Life Sciences Commons^™

The Role Of Slam-Sap Signaling In The Development Of Innate-Like Gamma Delta (Γδ) T Cells, Somen Kumar Mistri

Graduate College Dissertations and Theses

Gamma delta (γδ) T cells are unconventional T cells that are highly enriched in the mucosal tissues such as the lung, gut, and skin, where they play critical roles in host immune surveillance, autoimmunity, and anti-tumor immunity. γδ T cells are notable for their ability to rapidly produce large amounts of cytokines such as IL-17 (γδT17), IFN-γ (γδT1), and IL-4 (γδT2). Interestingly, unlike their well-studied conventional αβ T cell counterparts, most γδ T cells acquire their functional programming during specific developmental windows of thymic development using mechanisms that remain unclear. Here, we investigated the role of the SLAM-SAP signaling pathway …

Applications Of Bayesian Hierarchical Detection Models, Emily Beasley

Graduate College Dissertations and Theses

Bayesian hierarchical detection models are useful for addressing uncertainty in datasets in the form of detection error and can be adapted to a variety of research questions. This dissertation uses three case studies to highlight advantages of Bayesian hierarchical detection models: 1) using prior information to model undetected species, 2) efficiently modeling a naturally hierarchical system, and 3) correcting for observation bias in two interconnected ecological metrics for effective disease management.Detection error can bias ecological observations, especially when a species is never detected during sampling. In many communities, the probable identity of these species is known from previous research, but …

Functional Characterization Of A Putative Long Non-Coding Rna U90926: Role In Inflammation And Adipose Tissue Homeostasis, Bristy Sabikunnahar

Graduate College Dissertations and Theses

Long non-coding RNAs (lncRNAs) are one of the most commonly transcribed functional non-coding RNAs in mammalian genomes, yet majority of them remain understudied. Recent advancement in high throughput sequencing and computational knowledge have revealed the identity of thousands of lncRNAs and their association with numerous diseases and cellular processes. In the last two decades, flurries of studies showed experimentally that lncRNAs regulate a myriad of essential biological processes including immune system. Although a large number of lncRNAs have been identified in a variety of immune cells, only a handful of them have been characterized for biological function and mechanisms. In …

A Multi-Scale Examination Of Skeletal Muscle’S Contribution To Local And Systemic Immunomodulation, Joseph J. Bivona Iii

Graduate College Dissertations and Theses

The innate immune system requires input from a myriad of tissues and cell types to adequately prepare, locate, and neutralize infections. Skeletal muscle’s widespread distribution throughout the body and its potent ability to secrete cytokines makes it a vital signaling organ to alert the immune system during both localized and systemic injuries and illnesses. This dissertation first deciphers the crosstalk between skeletal muscle myocytes and macrophages during acute lung injury, reporting the macrophage-derived cytokine, tumor necrosis factor α, to be necessary for eliciting the full potential of the skeletal muscle inflammatory milieu. Next, the total contribution of skeletal muscle mediators …

The Impact Of Nitric Oxide On Dendritic Cell Metabolism, Julia Priscilla Snyder

Graduate College Dissertations and Theses

Dendritic cells (DCs) are sentinel immune cells capable of directly sensing and responding to pathogens. Upon pathogen recognition, DCs undergo a process of activation that allows them to participate in the proinflammatory response at the site of infection and to initiate the adaptive immune response through antigen presentation to T cells. Because activated DCs serve as the critical link between innate and adaptive immunity, modulating DC activation could be a powerful tool in various clinical contexts such as vaccine design. DC activation is accompanied by widespread changes in metabolism including the rapid upregulation of glycolysis, which is sustained in DCs …

The Microbiome As An Environmental Risk Factor For Multiple Sclerosis, Theresa Montgomery

Graduate College Dissertations and Theses

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. The etiology of MS is complex and poorly understood; however, disease risk is likely combinatorial due to the effects of both genetics and environmental risk factors. A recently identified environment risk factor for MS is the gut microbiome. However, the specific gut microbiota associated with disease risk, onset and/or progression, their mechanisms of action, and impact of host genetics remain unclear. Leveraging the primary autoimmune mouse model of MS, experimental autoimmune encephalomyelitis (EAE), in a genetically diverse mouse model consisting of 29 unique genotypes, combined with gut …

