Immunology and Infectious Disease Commons^™

Effect Of Macrophage Expressed Α7 Nicotinic Acetylcholine Receptor (Α7nachr) On Migration Of Macrophages During Inflammation, Kasey Keever

Electronic Theses and Dissertations

Sepsis is a life-threatening condition characterized by overwhelming inflammation, resulting in organ system damage, leading to a high mortality rate. Care in the clinical setting is supportive, and there are no approved sepsis-specific treatments. In septic mice, activation of the cholinergic anti-inflammatory pathway decreases cytokine secretion by leukocytes and improves survival. The cholinergic anti-inflammatory pathway is a reflex of the parasympathetic nervous system, converging on the α7 nicotinic acetylcholine (α7nAChR) at the surface of macrophages. Signaling through the receptor blocks NF-kB activation, thus cytokine secretion. Receptor activation has other effects on macrophages, including modulating their migration to …

Endothelial Interleukin-17 Receptor D (Il17rd) Promotes Western Diet-Induced Aortic Myeloid Cell Infiltration, Shivangi Pande

Electronic Theses and Dissertations

The Interleukin-17 (IL17) family is a group of cytokines implicated in the etiology of several inflammatory diseases. Interleukin-17 receptor D (IL17RD), also known as Sef (similar expression to fibroblast growth factor), belonging to the family of IL17 receptors, has been shown to modulate IL17A-associated inflammatory phenotypes. The objective of this study was to test the hypothesis that IL17RD promotes endothelial cell activation and consequent monocyte adhesion. We utilized primary human aortic endothelial cells and demonstrated that RNAi targeting of IL17RD suppressed transcript levels by 83% compared to non-targeted controls. Further, RNAi knockdown of IL17RD decreased the adhesion of THP-1 cells …

Illuminating Underappreciated Mechanisms Of Receptor Regulation In Human Lymphocytes., Cassandra Woolley

Electronic Theses and Dissertations

A thorough understanding of receptor regulation is imperative to predict expression in varying contexts of disease or treatment. Lymphocyte surface receptors are often used as biomarkers and drug targets, making them particularly important for study. For receptors of debated functionality, such as the Fc receptor for IgM (FcMR), understanding regulation can also help to predict expression in vivo to supplement hypotheses of biological roles. Various mechanisms exist for altering receptor surface expression, including direct feedback mechanisms such as ligand-induced endocytosis and broader mechanisms such as transcriptional and translational control. In this dissertation, we explore selected underappreciated mechanisms of lymphocyte receptor …

Characterization Of The Immunoglobulin Lambda Chain Across Diverse Human Populations., William Gibson

Electronic Theses and Dissertations

The adaptive immune system relies on a diverse set of over one hundred immunoglobulin (IG) genes across three genomic loci that are variably combined to form antibodies (Ab). The IG Lambda locus is one of two loci which encodes the IG light chain. The complexity of the IGL locus severely limits the effective use of standard short-read sequencing, limiting our knowledge of population diversity in these loci. We leveraged single molecule real-time (SMRT) long-read sequencing in conjunction with IGL-targeted DNA capture to develop the method IG-Cap for accurate and high-throughput sequencing of the IGL locus. We benchmarked this method using …

Biophysical Factors Impacting Sea Lice Settlement And Survival, Eleanor R. Glahn

Electronic Theses and Dissertations

Atlantic salmon (Salmo salar L.) aquaculture production in Maine is a valuable contributor to the economy, the expansion of which has been challenged by the parasitic salmon louse Lepeophtheirus salmonis. As planktonic organisms, the life of the salmon louse is primarily dictated by the physical conditions of the environment: the temperature for development time, salinity for survival, and current velocity for transport. Salmon lice are obligate parasites for whom the successful infection of a suitable host is critical to completion of their life cycle. However, little is understood about the effects of current velocity on infection success. Hydrodynamic …

Comparative Characteristics Of Integrin Αdβ2 Binding To Native Fibrinogen And Fibrinogen Modified By Dha Oxidation During Inflammation, Ajibola Ilesanmi

Electronic Theses and Dissertations

2-ω-carboxyethylpyrrole (CEP) is a product of docosahexaenoic acid (DHA) oxidation, which forms covalent adducts with different proteins. CEP-modified proteins can interact with macrophage receptor, integrin αDβ2. This study aims to compare αDβ2 binding to its physiological ligand, fibrinogen, and CEP-modified fibrinogen, which is formed during inflammation. We hypothesize that modification of fibrinogen changes its ligand-binding properties to integrin αDβ2 which can affect macrophage migration and retention. Recombinant αD I-domain and αDβ2-transfected HEK293 cells were used for the experiments. Using biolayer interferometry, we found that the affinity of αD I-domain binding to fibrinogen-CEP was higher than fibrinogen and inhibited by the …

