Immunology and Infectious Disease Commons^™

Filifactor Alocis Disrupts Efferocytosis To Sustain Inflammation In Periodontitis, Ella Dye, Silvia Uriarte, Ruth Idowu

The Cardinal Edge

Background: Filifactor alocis is a Gram-positive, obligate anaerobe that has emerged as a diagnostic marker of periodontitis. Neutrophils and macrophages are key players in oral immune homeostasis. Neutrophils are short-lived cells and constitutively undergo apoptosis. This apoptotic program can be accelerated or delayed by bacterial interactions. Macrophages clear apoptotic neutrophils via “efferocytosis,” a crucial mechanism for resolving inflammation and preventing tissue damage. The efferocytic process downregulates the expression and release of proinflammatory cytokines such as interleukin (IL)-6 and IL-23 while promoting anti-inflammatory responses. Our previous findings demonstrated that F. alocis delays neutrophil apoptosis, with fewer apoptotic cells observed after 18 …

Avaren-Fc's Effects On Lymphoma Cells., Jacob Hahn

Electronic Theses and Dissertations

This thesis investigates the therapeutic potential of Avaren-Fc (AvFc), a novel lectin fusion protein that integrates the Fc region of human IgG1 with the engineered lectin Avaren, specifically targeting lymphoma. The study delineates the in vitro binding capabilities of Avaren-Fc with a human B-cell lymphoma cell line, a canine B-cell lymphoma cell line, healthy canine peripheral blood mononuclear cells (PBMCs), and healthy human PBMCs. AvFc was shown to exhibit significant binding to human lymphoma cells. Furthermore, the direct cytotoxicity of Avaren-Fc against canine lymphoma cells, canine lymphoma cells and healthy canine PBMCs was assessed. It was found that there is …

Enzymatic Depletion Of Adenosine To Potentiate Cancer Immunotherapy., Omar Sadi Sarkar

Electronic Theses and Dissertations

Immune checkpoint blockade (ICB) therapies have revolutionized cancer treatment, but many patients still do not respond well. To improve therapeutic outcomes, chemotherapy is often combined with immunotherapy, as chemotherapy is known to promote immunogenicity. However, many patients develop resistance to this combination therapy, and the reasons behind it are not fully understood. In this study, we explored how platinum-based chemotherapy, specifically cisplatin, affects tumor signaling to create an immunosuppressive tumor microenvironment (TME). We found cisplatin triggers ataxia telangiectasia mutated (ATM)-mediated DNA damage signaling and induces higher expression of prostaglandin E₂ (PGE₂) via a cyclooxygenase-2 (COX-2) mediated pathway. We speculate DNA …

Tumor Infiltrating Lymphocytes: From Discovery To Clinical Application., Lewis Clayton Chew

Electronic Theses and Dissertations

This thesis explores the evolution of TIL therapy from its discovery to clinical application, focusing on its use in treating metastatic cancer. Adoptive cell therapy (ACT), particularly TIL therapy, has emerged as a promising alternative to traditional treatments like chemotherapy. This review article traces the historical development of TILs, highlighting key experiments and clinical trials that have shaped its understanding and application as a therapeutic strategy for patients with metastatic and difficult to treat cancers including melanoma. Importantly, this article highlights recent advancements, including the FDA approval of Lifileucel, and explores emerging strategies to enhance therapeutic efficacy of TILs through …

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 …

Sars-Cov-2 Modulates Pla2g2d/Pgd2 Signaling To Manipulate Host Immune Response To Increase Disease Severity., Dante L. Hamiel

Electronic Theses and Dissertations

Background: Previous studies suggested that SARS-CoV-2 infection could cause diverse immune and metabolic dysregulations, although the underlying mechanisms remain poorly understood. In addition, viruses may escape the immune response by modulating cellular metabolism, mitochondria, and protein functions indicating that immune or metabolic components may represent novel targets for anti-viral strategies. However, whether immune and metabolic disorders interact or affect each other waits to be determined. On the other hand, previous investigations identified the critical roles of a cell membrane-bound phospholipase PLA₂G2D and its downstream products PGD₂ in regulating the metabolism and inflammation in respiratory system. More importantly, …

