Immunology of Infectious Disease Commons^™

Identifying Correlates Of Protection Of A Pneumonic Plague Vaccine., Caleb Samuel Whitley

Electronic Theses and Dissertations

Pneumonic plague is caused by inhalation of the bacterial pathogen Yersinia pestis. The immune response during Pneumonic plague occurs in two phases; an initial asymptomatic phase followed by a highly inflammatory and destructive phase resulting in 100% mortality if left untreated. The rapid onset of severe disease following the asymptomatic phase makes it difficult to administer antibiotics in time to prevent lethal outcomes. Therefore, the development of an effective vaccine is likely needed to combat pneumonic plague in areas of the world where Y. pestis remains endemic. One candidate subunit vaccine is protective in mice, a natural host for …

Orchestrated Architecture Dismantling: Borrelia Burgdorferi’S Coordinated Destruction Of Adaptive Immune Responses, Craig A. Land

Electronic Theses and Dissertations

Borrelia burgdorferi represents the most prevalent vector-borne bacteria in North America, affecting ~476,000 Americans annually yet persisting despite robust immune responses. This project reveals spirochetes target adaptive immunity through coordinated lymphatic colonization and precision immune dysregulation.

Using comparative host models (C57BL/6 vs. reservoir Peromyscus leucopus), we demonstrate lymph node colonization within 48-hours, with spirochetes exploiting LYVE-1-positive lymphatic structures as dissemination highways while avoiding the interior of follicular regions. Critically, we identify targeted CD4+ T-cell elimination in germinal center border zones at 21-DPI, precisely when these cells should be coordinating protective immunity. Concurrent upregulation of inhibitory receptor CD32b creates molecular …

Interactions Of The Sars-Cov-2 Viral Genome 3’-Untranslated Region With Viral And Host Rnas, Caleb Frye, Mihaela Rita Mihailescu

Electronic Theses and Dissertations

This dissertation focuses on the characterization of RNA-RNA interactions within the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome and with host microRNAs. As the causative agent of coronavirus disease 2019 (COVID-19), SARS-CoV-2 has evolved rapidly since its appearance. This has warranted prompt characterization of the virus particularly of its single stranded RNA (ssRNA) genome. By using a combination of bioinformatics, biophysics, and/or biological assays, we analyzed the SARS-CoV-2 viral genomic RNA and uncovered interactions of genomic RNA with host RNAs, highlighting an underutilized method of targeting RNA viruses. We showed here that the conserved elements in the viral genomic …

Porphyromonas Gingivalis Inactivates Anti-Viral Immunity At The Oral And Respiratory Epithelium., Carlos J. Rodriguez Hernandez

Electronic Theses and Dissertations

The host microbiome plays an important role in fine-tuning host immune responses in a manner that ultimately impacts outcomes in viral infection. Symbiotic relationships between commensal bacteria and host epithelial and immune cells prime interferon (IFN) signaling, modulating the nature and intensity of the immune response to viral infections at mucosal barrier surfaces. In this doctoral thesis, I explore how dysbiotic shifts in the oral microbial communities modulate antiviral responses at the oral and oro-respiratory mucosal barriers. I identified that in response to a viral challenge, gingival epithelial cells (GECs) preferentially induced type III IFNs (IFN-λ), a newly described family …

Inhibition Of Pro-Inflammatory Lipid Mediators By Yersinia Pestis., Amanda Brady

Electronic Theses and Dissertations

Yersinia pestis causes the human disease known as plague. A key manifestation of plague is a delayed inflammatory response. Because this delay in inflammation is required for virulence, I was interested in defining the molecular mechanisms used by Y. pestis to evade immune recognition. Eicosanoids are produced early during infection and necessary to initiate a rapid inflammatory response. Despite the importance of these lipids in mediating inflammation, the role of eicosanoids during plague has not been previously investigated. Using an intranasal mouse model infection, I determined the kinetics of eicosanoid synthesis during pneumonic plague. I further demonstrated that LTB_{4 …}

Regulation Of Cd4 T Cell Functions By Ncrna-Mediated Signaling Pathways During Chronic Viral Infections, Lam Nguyen

