Immunology and Infectious Disease Commons^™

Pi3kδ Inhibition Alters Cd8 T Cell Differentiation And Reprograms The Tumor Microenvironment Following Adoptive Immunotherapy, Alexandrea Joy Turnquist

Dartmouth College Ph.D Dissertations

T cell exhaustion remains a significant barrier to effective adoptive cell therapy in solid tumors. Here, we demonstrate that in vitro treatment with the PI3Kδ inhibitor CAL-101 generates T cells with enhanced stemness and metabolic fitness, though the stemness of these cells is not dependent on HIF-1α -dependent mechanisms. These cells show increased mitochondrial dependence and spare respiratory capacity while maintaining normal basal metabolism. Under chronic antigen stimulation, CAL-101-treated T cells, including human T cells, resist terminal exhaustion and maintain stem-like properties. Using single-cell RNA sequencing and spatial transcriptomics of B16 melanoma tumors, we found that CAL-101-treated T cells preferentially …

Exploring Foundations Of Animal Host-Microbe Interactions In A Freshwater Sponge, Jacob S. Pawley

Electronic Theses and Dissertations

The most ancient eukaryotic immune defense mechanisms evolved in unicellular species. Multicellular eukaryotes, however, expanded these mechanisms to meet challenges unique to multicellular life, including barrier formation, long-distance cell signaling, and coordinated responses that eliminate microbial threats while minimizing damage to the host. As such, animal immune signaling pathways are exceptionally intricate and diverse. Though, most of what is understood about animal host–microbe interactions stems from a small handful of model systems. Here, I evaluate host–microbe interactions and innate immunity in sponges using the highly tractable freshwater sponge, Ephydatia muelleri. I report the discovery of an external host-derived matrix …

Identification And Characterization Of Novel Immune Modulating Genes In Parkinson's Disease, Kathleen Chaundy Paul Murphy

Dartmouth College Ph.D Dissertations

Parkinson’s disease (PD) is a progressive age-related neurodegenerative disorder characterized by both motor and non-motor symptoms. The poorly understood prodromal period, decades-long progression, and disease-phenotype heterogeneity continue to impede the development of preventive and curative therapies. A growing appreciation of immune system changes during the progression of PD suggests that evaluating peripheral immune cells may help identify signatures relevant to disease etiology. We aimed to expand our understanding of the peripheral immune compartment in PD via two lines of investigation: (1) by employing single-cell RNA sequencing to profile the transcriptomes of peripheral blood mononuclear cells (PBMCs) from a cohort of …

Antigen Discovery In Multiple Myeloma Using Integrated Long-Read Transcriptomics And Immunopeptidomics, Aya Albittar

Dissertations and Theses (Open Access)

Multiple myeloma (MM) remains an incurable plasma cell malignancy, with relapse driven by persistent chemotherapy-resistant cells and residual disease following treatment. Although immunotherapies have transformed MM care, their success depends on identifying tumor-specific antigens that can be safely targeted. While aberrant genomic structural variation and transcriptional dysregulation are increasingly recognized as sources of novel antigens in MM, the HLA-presented antigenic landscape of MM remains incompletely characterized, particularly for non-canonical, structurally-derived peptides, and long-read transcriptome-informed immunopeptidomic data specific to MM remain scarce.

We established an integrated antigen discovery platform combining long-read RNA sequencing (Iso-Seq) with mass spectrometry-based HLA immunoprecipitation and immunopeptidomics …

Development Of Novel Plasminogen Activators From Fragments Of Streptokinase Enzyme, Vijay G Mr

Theses and Dissertations

Thrombotic disorders such as myocardial infarction, ischemic stroke, pulmonary embolism and deep vein thrombosis remain major causes of mortality and disability worldwide, creating a continuing need for effective, safe and affordable thrombolytic therapy. Streptokinase is one of the most widely used plasminogen activators because of its activity, low cost and broad availability. However, its wider clinical utility is limited by high immunogenicity, allergic reactions, neutralizing antibody formation and poor suitability for repeat administration. This thesis aimed to develop novel streptokinase-derived plasminogen activators by identifying smaller functional fragments that retain thrombolytic activity while potentially reducing immunogenicity.