Proteolytic Manipulation Of Neutrophil Responses And The Efferocytic Synapse By Porphyromonas Gingivalis., Kelley N. Cooper

Electronic Theses and Dissertations

Porphyromonas gingivalis (Pg) is etiologically associated with chronic periodontitis, a highly prevalent chronic inflammatory disease characterized by the destruction of hard and soft tissues of the periodontium. Pg is adapted to live in the human oral subgingival niche, a hostile environment dominated by excessive numbers of activated neutrophils and antimicrobial mediators. Its survival is contingent upon prompt and effective inactivation of neutrophil effector functions. In this dissertation, I uncover a novel pathogenic mechanism employed by Pg that disarms the antimicrobial capacity of live neutrophils and simultaneously sequesters them within macrophages. Mechanistically, RgpB, a cysteine protease produced by Pg …

Differential Responses Of Human Neutrophils To Legionella Species., Hannah E. Hanford

Electronic Theses and Dissertations

Legionella species are Gram-negative facultative intracellular bacterial pathogens commonly found in freshwater or soil environments where they survive and replicate within their natural protozoan hosts. Humans serve as an accidental host for Legionella species after inhalation of contaminated aerosolized water droplets or soil particles enabling the bacteria to enter the lungs, infect alveolar macrophages, and result in severe pneumonia. Evasion of degradation and proliferation within alveolar macrophages by Legionella species and manifestation of “Legionnaires’ disease” is dependent on the Dot/Icm type IV secretion system (T4SS). The T4SS apparatus is a needle-like channel for translocation of over ~350 effector proteins, depending …

Uncovering The Hidden Diversity Of Antibody Heavy Chains And Their Implications For Autoantibody Mediated Disease., Easton Earl Ford

Electronic Theses and Dissertations

Understanding the diversity of antibody (IG) molecules at the DNA and RNA level is imperative for understanding immunological processes and disease. Much of the work to uncover IG diversity has been focused on diversity in the variable region of the IG molecule which is crucial for antigen binding. However, the diversity of the constant region responsible for the functions of IG has largely been ignored in the field of immunogenetics. The work presented in this thesis challenges the dogma that the constant region is invariant in terms of genetic diversity. In this thesis we present the development of a long-read …

Molecular Mechanisms Of Exercise-Stimulated Resolution Of Inflammation And Its Dietary Dependence., Ernesto H. Pena Calderin

Electronic Theses and Dissertations

Diet-induced obesity and adipose tissue (AT) inflammation that ensues sets the stage for systemic metabolic inflammation, disrupted insulin signaling, and eventual type 2 diabetes (T2D) development. At the center of this pathology lies a disruption in endogenous inflammation resolution pathways characterized by an imbalance in lipid mediator production (greater abundance of pro-inflammatory to pro-resolving lipids). Additionally, obese states are characterized by adrenergic deficiency, especially in response to physical activity. Inflammatory processes have been experimentally mitigated by either the pharmacological inhibition of pro-inflammatory signals (i.e., Leukotriene B₄ (LTB₄) and its receptor BLT1, which establishes a potent chemotactic stimulus …

Investigation Of Avaren-Fc's Therapeutic Potential Against Ovarian Cancer., Katarina Lee Mayer

Electronic Theses and Dissertations

This thesis describes the investigation of Avaren-Fc (AvFc), a novel lectin-based therapeutic fusion protein consisting of the recombinant Avaren lectin and the Fc region of human IgG1, against ovarian cancer. AvFc possesses selectivity toward tumor associated N-linked high-mannose-type glycans. The present study demonstrates AvFc’s in vitro activity against OVCA cell lines via antibody-dependent cell-mediated cytotoxicity and its ability to extend the survival of mice challenged with murine ID8 OVCA cells after repeated systemic administration. Furthermore, AvFc treatment in this model was found to increase the presence of peritoneal leukocytes, suggesting a shift toward an improved antitumor immune response. Another key …