Electronic Theses and Dissertations

CD4 T cell homeostasis and competency are critical for the effectiveness of antiviral immunity. However, CD4 T cells derived from people living with HIV (PLWH) and individuals with chronic HCV infection often exhibit an inflammaging phenotype, evidenced by persistent inflammation, immune activation, exhaustion, senescence, and cellular apoptosis. Despite intensive investigations, the molecular mechanisms underlying CD4 T cell dysfunction in antiretroviral therapy (ART)-controlled PLWH and HCV-infected patients remain poorly understood. By investigating the roles of non-coding (nc)RNA transcripts in regulating the functions of CD4 T cells derived from PLWH and HCV-infected patients, we demonstrated that long non-coding (lnc)RNA - growth arrest-specific …

Role Of The Anti-Viral Immune Response In Neural Cell Modulation And Neurological Sequelae Of Childhood Viral Infections, Yashika Kamte

Electronic Theses and Dissertations

Viral infections of the central nervous system (CNS) often result in neurological sequelae and are considered a risk factor for the development of neurological disease. Moreover, the outcomes of a viral infection are largely dependent on the age of the host, with younger hosts developing more profound neuropathology. Perhaps the developing brain coupled with an immature immune system contributes to worse outcomes in the very young. Children suffering from brain infections are more prone to develop enduring neurological impairments even after recovery from the infection. Although majority of the brain growth occurs in utero, neurodevelopment continues throughout the juvenile …

Intestinal Microbiome, Fecal Fermentation Profile, And Health Indices In Hiv Infected Men Versus Non-Infected Controls, Mary Andreae, Mary C. Andreae Mrs

Electronic Theses and Dissertations

Many HIV-positive (HIV+) males on Highly Active Anti-Retroviral Therapy (HAART) experience metabolic abnormalities, including Non-Alcoholic Fatty Liver Disease (NAFLD) and lipodystrophy. The intestinal microbiota and short chain fatty acids (SCFA), participate in bidirectional communication with their host. Dysbiosis in HIV+ males on HAART demonstrate a Prevotella-rich enterotype shaped by multiple factors including, medications, adiposity, diet, intestinal permeability, and lifestyle; our objective was to investigate these factors. 19 HIV+ and 21 HIV- males were enrolled. BMI and hip-to-waist ratio (H:W) were obtained, and FibroScan for liver health. Intestinal permeability markers Claudin-21, flagellin, and intestinal fatty acid binding protein (IFABP) in …

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 …

The Mechanisms Of Mitochondrial Dysfunction In T Cell Aging During Chronic Viral Infection, Madison B. Schank

Electronic Theses and Dissertations

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections induce a myriad of disturbances to CD4 T cell functions, including mitochondrial compromise, excessive inflammation, increased telomeric DNA damage and attrition, cellular exhaustion and senescence, and accelerated aging. In this dissertation, the mechanisms underlying metabolic failure, accelerated aging, and cellular dysfunctions were evaluated in CD4 T cells from healthy subjects (HS) treated with a telomere-targeting drug (KML001) or HCV-infected individuals or people living with HIV (PLHIV) compared to HS. We observed that KML001-induced telomere injury resulted in mitochondrial swelling and decreased mitochondrial membrane potential, cellular respiration, mitochondrial DNA (mtDNA) copy …

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 …

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 …

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 …

Malaria, Microbes, And Mice: The Role Of The Gut Microbiota On The Immune Response To Plasmodium Infection And The Treatment Potential Of Microbiota Modulation., Morgan L. Waide

Electronic Theses and Dissertations

Plasmodium infection leads to over 200 million cases of malaria and 400,000 deaths worldwide each year. These deaths are largely in children under the age of five and pregnant women [1]. Caused by transmission of Plasmodium parasites by the female Anopheles mosquito, malaria poses a risk for over 40 percent of the world’s population [1]. Despite worldwide efforts to eradicate malaria leading to a decrease in malaria-associated mortalities in the early 2000s [2], growing resistance to the available antimalarials and the lack of an effective, long-lasting vaccine has caused this decrease to plateau in recent years [1, 3-6]. Furthermore, malaria …

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 …

Plasmodium Impairs Antibacterial Innate Immunity To Systemic Infections In Part Through Hemozoin-Bound Bioactive Molecules., Christopher Lynn Harding