A literature-guided fragment-based strategy was …

Engineering Fsh-Cer T Cells To Enhance Response To Epithelial Ovarian Cancer, Nolan J. Beatty

USF Tampa Graduate Theses and Dissertations

Ovarian cancer remains a significant cause of cancer-related mortality, with epithelial ovarian cancer (EOC) being the most common subtype. Despite advances in treatment, the 5-year survival rate for late-stage EOC remains low due to factors such as tumor heterogeneity and an immunosuppressive tumor microenvironment (TME). This study investigates the therapeutic potential of chimeric endocrine receptor (CER) T cells engineered to express follicle stimulating hormone (FSH) in a syngeneic mouse model of EOC expressing follicle stimulating hormone receptor (ID8-FSHR). We compared two different co-stimulatory domains—CD28ζ and 4-1BBζ—in FSH-CER T cells and found that FSH-CD28ζ CER T cells exhibited enhanced cytotoxicity, proliferation, …

Association Of Social Isolation, Loneliness, Social Strain And Support With Cancer Onset, And Frailty And All-Cause Mortality In People With Cancer, Joanne Elayoubi

USF Tampa Graduate Theses and Dissertations

Cancer is the second leading cause of death both in the United States and globally and for individuals over sixty-five. In 2026, approximately 2,114,850 new cancer cases are projected to emerge according to the National Center for Health Statistics (Siegel et al., 2026). Cancer incidence is increasing, making older adults sixty-five and older at risk of frailty and mortality following cancer. Although social isolation, loneliness, lack of social support, and social strain have been found to be risk factors for poor health and mortality, it is not clear the extent to which social relationships are associated with incident cancer, and …

Biologically Informed Negative Samplingfor Antibody Chain Pairing Classification, Ishita Singh

Computer Science Senior Theses

Antibody heavy and light chain (H/L) pairing is fundamental to antigen recognition and stability. While single-cell sequencing preserves native pairing information, widely used bulk repertoire and spatial transcriptomics platforms do not, motivating the need for efficient ML methods to infer H/L pairing. Training a binary classifier for this task faces the methodological challenge of a lack of true biological negatives, since natural selection eliminates B cells with incompatible H/L pairs.

In this thesis, I introduce a biologically informed negative sampling strategy for H/L pairing classification, drawing on known V-gene biases in heavy and light chain pairing. Pseudo-negatives are constructed by …

Immunomodulatory And Signaling Molecules From Plant-Associated Bacteria: Toll-Like Receptor 4 Agonist Adjuvants And Diketopiperazine-Mediated Communication, Marian Romaine

Dissertations, Theses, and Capstone Projects

Medicinal plants and their associated microbiomes constitute a rich source of bioactive natural products with applications in immunotherapy and microbial ecology. Herbal formulations have long been valued for safe immune enhancement, while bacterial signaling molecules govern community behaviors critical to pathogenesis, symbiosis, and environmental processes. Bacterial lipopolysaccharides (LPS) from plant-associated Gram-negative bacteria have emerged as potent TLR4 agonists, yet their endotoxic potential limits direct use, and diketopiperazines (DKPs) serve as versatile quorum-sensing mediators capable of modulating biofilms in mixed microbial systems.

The work in this thesis comprises two independent but complementary research strands. The first strand pursued the engineering of …

Examining The Ligands, Location, And Function Of Toll-Like Receptor 10, Kiefer Keanu Tam

Master's Theses

Toll-like receptors are a class of innate immune pattern recognition receptors that detect pathogen-associated molecular patterns and regulate downstream inflammatory responses. Toll-like receptor 10 remains the only human TLR whose ligand specificity, cellular localization, and immunological function are not fully defined. Emerging evidence suggests that TLR10 may play an anti-inflammatory role and can heterodimerize with TLR2 to modulate immune signaling. Previous studies from our laboratory demonstrated that stimulation with heat-killed Mycobacterium tuberculosis promotes TLR2-TLR10 heterodimerization and trafficking to the cell surface. In this study, we expanded our ligand panel to include additional gram-positive bacteria, particularly anti-inflammatory probiotic species, to further …