Determinants Of Antibody Immunity In Flavivirus Infections And Immunization, Huy Tu

Graduate College Dissertations and Theses

The most significant arthropod-borne viral infections in modern history are caused by species of the Flavivirus (FV) genus due to their global transmission. While immunization is effective at decreasing the burden imposed by some FV, vaccines for other FV such as Dengue virus (DENV) and Zika virus (ZIKV) are still in development or not widely available. A better understanding of the protective immune response, specifically the antibody response, to DENV and ZIKV will advance the vaccine development endeavors for these viruses. Utilizing longitudinal samples from controlled human immunization/challenge studies and natural infections, we investigated the antibody response to these viruses …

Metarhizium Anisopliae, Metarhizium Brunneum And Beauveria Bassiana Formulations For Biological Control Of Larval Winter Ticks, Dermacentor Albipictus, Cheryl Sullivan

Graduate College Dissertations and Theses

There is a critical need to develop effective, high-quality, fungal-based biopesticides for use against ticks. Dermacentor albipictus Petch (Acari: Ixodidae), the winter tick, is a one-host tick. They commonly infest large ungulates, particularly moose, Alces alces L. (Artiodactyla: Cervidae) on which they cause significant physiological and metabolic stress on densely parasitized individuals. Heavily infested calves can be killed. Entomopathogenic fungi in the genera Metarhizium (Hypocreales: Clavicipitaceae) and Beauveria (Hypocreales: Cordycipitaceae) are promising tick biological control agents. The larval stage of D. albipictus aggregates on the ground in a prolonged, quiescent state during the summer and then quests for hosts in …

Mutations In Ikaros Lead To An Altered Epigenetic And Chromatin Landscape Contributing To The Manifestation Of B-Cell Related Disorders, Princess Rodriguez

Graduate College Dissertations and Theses

IKAROS is expressed throughout the entire hematopoietic system and is required for lymphoid commitment and subsequent differentiation towards the B-lymphoid fate. If absent, progenitor and mature B-cell subsets are not expressed. IKAROS (encoded by IKZF1) is a zinc-finger transcription factor shown to regulate gene expression either directly or through the recruitment of chromatin remodeling complexes. The epigenetic gene regulatory mechanisms, including the posttranslational modification to histone proteins, as well as the expression of noncoding RNAs (ncRNAs) are important to control as perturbations in these processes contribute to the manifestation of human diseases. If left unregulated, uncontrolled growth, aberrant cell activation, …

Genetic And Functional Approaches To Understanding Autoimmune And Inflammatory Pathologies, Abbas Raza

Graduate College Dissertations and Theses

Our understanding of genetic predisposition to inflammatory and autoimmune diseases has been enhanced by large scale quantitative trait loci (QTL) linkage mapping and genome-wide association studies (GWAS). However, the resolution and interpretation of QTL linkage mapping or GWAS findings are limited. In this work, we complement genetic predictions for several human diseases including multiple sclerosis (MS) and systemic capillary leakage syndrome (SCLS) with genetic and functional data in model organisms to associate genes with phenotypes and diseases.

Focusing on MS, an autoimmune inflammatory disease of the central nervous system (CNS), we experimentally tested the effect of three of the GWAS …

Pharmacological Inhibition Of Hif-1 Alpha And Its Effects On Dendritic Cell Metabolic Reprogramming, Warrick Sahene

Graduate College Dissertations and Theses

Dendritic cells (DCs) are antigen presenting cells (APCs), a subtype of immune cells that present cellular information to T cells in the immune system. Hypoxia inducible factor 1 alpha (HIF-1 alpha) is an important transcription factor that facilitates dendritic cell metabolism by upregulating glycolysis in activated DCs. In this project, we examined the effects of HIF-1 alpha inhibition on metabolic processes of dendritic cells. Using techniques such as flow cytometry, western blotting, and extracellular flux analyzers, we used a selective inhibitor of HIF-1 alpha to test the hypothesis that HIF-1 alpha promotes glycolytic dependent processes such as glucose production, survival, …