Electronic Theses and Dissertations

Despite efforts to decrease the global health burden of malaria, infections with Plasmodium species continue to cause over 200 million episodes of malaria each year which resulted in 405,000 deaths in 2018 [1]. One complication of malaria is increased susceptibility to invasive bacterial infections. Plasmodium infections impair host immunity to non-Typhoid Salmonella (NTS) through activities of heme oxygenase I (HO-I) )-induced release of immature granulocytes and myeloid cell-derived IL-10. Yet, it is not known if these mechanisms are specific to NTS. We show here, that Plasmodium yoelii 17XNL (Py) infected mice had impaired clearance of systemic Listeria monocytogenes (Lm) during …

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 …

Roles Of Endothelial Cell Heat Shock Protein A12b And Β-Glucan, A Reagent For Trained Immunity In The Regulation Of Inflammation In Sepsis, Fei Tu

Electronic Theses and Dissertations

Sepsis is dysregulated host immune response to infection causing life-threatening organ dysfunction. Endothelial cell dysfunction and uncontrolled inflammatory responses are two contributors for sepsis-induced mortality. The crosstalk between endothelial and immune cells plays a critical role in the pathophysiology of sepsis. Therefore, understanding the mechanism of interaction between endothelial and immune cells will provide novel information to develop therapeutic strategies for sepsis.

Pathogen associated moleculear patterns (PAMPs) and/or damage associated molecular patterns (DAMPs) produced during sepsis, activate endothelial cells to increase the expression of adhesion molecules, attracting immune cell infiltration into the tissues. Uncontrolled inflammatory responses during the early phase …

Development Of In Vitro Models To Study The Rapid Extraintestinal Dissemination Of Salmonella., Adarsh Gopinath

Electronic Theses and Dissertations

Salmonella appears in the bloodstream of mice in as little as 15 minutes after oral inoculation and establishes persistent colonies in the spleen and liver. While its pathway to blood is undetermined, this phenomenon is dependent on the activity of Salmonella pathogenicity island 2 (SPI-2) coded type III secretion system (T3SS) and CD18+ phagocytes. We hypothesize that dendritic cells associated with the basal face of the gut epithelium, that are naturally migratory and known to sample for luminal antigens directly transport Salmonella to the bloodstream. This process comprises of at least two phases, dissociation and reverse transmigration. We define dissociation …

Telomeric Dna Damage And Repair Machineries In Hiv Infection, Lam Nguyen

Electronic Theses and Dissertations

In this thesis, we investigated T cell homeostasis and DNA damage repair machineries in HIV infection. We found that the frequencies of CD4T cells were low, which is associated with cell apoptosis in HIV patients compared to healthy subjects. Importantly, these events were closely correlated to the increase in T cell exhaustion, senescence, DNA damage, and telomere attrition. Mechanistically, while the DNA damage sensors Mer11, Rad50, and NBS1 (MRN) complexes remained intact, the ataxia-telangiectasia mutated (ATM) kinase and its downstream checkpoint kinase 2 (CHK2) were significantly inhibited during HIV infection. Additionally, telomeric repeat-binding factor 2 (TRF2) that functions to protect …

Type Ix Secretion System: Characterization Of An Effector Protein And An Insight Into The Role Of C-Terminal Domain Dimeration In Outer Membrane Translocation., Lahari Koneru

Electronic Theses and Dissertations

Porphyromonas gingivalis and Tannerella forsythia are two of the primary pathogens that are associated in the etiology and progression of chronic periodontitis. In T. forsythia, KLIKK proteases are the recently identified group of proteolytic enzymes that are secreted through Type IX secretion system (T9SS). Among, these KLIKK proteases a synergistic relationship was observed between karilysin and mirolysin in invading the host complement system for the survival of the bacteria. Since, karilysin has been already characterized, in this study we propose to study about mirolysin through structural, biochemical and biological characterization. The obtained results from the experiments has shown the …

Characterization Of Filifactor Alocis And Its Immune Evasion Strategies Employed Against Human Neutrophils., Cortney Linn Armstrong