Global Health Financing Of Diagonal Interventions: Building Resilient And Sustainable Health Systems In Sub-Saharan Africa, Lucy Kim

Master in Public Policy Theses

Background: Global health financing has historically prioritized disease-specific “vertical” programs over broader “horizontal” strengthening of general health systems. Vertical programs in HIV have led to unprecedented reductions in mortality worldwide, but HIV remains a significant public health threat in sub-Saharan Africa, where vertical strategies have long been criticized for creating fragmented health systems. In response, global health strategies have shifted towards combining vertical investments with broader horizontal activities, commonly referred to as “diagonal” programming. While evidence suggests that diagonal programming has the potential to create more resilient and sustainable health systems, evaluating its value for money is challenging due to …

From Cranes To Clinics: Genomic Epidemiology At The Human-Animal Interface, Sarah Shrum

Biology ETDs

Emerging infectious diseases represent a significant, increasing threat to human life, economic stability, and global security. The One Health framework, which promotes human health and wellness through the understanding that animal, environmental, and human health are interwoven, is critical to understanding pathogen emergence and transmission. This is underscored by the fact that roughly 60% of all human pathogens and 75% of emerging infectious disease are zoonotic, meaning they are transmitted from animals to humans.

The work presented in this dissertation integrates genomic epidemiology, ecological analysis, and One Health Surveillance approaches to characterize cross-species circulation of opportunistic yeast pathogens (Candida …

Potential Innate And Adaptive Roles Played By Γδ T Cells In A Bacterial Immunization Model, Lee Anne Talbot

Seton Hall University Dissertations and Theses (ETDs)

Francisella tularensis is a highly infectious intracellular bacterium and the causative agent of tularemia, with pulmonary infection resulting in severe disease and high mortality if untreated. While protective immunity to F. tularensis has been largely attributed to CD4⁺ T cell–mediated IFN-γ responses, the contribution of γδ T cells to mucosal immunity and vaccine-induced protection remains poorly defined. The objective of this study was to characterize the role of γδ T cells during primary pulmonary infection with F. tularensis live vaccine strain (LVS) and following intranasal immunization with inactivated F. tularensis (iFt) prior to LVS challenge.

Using a murine intranasal infection …

In Vitro Modeling Of Macrophage And Cd8+ T Cell Activation: Evaluating Immortalized Cell Lines For Use In Undergraduate Immunology Laboratories, Lucy Groothuis

Masters Theses

The immune system is a complex, highly coordinated network of cells and signaling molecules that protects the body from infection and disease. Immunology is therefore a fundamental component of undergraduate education for students pursuing careers in medicine and biomedical research. Despite its importance, many undergraduate immunology courses lack a laboratory component. To address this gap, we developed an open-access immunology laboratory manual and evaluated its ability to generate meaningful data using primary murine cells and commercially available cell lines. Given the cost and logistical constraints of using mouse models in an undergraduate laboratory setting, we evaluated whether immortalized cell lines …

Optimization Of Refolding, Purification, And Analytical Characterization Of Proinsulin(F25d) Soluble Antigen Array Immunotherapy, Abigail Richardson

McKelvey School of Engineering Graduate Student Theses & Dissertations

Type 1 Diabetes (T1D) is characterized by autoreactive immune responses to insulin and its precursor, proinsulin. Soluble antigen arrays (SAgAs) displaying the metabolically inactive proinsulin variant, proinsulin(F25D), represent a promising antigen‑specific immunotherapy candidate for T1D. However, the production of these platforms is hindered by substantial practical challenges, including protein aggregation, inefficient refolding, and the lack of sensitive analytical tools to verify quality and dosage. This work establishes an integrated, scalable pipeline for the purification, conjugation, and quantification of a proinsulin(F25D) SAgA. First, we optimized the refolding of recombinant methionine-proinsulin(F25D) (M-PI(F25D)) from inclusion bodies using controlled buffer systems and created a …

From Antigen Presentation To Tumor Control: Mechanisms Of Type I Conventional Dendritic Cell-Based Cancer Vaccines, Josue E. Pineda