Dna Methylation And The Response To Infection In Introduced House Sparrows, Melanie Gibson

Electronic Theses and Dissertations

Epigenetics is the study of molecular modification of a genome without changing its base pairs. The most studied type of epigenetic mechanism is DNA methylation, which is capable of turning a gene “on” or “off.” Epigenetic potential is the capacity to which an individual can have methylation on its genome. The more CpGs available, the greater the epigenetic potential. In invasive species, genetic variation has been observed to be paradoxical: not much of it exists on a genomic level, but epigenetically, phenotypic variation can occur. The focus on shift in gene expression in this study is on Toll-Like Receptor 4 …

Investigating The Pi3k/Akt/Atm Pathway, Telomeric Dna Damage, T Cell Death, And Crispr/Cas9-Mediated Gene Editing During Acute And Chronic Hiv Infection, Sushant Khanal

Electronic Theses and Dissertations

Human Immunodeficiency Virus (HIV) infection initiates major metabolic and cell- survival complications. Anti-retroviral therapy (ART) is the current approach to suppress active HIV replication to a level of undetected viral load, but it is not a curative approach. Newer and sophisticated gene editing technologies could indeed be a potent antiviral therapy to achieve a clinical sterilization/cure of HIV infection. Chronic HIV patients, even under a successful ART regimen, exhibit a low-grade inflammation, immune senescence, premature aging, telomeric DNA attrition, T cell apoptosis, and cellular homeostasis. In this dissertation, we investigated CD4 T cell homeostasis, degree of T cell apoptosis, an …

A Functional Study Of Topological Dna Problem In Human T Cells During Chronic Viral Infection, Xindi Dang

Electronic Theses and Dissertations

T cells play an important role in adaptive immune system against viral infections, while premature aging and dysfunction of T cells induced by unrepaired DNA damages are always non-negligible snags during the long-term of fighting with chronic viral infections, such as Hepatitis B virus (HBV), Hepatitis C virus (HCV) or Human Immunodeficiency Virus (HIV) infection. In this dissertation, we investigated the role of topological DNA damage in reprogramming telomeric DNA damage responses (DDR), mitochondrial metabolisms, and T cell functions using CD4+ T cells derived from individuals with chronic viral infections or healthy subjects treated with topoisomerase inhibitors. The healthy human …

Neural Stem Cells: Age-Dependent Outcomes During Viral Infections In The Central Nervous System, Manisha N. Chandwani

Electronic Theses and Dissertations

Viral infections in the central nervous system (CNS) are associated with neurodevelopmental and neurobehavioral deficits. The outcomes of viral infections can be driven by damage and death of neurons. Neural stem cells (NSCs) play key roles in neurodevelopment, repair, and physiological brain function. During a viral infection, NSC activity can disturbed by direct infection of NSCs by the virus or by anti-viral immune response. Here, we aimed to assess whether the anti-viral immune response can impact NSC activity during an immunocompetent response in the adult brain. We utilized a transgenic mouse model of Measles virus infection where only the CNS …

Investigating Host Defenses Of North American Salamanders Against The Recently Emerged Chytrid Pathogen, Batrachochytrium Salamandrivorans, Kenzie Pereira

Electronic Theses and Dissertations

A recently emerged chytrid fungal pathogen, Batrachochytrium salamandrivorans (Bsal) threatens salamander biodiversity. Bsal susceptibility varies between and within salamander species, but little is known about the mechanisms underlying these differences. Susceptibility is likely influenced by numerous interacting factors, but my dissertation studied the role of host immune responses.

My first aim investigated between species differences by studying the bioactive properties of salamander skin peptides against Bsal and the related pathogen, B. dendrobatidis (Bd). Skin peptides were collected from five salamander species, used for in vitro assays, and analyzed by RP-HPLC. While skin peptides from one …

Weaving An Interdisciplinary Microbiome Career Using Threads From Different Ecosystems, Sarah Hosler

Electronic Theses and Dissertations

Animals have trillions of microorganisms living in or on many body sites, these communities of microorganisms are called microbiomes. Microbiomes are typically host-specific, and a lot of information about the host can be determined from investigating them. Microbiome research has many real-world applications, and this thesis utilizes the One Health perspective, which acknowledges the connection of humans, animals, and environments, and emphasizes the need for collaborative, interdisciplinary research. The first interdisciplinary project is an investigation into the bacteria in wild and cultured Atlantic deep-sea scallop, Placopecten magellanicus larvae. Adults in hatcheries can be induced to spawn, but the last two …

