cell responses in the lungs of mice after immunization and chronic respiratory infection. CD4+ T cells were the major population of T cells resident in the lung in comparison to CD8+ T cells. Polyclonal activation of resident CD4+T cells produced abundant levels of IL-4 in comparison to IFN-γ, indicating that Th2 cells were the major sub-population of CD4+ T cells. In contrast, resident CD8+ T cells were the sole producer of IFN-γ by naïve T lymphocytes. Furthermore, the distribution of T cells was similar between BALB/c, C3H/HeN, C57BL/6 and DBA/2N strains of mice. However differences in the distribution of CD8+T cells, as well as the levels of IL-4 and IFN-y production produced by resident T cells were found between C57 and the other strains of mice tested. These results demonstrate that host genetic factors may be involved in determining host susceptibility to respiratory disease. Differences in the intensity of antigenic stimulation provoke changes in the type of T cell response generated. Intranasal immunization with influenza (FLU) vaccine antigen alone initiated solely an antigen-specific Th2-like response. In contrast, the addition of the potent mucosal adjuvant cholera toxin (CT) in combination with FLU antigen induced not only resident Th2 responses, but also induced antigen-specific Th1-like responses. This change corresponded with a dramatic increase in the number of CD4+ T cells in the lung. Thus, intense immunization of respiratory T cells enhanced resident T helper cell responses, but also promoted the activation of Th1 responses. Chronic respiratory infection also elicited changes in the resident population of T cells consistent with pulmonary inflammatory immune responses. At early stages of infection, CD4+, but not CD8+ T cells increased in number within inductive respiratory lymphoid tissues (lower respiratory nodes [LRNs]). Between day 7 and 14 however, there was a dramatic increase in the number of CD4+ T cells in the lung. Interestingly, CD8+ T cells also increased in the lungs, suggesting their activation along mucosal sites during mycoplasma infection. Mycoplasma-specific IL-4 and IFN-γ production also increased in a tissue-specific/time-dependent manner. IL-4 production was initially observed in the LRNs, whereas significant levels of IL-4 and IFN-γ was produced in both tissues 14 days after infection. In comparison, IFN-γ was the predominate cytokine, produce at 14 days coinciding with pulmonary inflammation. Suggesting that intense activation promoted changes in the resident pulmonary Th2 environment, and possible is a major component of pulmonary inflammatory immune responses. Both CD4+ and CD8= T cells were shown to have a role in modulation of disease severity during mycoplasma disease. Observation of gross pulmonary lesions reveal that mycoplasma infected mice treated with anti-CD8 antibody showed increase clinical signs of disease and pronounced gross pulmonary lesions. Additionally the number of total mononuclear cells increased dramatically in the absence of CD8+ T cells. Thus, CD8+ T cells may have a regulatory role in controlling resident CD4+ T cells that increased 14 days after infection. Chemokine production is known to mediate the recruitment of lymphocytes to enhance the initiation of immunity as well as be responsible for modulating inflammatory responses. We find that mycoplasma increase the number of dendritic cells in the lung 14 days after infection, and stimulated the production of dendritic cell-derived ABCD-1 chemokine. Also, β-chemokine MIP-1α and MIB-1β production was observed during intense immunization as well as during mycoplasma infection. These results provide evidence for a potential mechanism through which changes in resident pulmonary T cell responses occur given the intensity of the immune response generated.Item The Impact of the Mycoplasma pulmonis MALP-2 Homologue on Disease Progression(2008-04-01) Spear, Marcia G.; Simecka, Jerry W.; Hodge, Lisa M.; Mathew, Porunelloor A.Spear, Marcia. The Impact of Mycoplasma pulmonis MALP-2 Homologue on Disease Progression. Master of Science (Biomedical Sciences), April 2008. 