Dissertations and Theses (Open Access)

Type 1 conventional dendritic cells (cDC1s) are important for generating and sustaining antitumor immunity. Accordingly, the abundance of cDC1s in human tumors correlates with improved outcomes in cancer. Capitalizing on this role, we previously demonstrated that vaccination with in vitro-derived murine cDC1s elicits durable tumor control in multiple preclinical models; however, the immunological mechanisms underlying the efficacy of cDC1 vaccination remain unclear. Here, we examined whether in vitro-derived cDC1s resemble tumor-infiltrating DC populations and whether MHC-I and MHC-II antigen presentation contribute to cDC1-mediated tumor control following vaccination in melanoma.

As expected, MHC-I- or MHC-II-deficiency had minimal impact on …

Understanding Epigenomic Landscapes In Cancer Progression And Immunotherapy Response, Jonathan Schulz

Dissertations and Theses (Open Access)

Nonmutational epigenomic reprogramming has emerged as a key hallmark of cancer that plays crucial roles in tumor evolution during its progression and response to therapy. However, the extent and nature of epigenomic reprogramming remains poorly understood. This dissertation examines how epigenetic regulation shapes cancer progression and response to immunotherapy. Working at the intersection of cancer biology and computational genomics, it develops analytical frameworks for characterizing chromatin structure and DNA methylation across diverse tumor contexts and uses these frameworks to address two complementary biological questions: how promoter-associated chromatin organization varies across cancer types, and how epigenetic perturbation modulates tumor immunogenicity in …

Drug Repurposing Against Giardia Targeting Lipid Rafts, Extracellular Vesicles, And Sphingolipid Synthesis, Breanna Chantal Pence

Open Access Theses & Dissertations

Giardia lamblia is a protozoan parasite responsible for the intestinal disease giardiasis worldwide. Giardia is one of the major intestinal parasites in the world, with over 500,000 new cases annually. Symptoms of giardiasis include diarrhea, abdominal pain, and nausea. Children are particularly vulnerable to giardiasis, with cases of malnutrition, stunted growth, and cognitive impairment in countries where the disease is endemic. Giardia consists of two morphologic forms: an infective cyst which transmits the disease and a motile trophozoite which attaches to the epithelium of the small intestine during infection. Metronidazole is a common treatment for giardiasis, but cases of toxicity …

Determining Zap-70 Signaling Pathways Mediated By Ccr7 In Tcr T Cell Activation, Vivian Torres

Open Access Theses & Dissertations

Activation of T lymphocytes is the main event that occurs in the adaptive immune response after engagement of the T cell receptor (TCR) with the peptide of the major histocompatibility complex (pMHC) molecules that are demonstrated by antigen presenting cells [1]. A key step in this process is the recruitment and activation of the zeta chain associated protein of 70 kDa (ZAP-70). ZAP-70 couples TCR engagement to downstream intracellular signaling pathways through phosphorylation of tyrosine residues within intracellular tyrosine activation motifs (ITAMs) [2]. Although there have been extensive studies on the signaling response through TCR activation, the regulatory influence of …

An Investigation Of Entamoeba Histolytica Chitin Synthases And Other Encystation Factors In Early Encystation, John N. Talledo

All Theses

Entamoeba histolytica is a food-and-water-borne human protozoan pathogen that relies on a two-stage life cycle for successful proliferation outside of the host. E. histolytica exists in its dormant cyst form while outside of its host and converts to the motile trophozoite (amoeba) form in the small intestine. The trophozoites colonize the large intestine to cause symptomatic disease in ~10% of infections, resulting in ~100 million cases of amoebic dysentery each year. Trophozoites can convert back to the cyst form, which is shed in feces to continue the infection cycle.