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 …}

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 …

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 …

Osteoimmunology And The Reconstruction Of Host Immunological Status In Treponemal Infection: Effect Of Activated Immune Cells By Oral Pathogens And Treponema Pallidum On Osteoclastogenesis., Michayla Gatsos

College of Arts & Sciences Senior Theses

Syphilitic infection caused by bacterium Treponema pallidum pallidum (Tp) offers an excellent model to study the long-lasting interplay between the immune and skeletal systems and could be used to reconstruct host immunological status. We propose that a hyper-inflammatory phenotype developed during acquired syphilis will have a systemic impact on most bone microenvironments involving inflammatory processes, such as the one developed in periodontal disease (PD). Using osteoimmunological in vitro protocols, we explore whether immune activation by Tp antigens and PD pathogens can impact osteoclastogenesis (OCG), ultimately helping to understand the bone alterations caused by systemic inflammatory processes in skeletal material. We …

Does Stress Physiology Mediate Disease Resistance In The Arizona Tiger Salamander (Ambystoma Mavortium Nebulosum)?, Megan Zerger

2023 Midwest Ecology & Evolution Conference

Amphibian biodiversity has greatly diminished in recent years due to disease. Panzootic pathogenic fungi Batrachochytrium dendrobatidis (Bd) causes the deadly disease chytridiomycosis (chytrid), a primary driver of catastrophic global amphibian declines and extinctions. The pathogenesis of chytrid is still unclear, as certain species and individuals within a species are differentially affected. Susceptibility and mortality of Bd are influenced by prolonged chronic stress. Prolonged glucocorticoid activity deleteriously affects many of the same physiological processes as Bd infections, and corticosterone is the primary glucocorticoid released by amphibians in response to stress. Thus, the objective of our study is to assess …

Spatiotemporal Patterns Of Ticks And Tick-Borne Disease Dynamics At Neon Sites Across A Sub-Continental Scale., Ana Sofia Rivera

2023 Midwest Ecology & Evolution Conference

At local scales, dynamics of ticks and tick-borne diseases such as Lyme disease are driven by resource pulses, such as mast seeding in forest trees, that creates increases in tick hosts. Tick-borne diseases in humans have nearly doubled between 1940 and 2004 and understanding the dynamics of infectious diseases has long been of interest for ecologists. The family Ixodidae is the most capable of transmitting pathogens to humans and tick-borne diseases are the most common vector of illness in the United States. The objective of this research is to characterize the spatiotemporal dynamics of ticks and tick-borne diseases, which may …

A Study Of Multiple Sclerosis, Christine Chen

The Cardinal Edge

No abstract provided.

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) …

Implementation Of A Drive-Through Covid-19 Mass Vaccination Site: Experiences From Louvax–Broadbent In Louisville, Kentucky, Ruth Carrico, Sarah Beth Hartlage, Valenchia Brown Msn, Aprn, Fnp-C, Sarah M. Bishop, Luanne Didelot, William Hayden, Beverly Williams Coleman, Sarah Tan, Delanor Manson, Kellie Kane, Dawn Balcom, Paul Kern

The University of Louisville Journal of Respiratory Infections

Background: Response to the COVID-19 pandemic has required innovative approaches to vaccination, including methods to rapidly and safely immunize communities. A major challenge to such a response involved access to untapped healthcare worker resources. The Louisville, Kentucky, response involved the use of a large volunteer workforce to supplement local public health employees in planning and implementing a large-scale drive-through vaccination event. The objective of this manuscript was to outline processes involved in training a mass immunization workforce and implementating a large-scale COVID-19 community vaccination.

Approach: Competency-based and standardized training was provided for every volunteer before working their shift. Volunteers worked …

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 …

Rsv-Induced Guillain–Barré Syndrome, Priyanga Jayakumar, Christe Shen, Dylan Goldsmith, Steven Lippmann

The University of Louisville Journal of Respiratory Infections

A patient with respiratory syncytial virus-induced Guillain–Barré Syndrome and acute disseminated encephalomyelitis is presented. This virus is the most common cause of upper respiratory infections, and it can become an etiology for extra-pulmonary pathology with serious complications. Such a case is rare, but the possibility of adverse comorbidities makes early diagnosis and treatment important.