64 pp., 3 tables, 8 illustrations. Using Mycoplasma pulmonis, this project looked at a possible critical component in mycoplasma disease, the MALP-2 homologue lipoprotein. Studies demonstrated other lipoproteins besides the MALP-2 homologue were critical for in vivo disease progression and in vitro macrophage IL-6, IL-12, and TNF-α cytokine production. This trend was also seen human endothelial kidney (HEK) cells transfected with toll-like receptor 1 (TLR2) and the heterodimer TLR2/6. An increase in IL-8 cytokine production seen in all stimulated HEK cell lines, indicating the lipoproteins involved in cell interactions are TLR2 mediated. This project suggests the M. pulmonis MALP-2 homologue is not the main lipoprotein involved in disease progression and cell interactions, indicating the MALP-2 homologue may not be an ideal target for vaccines or antibiotics.Item The Population Abundance and Associated Geographic and Demographic Factors of the Dengue Vectors, Aedes Aegypti and Aedes Albopictus in Dallas County, TX, USA(2007-05-01) Stahl, Matthew S.; Sue Lurie; Joon-Hak LeeStahl, Matthew S., The Population Abundance and Associated Geographic and Demographic factors of the Dengue Vectors Aedes aegypti and Aedes albopictus in Dallas County, TX. Master of Public Health (Environmental Health), May 2007, 40 pp., 7 figures, 2 tables, bibliography, 72 titles. The risk for dengue outbreak was assessed in North Central Texas in 2006 in response to increased case numbers in Texas and Mexican states in 2005. Data were collected from 54 sites in Dallas County, TX using oviposition traps and estimates from U.S. Census and Sourcebook America databases. Higher vegetation and shade displayed more Aedes species; standing water also showed more Aedes albopictus. Lower home values and lower incomes corresponded to more Aedes aegypti; lower household density displayed more Aedes albopictus. Other socio-economic and demographic factors did not have significant association with abundance. The methodology of this study may serve as a model for assessment of dengue vector abundance in other regions.Item Trace amine associated receptor 1 (TAAR1), a novel astrocyte receptor for METH-mediated neurotoxicity in HIV-1-associated neurocognitive disorders (HAND)(2015-05-01) Cisneros, Irma E.; Ghorpade, Anuja; Wordinger, Robert J.; Forster, Michael J.This dissertation explores the role of astrocyte trace amine associated receptor 1 (TAAR1), a novel G-protein coupled receptor (GPCR), in modulating the effects of methamphetamine (METH) on astrocyte-mediated excitotoxicity, thereby exacerbating HIV-associated neurocognitive disorders (HAND). The rising pandemic of methamphetamine (METH) abuse has multiple effects and interactions with HIV-1 in infected individuals, affecting both the periphery and the central nervous system (CNS). Moreover, there is a high prevalence of HIV-1 infection among METH users. Underlying evidence provides insight into the cellular mechanisms associated with METH and HIV-1 neurodegeneration, including the effects and byproducts of glial cells, specifically astrocytes. While indirect effects of METH and HIV-1 have been proposed in astrocytes the direct mechanisms by which they contribute to neurodegeneration and continue to evolve. Particularly, imbalance in glutamate homeostasis plays a vital role in METH- & HIV-1-mediated neurodegeneration. We propose METH activates a novel GPCR, trace amine associated receptor 1 (TAAR1), thereby regulating astrocyte-mediated glutamate uptake via excitatory amino acid transporter-2 (EAAT-2), exacerbating HIV-1-induced excitotoxicity. Importantly, our data demonstrate astrocyte functions leading to neurotoxic outcomes like excitotoxicity can be directly exacerbated through TAAR1 regulation. Additionally, extrinsic regulation of TAAR1 signaling, including cAMP, calcium, PKA and PKC, not only reduce activation of subsequent signaling factors, but also reduce or eliminate METH- and IL-1β-mediated alterations in astrocytes glutamate clearance abilities. Finally, preliminary studies indicate that astrocyte-TAAR1 may be a novel therapeutic target for the common morbidity of METH abuse in HAND