Aggregatibacter Actinomycetemcomitans Exploits And Modulates The Immune Response By Human Neutrophils For Survival In The Anaerobic Environment., Hazel Ozuna

Electronic Theses and Dissertations

Aggregatibacter actinomycetemcomitans (Aa) is a Gram-negative facultative anaerobe and an opportunistic oral pathogen, strongly associated with localized periodontitis and other inflammatory diseases. Periodontitis is a chronic inflammation of the periodontium resulting from the inflammatory response of the host towards the dysbiotic microbial community present at the gingival crevice. The host immune response creates a hostile environment for microorganisms; therefore, it is important for Aa to be able to regulate the necessary genes to survive and thrive in such an environment. Aaexpresses several virulence factors such as a cytolethal distending toxin (Cdt), lipopolysaccharide (LPS) and leukotoxin A (LtxA), …

Genomic Tools And Models For Investigating The Role Of Germline Diversity In Mouse Antibody Repertoire Development., Justin T. Kos

Electronic Theses and Dissertations

Given the diversity and complexity within immunoglobulin (IG) loci, effective mouse models first require characterization of intra-strain differences and construction of high-quality reference assemblies for IG loci in several representative strains. To understand light chain germline diversity across biomedically significant mouse strains, we profiled the expressed IGK and IGL repertoires of 18 commonly used laboratory mouse strains using AIRR-seq. Across strains, we observed germline IGKV sequences shared by three different IGK haplotypes and a more conserved IGLV germline repertoire among common laboratory strains. Pacific Biosciences (PacBio) Single-Molecule Real-Time (SMRT) sequencing was used to sequence and assemble bacterial artificial chromosomes (BAC) …

Understanding The Impact Of Human Germline Single-Nucleotide Variants, Samuel Adjei

Electronic Theses and Dissertations

No abstract provided.

A Post-Pneumonia Epizootic Evaluation Of The Rapid City, South Dakota Bighorn Sheep Herd, Amanda N. Ensrud

Electronic Theses and Dissertations

Pneumonia is a major factor affecting populations of free-ranging bighorn sheep (Ovis canadensis) across western North America. Pneumonia can occur in large-scale epizootics, during which greater than half of the population typically dies. After these epizootics, surviving ewes continue to conceive and bear lambs. However, lamb recruitment may remain low due to periodic or annual pneumonia outbreaks causing high lamb mortality rates, sometimes greater than 90%. Our study focused on the Rapid City, South Dakota bighorn sheep (BHS) herd that has recorded pneumonia-induced population decline since 2009. The first objective was to improve lamb health and survival by identifying and …

Amblyomma Quadricavum (Schulze, 1941) (Acari:Ixodidae): First Description Of The Nymphal Stage And Phylogenetic Assessment Of Its Taxonomic Status, Ashleigh V. Riggs

Electronic Theses and Dissertations

The hard tick (Acari: Ixodidae) Amblyomma quadricavum (Schulze, 1941) is a parasite of snakes and is endemic to the Caribbean region. Morphological characters of this species, namely its rudimentary eye structures, have led to debate about its taxonomic status. The species was originally assigned to the genus Aponomma. However, with revisions of the genus Aponomma, and the recent creation of new genera created for some basal former-Aponomma, it has been suggested that perhaps Amblyomma quadricavum might be a close relative of Robertsicus elaphensis, the Trans-Pecos rat snake tick of the southwest United States and New Mexico, another eyeless former-Aponomma species …

Retroviral Infection Dynamics In Maine's Wild Turkeys, Stephanie A. Shea

Electronic Theses and Dissertations

Widespread wild turkey reintroductions in the late 1900s have led to increases in population density and geographic distribution across North America. This rapid population expansion has put them into proximity with closely-related wild and domestic avian species, increasing the risks of pathogen transmission. Lymphoproliferative disease virus (LPDV) is an avian oncogenic retrovirus detected in wild turkeys in 2009, and previously known to infect domestic turkeys. Following its initial detection, surveys reported variable LPDV prevalence across eastern North America with most wild turkeys being asymptomatic, however diagnostic cases revealed 10% mortality of LPDV-infected individuals. Given its recent detection, little is known …

Q-Griffithsin Interactions And Utility For The Prevention And Treatment Of Mucosal Infections., Henry Nabeta