A Chemical Genetics Approach To Understand The Regulation Of Cryptosporidium Sexual Differentiation, Md Mahmudul Hasan

Graduate College Dissertations and Theses

Cryptosporidium species are eukaryotic intracellular parasites belonging to the phylum Apicomplexa. C. hominis and C. parvum cause diarrhea in humans which is self-limiting in immunocompetent adults but can have severe consequences in immunocompromised individuals and malnourished children. In developing countries, Cryptosporidium is one of the leading causes of moderate to severe diarrhea in children under five years of age. There is an urgent need for novel therapeutics against this parasite as the current treatment option is inadequate to treat the most vulnerable population to Cryptosporidium infection. Better understandings of the biology of Cryptosporidium would greatly enhance our capability to design …

Understanding The Role Of Androgen Receptor Signaling In Modulating P38-Alpha Mitogen-Activated Protein Kinase In Experimental Autoimmune Encephalomyelitis, Grace Kathryn Voorhees

Graduate College Dissertations and Theses

Multiple Sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system, characterized by axonal demyelination and multifocal inflammation. Like many autoimmune diseases, it is a sexually dimorphic disease, being 3-4 times more common in females than in males. p38α MAP kinase (MAPK) has an integral role in modulating inflammatory processes in autoimmunity. Conditionally ablating p38α MAPK in myeloid cells in B6 mice shows a sex difference in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). In the absence of sex hormones, this sex difference was reversed, suggesting a role for sex hormones in modulating p38α MAPK signaling …

Regulation Of Natural Killer T Cell Subset Development And Function By Slam Family Receptors, Victoria Devault

Graduate College Dissertations and Theses

Semi-invariant natural killer T (iNKT) cells are critical components of the host immune response in peripheral tissues such as the lung, liver, and gut, and they play important roles in cancer, bacterial infections, autoimmunity, wound repair, and atherosclerosis. Tissue-resident iNKT cells exert their effects early in the developing immune response by rapidly producing a wide variety of cytokines and chemokines, and it was recently discovered that different tissues possess iNKT cell subsets that preferentially produce IFN-γ (NKT1), IL-4 (NKT2), or IL-17 (NKT17). Despite their critical role in the immune response, the mechanisms that regulate iNKT cell function in the periphery …

The Contribution Of Metabolism To The Regulation Of Caspase Activity And Cell Death In T Lymphocytes, Michael Anthony Secinaro

Graduate College Dissertations and Theses

During an immune response, T cell activation is mirrored by a dramatic metabolic shift from oxidative phosphorylation to glycolysis. The upregulation of glycolysis allows the cell to generate the molecules needed to rapidly proliferate and to synthesize effector molecules. The resolution of the T cell response is characterized by equally fast death of most effector T cells. The remaining T cells shift back to oxidative phosphorylation, allowing the cell to survive as a memory T cell. The upregulation of glycolysis and proliferation during the effector phase is paralleled by an increased sensitivity to T cell receptor restimulation-induced cell death (RICD). …

Characterizing The Role And Regulation Of Glycogen Metabolism In Dendritic Cell Immune Responses, Phyu Myat Thwe

Graduate College Dissertations and Theses

Dendritic cells (DCs) are the most potent professional antigen presenting cells (pAPCs) of the immune system and play a fundamental role in coordinating innate and adaptive immune responses. Through the expression of a wide array of pattern recognition receptors (PRRs), such as toll-like receptors (TLRs), DCs recognize a variety of microbial pathogens and infectious stimuli. Stimulation of DCs through TLR ligation results in a rapid series of activation-associated events, termed "maturation," which include the upregulation of surface co-stimulatory molecule expression, inflammatory cytokine secretion, and stimulation of naïve T cells via antigen presentation by MHC molecules.