Currently, there is a lack of understanding of the exact molecular …

Understanding The Role Of Toxs As A Bile Sensing Component Of The Toxrs Virulence Regulatory System In Vibrio Spp., Minje Kim

Dartmouth College Ph.D Dissertations

Pathogenic Vibrio bacteria, such as V. cholerae and V. parahaemolyticus, colonize in the human small intestine to cause severe gastrointestinal disease. During the infection, these bacteria encounter bile salts, antimicrobial cholesterol metabolites secreted into the intestine. Pathogenic Vibrio species have evolved to utilize bile salts as signals to regulate virulence. The signaling depends in part on ToxRS, a conserved co-component transmembrane transcription regulator. ToxRS consists of the transcription factor ToxR and its membrane-tethered binding partner ToxS. ToxS is required for ToxR stability and full transcriptional activity. Although bile salts are known to influence ToxRS-dependent virulence gene expression, the molecular …

Exploration Of A Relationship Between The Activities Of Trail And 4’-Trifluoromethoxychalcone., Abigail C. Ernst

Undergraduate Theses

Cancer is the overgrowth of dysregulated or mutated cells that affects 1 in 3 Americans. Chalcones are natural products with many possible derivatives, such as 4’-trifluromethoxychalcone (4TF), developed in Dr. Krzysiak’s lab, which exhibit anticancer activity against cancer cell lines. Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) is a tumor surveillance cytokine that acts on two receptor types: death receptors and decoy receptors. One way cancer cells can become resistant to TRAIL is by upregulating decoy receptors and/or downregulating death receptors. In this study, MTS assays evaluated the potential relationship between TRAIL and 4TF that sensitizes A549 cells to TRAIL. The …

Cell-Free Mitochondrial Dna (Mtdna) Triggers Vascular Dysfunction Via Toll-Like Receptor 9 (Tlr9)-Dependent Activation Of Inflammasomes, Mohin Amin

Senior Theses

Hypertension is the leading global risk factor for mortality and is closely associated with vascular inflammation and dysfunction. Damaged mitochondria release cell-free mitochondrial DNA (cf-mtDNA), which activates toll-like receptor 9 (TLR9). The binding of TLR9 to mtDNA activates the NLRP3 inflammasome pathway, promoting the release of pro-inflammatory cytokines via gasdermin D (GSDMD), therefore worsening inflammation. However, the mechanisms linking mitochondrial injury to inflammation-induced vascular dysfunction remain unclear. We hypothesize that cf-mtDNA triggers TLR9-dependent NLRP3 inflammasome activation contributing to vascular and endothelial dysfunction. To assess that, adult male C57BL/6 were exposed to 28 consecutive days of chronic unpredictable stress (CUS) or …

Evaluation Of Tick-Derived Peptides For Transmission-Blocking Vaccine Candidates, Madelyn Futral

Honors Theses

The lack of effective preventive measures for tick-borne diseases represents a major public health challenge. Transmission-blocking vaccines targeting tick molecules essential for feeding or reproduction could provide a sustainable and broad-spectrum solution. In this study, we evaluated two tick-derived proteins as potential vaccine antigens, subolesin, a key regulator of blood-feeding and cellular processes, and vitellogenin, a protein involved in egg development. Using bioinformatic tools, we identified immunogenic peptide sequences from each protein and chemically conjugated them to virus-like particles (VLPs) to enhance antigen presentation. C57BL/6 mice were immunized intradermally with VLP-peptide conjugates, followed by a booster dose. Blood and spleen …

Increased Backbone Rigidity Of Artificial Transcription Factors, Jasmine Glover, Emma Otey, Joanna K. Kwao, Nicholas Truex

Senior Theses

Programming DNA-binding proteins is an effective strategy for developing therapeutics that regulate gene expression. These proteins can directly bind to DNA to activate or repress transcription of specific genes. Zinc finger proteins are a class of DNA-binding proteins commonly found in eukaryotic organisms. Their DNA-binding function is derived from unique amino acid sequences within each domain that recognizes specific nucleotides, allowing each finger to selectively recognize three DNA base pairs. Adjoining of multiple domains in tandem allows recognition of a specific DNA sequence. Artificial transcription factors can be made of multiple zinc finger domains arranged in tandem and engineered to …

Analyzing Antibody Immune Response In Α1,3galt-Ko Mice After Intranasal Vaccination Of Α-Gal Virus-Like Particle, Faith Brown