Electronic Theses and Dissertations

Griffithsin (GRFT) is a carbohydrate binding agent (lectin) that was originally identified in the red alga Griffithsia sp. Q-Griffithsin (Q-GRFT) is an oxidation stable analog of GRFT. GRFT has demonstrated inhibitory activity against HIV-1, Coronaviruses, Hepatitis C, influenza and Ebola viruses. The broad-spectrum activity suggests the potential utility of this lectin in a wide range of viral infections. However, the lectin’s activity in mucosal infections has not been extensively studied. Using in vitro, ex vivo and in vivo assays, we have demonstrated that Q-GRFT maintains the ability to bind glycosylated ligands following incubation in murine, macaque and human rectal …

Trained Immunity Enhances The Immune Response And Maintains Microbiome Diversity In Aging And Sepsis, P. Spencer Gill

Electronic Theses and Dissertations

The global population is rapidly aging. It is estimated that over the next thirty years, the number of individuals >60 years of age will increase by over a billion, and the number of individuals over age 80 may increase by 300 million. As humans age, our immune system becomes progressively weaker through a process called immune senescence. This age-related decrease in immune function increases susceptibility to infection and chronic diseases. Sepsis is a leading cause of death worldwide. Over the past two decades, there has been an increased incidence of sepsis which is due, in part, to our aging population …

Genital Chlamydia Infection Is Influenced By The Female Sex Hormones Estrogen And Progesterone In Vivo, Amy Gail Gravitte

Electronic Theses and Dissertations

Chlamydia is the most common bacterial sexually transmitted infection in the United States and worldwide. It often goes unnoticed due to lack of symptoms and left untreated it can ascend the female genital tract to cause sequelae like pelvic inflammatory disease and irreversible tubal infertility. In reproductive-aged women, female sex hormones estrogen (E2) and progesterone (P4) concentrations fluctuate during the menstrual cycle and are influenced by hormonal contraceptives and hormone replacement therapy. E2 and P4 influence genital Chlamydia infection in women and mice, but these multifactorial interactions are not entirely mapped out. The complex interplay of E2 and P4 with …

Deciphering The Perpetual Fight Between Virus And Host: Utilizing Bioinformatics To Elucidate The Host's Genetic Mechanisms That Influence Jc Polyomavirus Infection, Michael P. Wilczek

Electronic Theses and Dissertations

JC polyomavirus (JCPyV) is a human-specific pathogen that infects 50-80% of the population, and can cause a deadly, demyelinating disease, known as progressive multifocal leukoencephalopathy (PML). In most of the population, JCPyV persistently infects the kidneys but during immunosuppression, it can reactivate and spread to the central nervous system (CNS), causing PML. In the CNS, JCPyV targets two cell types, astrocytes, and oligodendrocytes. Due to the hallmark pathology of oligodendrocyte lysis observed in disease, oligodendrocytes were thought to be the main cell type involved during JCPyV infection. However, recent evidence suggests that astrocytes are targeted by the virus and act …

Lexicographic Sensitivity Functions For Nonsmooth Models In Mathematical Biology, Matthew D. Ackley

Electronic Theses and Dissertations

Systems of ordinary differential equations (ODEs) may be used to model a wide variety of real-world phenomena in biology and engineering. Classical sensitivity theory is well-established and concerns itself with quantifying the responsiveness of such models to changes in parameter values. By performing a sensitivity analysis, a variety of insights can be gained into a model (and hence, the real-world system that it represents); in particular, the information gained can uncover a system's most important aspects, for use in design, control or optimization of the system. However, while the results of such analysis are desirable, the approach that classical theory …

Harnessing The Power Of Trained Immunity In The Setting Of Pancreatic Cancer: A Novel Mechanism Of Immune Trafficking And Tumor Control., Anne Elena Geller

Electronic Theses and Dissertations

Despite the success of immunotherapy in many types of cancer, pancreatic adenocarcinoma (PDAC) has yet to benefit. Innate immune cells are critical to antitumor immunosurveillance and recent studies have revealed that these populations possess a form of memory, termed trained innate immunity, which occurs through transcriptomic, epigenetic, and metabolic reprograming. Though trained innate immunity has mostly been investigated in the context of infection, the induction of trained innate immunity could also protect against tumors, and specifically pancreatic tumors. Here, we demonstrate that yeast-derived particulate β-glucan, a known inducer of trained immunity, traffics to the pancreas following IP administration. This causes …

Optimized Microbial Recombinant Production Of Hiv-1 Anti-Envelope Antibody Fragments With Applications To Single Particle Tracking Of Virus Assembly, Merissa Michelle Bruns