Assessment Of Pathogenic Changes In The Gut-Liver Axis In Plwh With Heavy Alcohol Drinking And Gut Dysbiosis Marked By Decreased Butyrogenic Potential., Smita Ghare, Vaughn Bryant, Richa Singhal, Sabina Gautam, Chanakya Charan Tirumala, Andrea Reyes-Vega, Craig J. Mcclain, Ronald Cohen, Varand Govind, Robert L. Cook, Shirish Barve

Faculty and Staff Scholarship

Purpose: People living with HIV infection (PLWH) experience increasing risk for non-AIDS diseases including liver dysfunction and injury. Both HIV-infection and heavy alcohol drinking (HAD) are known to cause gut microbial dysbiosis and systemic inflammation that may potentially contribute to altered Gut-Liver axis. However, the specific pathogenic features associated with combinatorial harmful effects of alcohol and HIV infection on gut-liver interactions are not completely understood. This study evaluate the pathogenic changes in the Gut-Liver axis in PLWH with HAD.

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 …

H1n1 Influenza Virus (Swine Flu): A Comprehensive Insight Into Escalating Catch-22 Scenarios, Muhammad Shahzaib, Ehsan Ul Haq

The University of Louisville Journal of Respiratory Infections

Introduction: Viruses have always been a major cause of various disastrous pandemics in mankind’s history. H1N1 became a threat when its original strain was first discovered back in the swine flu pandemic of 2009. It became highly catastrophic on a large scale because none of the therapeutic interventions and methodologies that were already present at the time were effective against the virus.

Methods: A vast amount of literature and research is available regarding H1N1 influenza from different reputable sources online. The data were gathered with the contrasting and relative situations of 1918 and 2009 pandemics in mind. The overall extracted …

Epigenetic Mechanisms Underlying Hiv-Infection Induced Susceptibility Of Cd4+ T Cells To Enhanced Activation-Induced Fasl Expression And Cell Death., Smita Ghare, Paula M. Chilton, Aakarsha V. Rao, Swati Joshi-Barve, Paula Peyrani, Andrea Reyes-Vega, Craig J. Mcclain, Kendall Bryant, Robert L. Cook, Mathew Freiberg, Shirish Barve

Faculty and Staff Scholarship

Background:

Chronic immune activation and CD4⁺ T cell depletion are significant pathogenic features of HIV infection. Expression of Fas ligand (FasL), a key mediator of activation-induced cell death in T cells, is elevated in people living with HIV-1 infection (PLWH). However, the epigenetic mechanisms underlying the enhanced induction of FasL expression in CD4⁺ T lymphocytes in PLWH are not completely elucidated. Hence, the current work examined the effect of HIV infection on FasL promoter-associated histone modifications and transcriptional regulation in CD4⁺ T lymphocytes in PLWH.

Method:

Flow cytometric analysis was performed to examine the Fas-FasL expression on …

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 …

Covid-19 And The Unseen Benefits Of Dexamethasone, Muhammad Arif Khan, Ikram Ullah, Dawood Ahmed

The University of Louisville Journal of Respiratory Infections

According to current World Health Organization (WHO) updates, the COVID-19 pandemic has spread all over the globe, affecting 216 countries, and has caused 8,860,331 confirmed cases and 465,740 deaths as of June 24, 2020. Many countries cannot afford nucleic acid tests to confirm COVID-19 infection; as a result, people cannot know the COVID-19 status of the people living around them. The use of dexamethasone in COVID-19 hospitalized patients for up to 10 days lowered 28-day mortality compared to patients receiving standard of care plus mechanical ventilation at randomization (by 12.3 age-adjusted percentage points, approximately one-third of proportional reduction) and patients …