Honors Theses

In this study, we evaluated the immunogenicity of intranasal immunization with α-Gal-conjugated virus-like particles (VLPs) in an α1,3-galactosyltransferase-knockout (α1,3GalT-KO) mouse model that mimics the human immune response to the α-Gal epitope. The carbohydrate epitope galactose-α-1,3-galactose (α-Gal) is expressed on the cell surface of several pathogens, including Leishmania species. This molecule is absent in humans and has emerged as a promising immunogenic vaccine target. α1,3GalT-KO mice were intranasally immunized with 10 μg either Qβ-α-Gal or Qβ per nostril and boosted twice prior to sample collection. Blood and lung lavage samples were used to evaluate the antibody response. The Qβ-α-Gal group developed …

Role Of Listeria Adhesion Protein In Monocyte-Associated And Extracellular Translocation Of Listeria Monocytogenes Across The In Vitro Placental Barrier Co-Culture Model, Ayesha Atique

Biological Sciences Theses & Dissertations

Listeria monocytogenes is a facultative intracellular foodborne pathogen capable of crossing the placental barrier, leading to miscarriage, stillbirth, and neonatal sepsis, and has a fetal/neonatal fatality rate of ~20–30%. Although the importance of canonical virulence factors such as Internalin A (InlA) and Internalin B (InlB) in L. monocytogenes crossing of the placental barrier has been demonstrated, clinical strains lacking functional canonical internalins have been reported to cause severe neonatal disease, suggesting additional mechanisms of placental translocation.

To investigate these virulence mechanisms, we adapted a physiologically relevant co-culture human placental barrier Transwell model composed of BeWo trophoblasts and primary human placental …

Mitochondria Dynamics In Microglia During Health, Inflammation, And Aging, Alicia Nicole Pietramale

Dartmouth College Ph.D Dissertations

Microglia continually surveil the brain, allowing for rapid detection of tissue damage or infection. Microglial metabolism is linked to tissue homeostasis, yet how mitochondria are subcellularly partitioned in microglia and dynamically reorganize during surveillance, injury responses, and phagocytic engulfment in the intact brain has remained unclear. In this dissertation, I combine intravital imaging, ultrastructural analyses, and metabolic and cytoskeletal markers to investigate how mitochondrial organization relates to microglial function across health, inflammation, and aging.

I first show that microglial processes diverge in their mitochondrial content, with some containing multiple mitochondria while others are completely void. This heterogeneous partitioning is conserved …

Targeting Il-1 Signaling In Recessive Dystrophic Epidermolysis Bullosa: Improved Survival And Pathogenesis In Rdeb Mouse Model, Rahim Hirani

NYMC Student Theses and Dissertations

Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating inherited blistering disorder caused by biallelic mutations in COL7A1, resulting in deficiency of type VII collagen (C7) and loss of dermal–epidermal adhesion. Beyond mechanical fragility, RDEB is characterized by chronic inflammation, progressive fibrosis, impaired wound healing, severe pain, and an exceptionally high risk of aggressive cutaneous squamous cell carcinoma. Emerging transcriptomic and cytokine profiling studies have identified interleukin-1 alpha (IL-1α) as a dominant and temporally upstream inflammatory mediator in RDEB skin. The central hypothesis of this dissertation is that IL-1α signaling functions as a key initiator and amplifier of inflammation-driven pathology …

Targeting Cancer With T Cells: Preclinical And In Silico Insights To Improve Immunotherapies, Nina Obertopp

USF Tampa Graduate Theses and Dissertations

T-cell–based immunotherapies are often constrained by limited trafficking and persistence in tumors and by functional exhaustion under chronic antigen exposure. This dissertation addresses these barriers through two distinct strategies: (i) preclinical studies testing how radiation therapy modulates tumor-infiltrating lymphocytes (TIL) therapy, and (ii) agent based modeling (ABM) to optimize treatment day treatment-free intervals (TFI) in T-cell engager (TCE) therapy. (i) In a human papillomavirus–positive (HPV⁺) head-and-neck cancer (HNC) model, a single local-dose of RT (8 Gy) delivered five days before tumor harvest increased the success and functional quality of ex vivo TIL outgrowth from tumor fragments, enriching polyfunctional CD8⁺ subsets. …