Electronic Theses and Dissertations

In my findings, I have established a set series of protocols to recombinantly produce, purify and apply various fluorescent probes in vitro for the fluorescent labeling and study of the human immunodeficiency virus type 1 (HIV-1) envelope (Env) protein during HIV viral assembly. There remains insufficient knowledge about the molecular dynamics and interactions of HIV-1 Env protein with its counterpart, Gag, on the inner host cell surface during assembly of a mature virus particle. There also remains an insufficient amount of data for the understanding and clarification of the mechanism of action of a known host cell HIV-1 restriction factor, …

Transcriptional Regulation Of Duox-Dependent Reactive Oxygen Species Production Against Bacterial Infection In The Gut Of Cat Fleas (Ctenocephalides Felis)., Ryne W. Maness

Electronic Theses and Dissertations

Fleas (Order Siphonaptera) are opportunistic blood feeders that parasitize a wide variety of mammals and birds. They also transmit bacterial pathogens that cause diseases in humans (e.g., murine typhus, flea-borne spotted fever, cat scratch disease, and plague). Because they acquire infectious pathogens while blood feeding, the flea gut is considered to be the initial site of infection. While immune responses have been well documented in other disease vectors, few studies have identified the immune mechanisms involved in defense of the flea gut. In other hematophagous insects, the synthesis of reactive oxygen species (ROS) is the immediate immune defense mechanism against …

Disease Prevalence And The Population Genetic Structure Of Crassostrea Virginica Along The Georgia Coast, Sarah Batchelor

Electronic Theses and Dissertations

The Eastern Oyster, Crassostrea virginica, is an ecologically important species that plays a role in protecting shorelines, water filtration, and providing habitat and food for various fish species. Perkinsus marinus and Haplosporidium nesloni are two pathogens currently affecting oyster populations. These pathogens have both been documented as causes of mass mortality events along the East coast. They greatly diminish the health of oysters, resulting in the degradation of oyster tissue, reduction in growth and reproductive ability, and may cause death. In this study, wild oysters were collected from eleven locations along the Georgia coast to investigate the presence, intensity, …

Immune Activation Induces Telomeric Dna Damage, Reduces Memory Precursors, And Promotes Short-Lived Effector T Cell Differentiation In Chronic Hcv Infection, Lam Nguyen

Electronic Theses and Dissertations

Chronic hepatitis C virus (HCV) infection exhibits persistent high viral load, inducing T cells differentiation and dysfunction in chronically infected individuals. Recent longitude studies in both HCV specific- and bulk T cells reveal that chronic immune stimulation is the driving force for the impaired T cell functions, however, the underlying mechanisms remain elusive. Here, we show that peripheral CD4⁺ T cells from chronically HCV-infected patients exhibit lymphopenia with the reduction of naïve population and expansion of effector memory T cells. CD4⁺ T cells from HCV patient also display elevated activation markers. including HLA-DR, GLUT1, Granzyme B, and short-lived …

Biophysical And Stable Isotopic Profiles Of The Salmon Louse Lepeophtheirus Salmonis (Krøyer, 1837), Emma Taccardi

Electronic Theses and Dissertations

The salmon louse Lepeophtheirus salmonis is a parasitic copepod that infects wild and farmed salmonids throughout the northern hemisphere. L. salmonis represents the largest economic hurdle of the Atlantic salmon (Salmo salar) industry, with an estimated annual cost of nearly $1 billion globally due to production losses and anti-parasitic control measures. Salmon farming in Maine has existed for decades and is a critical economic driver, yet the region is underrepresented in global sea lice research. The aim of this work was to examine parasites in the context of animal trophic transfer and characterize physiological condition by quantifying the …

Development, Expansion And Role Of Myeloid-Derived Suppressor Cells In Post-Sepsis Immune Suppression, Tuqa Alkhateeb

Electronic Theses and Dissertations

Myeloid-derived suppressor cells (MDSCs) numbers increase significantly in sepsis and are associated with high mortality rates. These myeloid cell precursors promote immunosuppression, especially in the late (post sepsis) stage. However, the mechanisms that underlie MDSC expansion and programming are not completely understood. To investigate these mechanisms, we used a cecal-ligation and puncture (CLP) mouse model of polymicrobial sepsis that progresses from an early/acute proinflammatory phase to a late/chronic immunosuppressive phase. Previous studies in our laboratory showed that microRNA (miR)-21 and miR-181b elevate levels of the transcription factor nuclear factor 1 (NFI-A) that promotes MDSC expansion. We report here that miR-21 …