Activation of DCs through TLRs …

Altered Gastrointestinal Motility In Multiple Sclerosis, Estelle Trego Spear

Graduate College Dissertations and Theses

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that causes motor, visual, and sensory symptoms. Patients also experience constipation, which is not yet understood, but could involve dysfunction of the enteric nervous system (ENS). Autoimmune targeting of the ENS occurs in other autoimmune diseases that exhibit gastrointestinal (GI) symptoms, and similar mechanisms could lead to GI dysfunction in MS. Here, we characterize GI dysmotility in the experimental autoimmune encephalomyelitis (EAE) model of MS and test whether autoantibodies targeting the ENS are present in the serum of MS patients.

Male SJL or B6 mice were induced with …

Methods To Identify And Develop Drugs For Cryptosporidiosis, Rajiv Satish Jumani

Graduate College Dissertations and Theses

Cryptosporidiosis is a common diarrheal disease caused by intestinal infection with the apicomplexan parasite Cryptosporidium, in humans usually either with C. hominis or C. parvum. Unfortunately, given a large burden of disease in children and immunocompromised people like AIDS patients, the only currently approved treatment, nitazoxanide, is unreliable for these patient populations. To address the urgent need for new drugs for the most vulnerable populations, large phenotypic screening efforts have been established to identify anti-Cryptosporidium growth inhibitors in vitro (hits). However, in the absence of a gold standard drug, the in vitro and in vivo characteristics that should be used …

An Analysis Of Between-Cow Variation In Innate Immunity In Relation To Mastitis Severity, Filiz Korkmaz

Graduate College Dissertations and Theses

Bovine mastitis remains one of the costliest diseases affecting the dairy industry. Individual susceptibility to mastitis and severity of infection varies between animals and can only be partially explained by genetics. As such, understanding how genetic predisposition coordinately interacts with epigenetic modifications and environmental exposures is necessary to bridge the gap in missing heritability. The role of DNA methylation in regulating the response to bacterial lipopolysaccharide (LPS) was first determined by performing reduced representation bisulfite sequencing on fibroblasts isolated from heifers at 5- and 16-months of age that exhibit an age-dependent up-regulation in LPS-responsiveness. More than 14,000 differentially methylated sites …

Methylation Controlled J Protein Is A Master Regulator Of Mitochondrial Metabolism, Devin Pierre Champagne

Graduate College Dissertations and Theses

Methylation controlled J protein (MCJ) is a negative regulator of mitochondrial metabolism that has a substantial impact on overall cell metabolism and function. MCJ is highly expressed by naïve CD8+ T cells, however its role in their immune effector functions was unknown. In this dissertation, it will be demonstrated that MCJ restricts the mitochondrial metabolism of CD8+ T cells, in part by reducing respiratory supercomplex formation. MCJ deficiency enhances the immune effector functions and memory responses of CD8+ T cells in a mitochondrial ATP dependent manner. As a consequence, protection to influenza virus infection is substantially improved. Reduced expression of …

Uncovering The Variable Life History Traits And Strategies Of The Gregarine Parasite, Monocystis Perplexa, In Its Invasive Earthworm Host, Amynthas Agrestis, Erin L. Keller

Graduate College Dissertations and Theses

Parasite life histories influence many aspects of infection dynamics, from the parasite infrapopulation diversity to the fitness of the parasite (the number of successfully transmitted parasites). Studies of medically important parasites, such as the parasite responsible for malaria (Plasmodium spp.), demonstrate the usefulness of investigating the life histories of parasites to better understand infection characteristics such as parasite load and probability of transmission.

The gregarines are a diverse group of apicomplexan parasites that infect invertebrates, and are particularly common in insects and annelids. Given the great biodiversity and importance of their hosts, coupled with their close evolutionary relationship with important …

The Cardiovascular Epidemiology And Genome-Wide Associations Of Biomarkers Of Innate And Adaptive Immunity: Scd163 And Sil2ra, Jon Peter Durda