Electronic Theses and Dissertations

Periodontal disease is among the most common of inflammatory conditions and is caused by bacterial and host derived factors. The presence of bacteria drives the recruitment of neutrophils, professional phagocytes, to migrate to specific oral sites where they produce potent antimicrobials to kill their target. However, this inflammation and production of antimicrobials must be strictly regulated to minimize collateral host tissue damage. Human neutrophils recognized the oral pathogen Filifactor alocis through Toll-like receptor (TLR) 2 and upon binding, activated both p38 MAPK and ERK signaling pathways, known to be involved in neutrophil cell migration and degranulation. F. alocis also stimulated …

Range-Wide Prevalence And Impacts Of Pseudocercosporella Inconspicua On Lilium Grayi And An Assessment Of L. Superbum And L. Michauxii As Reservoirs, Cindy L. Barrett

Electronic Theses and Dissertations

Lilium grayi (Gray’s Lily), a southern Appalachian endemic species, is threatened by a Lilium-specific fungal pathogen, Pseudocercosporella inconspicua. The disease is characterized by tan lesions that can cause early senescence, while also lowering seed production and viability. This project tested for P. inconspicua conidia and accessed health at nine locations. The disease was present and ubiquitous across the range of L. grayi. Through identification of P. inconspicua conidia in the field, L. superbum (Turk’s Cap Lily) was identified as an additional host, while L. michauxii (Michaux’s Lily) was disease-free. However, infection was inducible in both species. With …

Cannabinoids Suppress The Innate Immune Response To Periodontal Pathogen Porphyromonas Gingivalis In Gingival Epithelial Cells., Rajarshi Guha Niyogi

Electronic Theses and Dissertations

Marijuana is widely used in the United States for recreational and medicinal purposes. Despite the proposed beneficial effects of cannabis on certain medical conditions, there is also a concern there is also a concern over negative health consequences of marijuana smoking. Recently, cannabis use has been established as a dose related risk factor for chronic periodontitis. Although the induction / exacerbation of chronic periodontitis in marijuana users has been established epidemiologically, the mechanisms underlying such predisposition are still unknown. It has long been suggested that marijuana has anti-inflammatory properties, while human epithelial cells are known to express cannabinoid receptor type …

Endothelial Hspa12b Is A Novel Protein For The Preservation Of Cardiovascular Function In Polymicrobial Sepsis Via Exosome Mir-126, Xia Zhang

Electronic Theses and Dissertations

Sepsis is the most frequent cause of mortality in most intensive care units. Cardiovascular dysfunction is a major complication associated with sepsis, with high mortality rates up to 70%. Currently, there is no effective treatment approach for sepsis.

The integrity of the endothelium is fundamental for the homeostasis of the cardiovascular system. Sepsis induces endothelial cell injury which is the key factor for multiple organ failure. The increased expression of adhesion molecules and chemokines in endothelial cell promotes leukocytes infiltration into the tissue. The loss of tight junction proteins and increased permeability of the endothelial cells will provoke tissue hypoxia …

Comparison Of Anti-Pneumococcal Functions Of Native And Modified Forms Of C-Reactive Protein, Donald Neba Ngwa

Electronic Theses and Dissertations

The anti-pneumococcal function of native C-reactive protein (CRP) involves its binding to phosphocholine molecules present on Streptococcus pneumoniae and subsequent activation of the complement system. However, when pneumococci recruit complement inhibitory protein factor H on their surface, they escape complement attack. Non-native forms of CRP have been shown to bind immobilized factor H. Accordingly, we hypothesized that modified CRP would bind to factor H on pneumococci, masking its complement inhibitory activity, allowing native CRP to exert its anti-pneumococcal function. As reported previously, native CRP protected mice from lethal pneumococcal infection when injected 30 minutes before infection but not when injected …

T-Cell Dysfunction By Hcv Core Protein Involves Pd-1/Pd-L1 Signaling., Billy Ellis King

Electronic Theses and Dissertations

In 1989 the hepatitis C virus was identified as a significant cause of post-transfusion hepatitis. Nearly two decades later there is still no vaccine, inadequate treatment options, and limited understanding of how the virus establishes chronicity in the majority of the people it infects. Recent reports suggest that the interaction of a negative co-stimulatory pathway mediated by PD-1 and PDL-1 is associated with persistent viral infection. The role, if any, that PD-1/PDL-1 has in HCV infection is unknown. In this study we report that PD-1 is upregulated in T-cells from persons with chronic HCV infection when compared to healthy donors. …