Graduate College Dissertations and Theses

Cardiovascular disease (CVD) is a major cause of morbidity and mortality in the U.S. and worldwide. Atherosclerosis, the buildup of plaque in the arteries, is a common cause of CVD. For many years, research in atherosclerosis was focused on lipid metabolism and the accumulation of low-density lipoprotein in the arteries. While this research set public health guidelines for lipid management, lipid concentration was not the only factor influencing atherosclerosis and CVD events. Many scientists, as far back as the 1850’s recognized the role of inflammation in the progression of atherosclerotic disease. The continuous low levels of immune activation in the …

Functional Consequences Of Ama1-Ron2 Interaction During Host Cell Invasion By Toxoplasma., Shruthi Krishnamurthy

Graduate College Dissertations and Theses

T.gondii is a model organism of the phylum Apicomplexa that infects one third of the human population. While the majority of infections are asymptomatic or manifest with mild flu-like symptoms, toxoplasmosis can be fatal in immunocompromised individuals and in the developing fetus. The lytic cycle of tachyzoite-stage parasites causes damage to the host by repeated rounds of host cell invasion, intracellular replication and lysis of the host cell upon egress.

Invasion is a key step for the parasite to maintain its intracellular lifestyle. Apical Membrane Antigen 1 (AMA1) is an adhesin released from a unique set of secretory organelles called …

Role Of Interleukin-6 In Cd4 And Cd8 T Cell Effector Functions, Rui Yang

Graduate College Dissertations and Theses

IL-6 is an inflammatory cytokine that contributes to the pathogenesis of many immunological diseases including rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, allergic asthma, as well as the protection against infections caused by various pathogens. These are linked to its role in regulating CD4 T cell differentiation and effector function.

Most of these functions are dependent on the IL-6-mediated signaling through the transcription factor Stat3. In this thesis, we identify a novel molecular mechanism by which IL-6 regulates CD4 T cell effector function. We show that IL-6-dependent signal raises the levels of mitochondrial Ca2+ late during activation of CD4 T …

Characterization Of Inter-Animal Variation In The Innate Immune Response Of The Bovine And Its Relation To S. Aureus Mastitis., Aimee Benjamin

Graduate College Dissertations and Theses

Mastitis represents one of the major economical and animal welfare concerns within the dairy industry. Animals affected with this disease can experience a range of clinical symptoms from mild discomfort and swelling of the udder to a severe systemic inflammatory response that could result in the death of the animal. This range of responses is due to differences in pathogen, environment, and inter-animal differences in their innate immune response. A dermal fibroblast model was used to predict the magnitude of an animal's innate immune response towards an intra-mammary S. aureus challenge. Animals whose fibroblasts exhibited a low response phenotype, characterized …

Redox Control Of Allergic Airway Disease: Impact Of Glutaredoxin-1 On Epithelial Driven Inflammation And Allergen-Induced Airway Remodeling, James D. Nolin

Graduate College Dissertations and Theses

Asthma is a multi-faceted chronic inflammatory disease accompanied by loss of airway epithelial integrity leading to remodeling of the airways. Perturbations to the lung redox environment, including alterations in glutathione (GSH) content, have been reported in asthma. GSH can be conjugated to protein cysteines, controlling protein function in an oxidant-dependent process known as protein S-glutathionylation (PSSG). The thioltransferase, glutaredoxin-1 (Glrx1), deglutathionylates proteins under physiological conditions, restoring sulfhydryl groups of target proteins. Glrx1 is emerging as a critical player in settings of allergic airway disease, but its function in regulating epithelial cell responses to asthma-relevant cytokines has not been examined. Furthermore, …

An Investigation Of Epigenetic Contributions To Inter-Animal And Age Dependent Variation In The Bovine Innate Immune Response., Benjamin Green

Graduate College Dissertations and Theses

Mastitis represents a major issue within the dairy industry responsible for economic loss via decreased animal productivity and associated veterinary costs. Currently, there is a push to identify a phenotypic innate immune response that will yield dairy cows with an enhanced resistance to mastitis. Bovine dermal fibroblasts were used as a cell model to measure the response of individuals to Gram-negative bacterial stimuli through the TLR4 signaling pathway. Fibroblast cultures were isolated from 15 dairy heifers at 5, 11, and 16 months of age in order to determine the variability in responsiveness to LPS as well as to monitor the …