Immunity Commons^™

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 …

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 …

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 …

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 …

A Framework For Characterizing The Peripheral Immune Isonome Using Long-Read Single-Cell Rna Sequencing And Its Relevance To Neurological Disease, Patricia Hayes Doyle

Theses and Dissertations--Neuroscience

Long-read single-cell RNA sequencing provides an opportunity to understand human health and disease at isoform resolution, revealing cellular diversity and disease mechanisms difficult to resolve with bulk or short-read methodologies.

Using a modified PIPseq workflow and computational pipeline adapted for Oxford Nanopore (ONT) sequencing, we profiled isoform usage across immune cells, integrating marker expression and isoform discovery, generating the largest long-read single-cell dataset of human immune cells from a single individual to date. We identified non-canonical protein-coding variants of GZMB and CD3G enriched in unexpected cell types. We also discovered novel transcripts from CMC1 and LYAR with cell-type-specific signatures that …

Equid Major Histocompatibility Complex (Mhc) Evolution & Genome Organization, Lauren C. Johnson

Theses and Dissertations--Veterinary Science

The evolution of modern horses has a well-documented fossil record and has long been of interest to the genetics community. Although non-caballine equids (e.g. zebras, donkeys, and asses) can hybridize with horses, the resulting offspring are typically infertile. Despite these reproductive barriers, genomic analyses reveal regions of high sequence similarity among equid species. This dissertation investigates the role of historical introgression in the evolution of modern Equus species. The first chapter re-evaluates earlier findings derived from a limited horse population and a single reference genome. The variants of the identified regions were pushed through Ensembl’s Variant Effect Predictor to assess …

The Effect Of Sex On A-To-I Editing In Skeletal Muscle During Inflammation, Skyler Lee

Graduate Theses/Dissertations

Adenosine-to-inosine (A-to-I) RNA editing is a post-transcriptional mechanism mediated by ADAR enzymes that can alter RNA sequence, protein function, and gene regulation. Because ADAR1 is upregulated during inflammation and plays a critical role in innate immunity, previous studies investigated the effects of acute inflammation on RNA editing in male and female mice. Lipopolysaccharide (LPS) was used to induce inflammation, and RNA editing levels were examined in the heart, brain, and skeletal muscle. While editing levels in the heart and brain remained unchanged, skeletal muscle exhibited tissue- and sex-specific differences in editing. In this thesis, LPS treatment affected selective editing, increasing …

Host-Intrinsic Factors Determine Anti-Tumor Efficacy Of Exercise In Pancreatic Ductal Adenocarcinoma, Sumedha Pareek

Dissertations and Theses (Open Access)

Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths with a low 5-year relative survival rate of approximately 13.3% for all stages combined. We have previously shown that exercise can improve quality of life and enhance functional capacity among patients with PDAC. Exercise induces a variety of changes in the tumor microenvironment with beneficial effects in several tumor types. However, our understanding of the clinical effects of exercise and the mechanisms that mediate anti-tumor effects are limited in pancreatic cancer.

In this project, using C57BL/6 mice from Taconic Biosciences (Tac) and Jackson Laboratories (Jax), we established a …

Bmp Signaling Co-Regulation Of Immune Response And Lipid Metabolism, Katerina K. Yamamoto

Dissertations, Theses, and Capstone Projects

The Bone Morphogenetic Proteins (BMPs) are secreted peptide ligands of the Transforming Growth Factor beta (TGF-β) family, initially identified for their roles in development and differentiation across animal species. They are now increasingly recognized for their roles in physiology and infectious disease. In the nematode Caenorhabditis elegans, the BMP ligand DBL-1 controls fat metabolism and immune response, in addition to its roles in body size regulation and development. DBL-1 regulates classical aspects of innate immunity, including the induction of anti-microbial peptides. We theorized that BMP-dependent regulation of fat metabolism could also promote resilience against microbial pathogens. We found that …

Computational Frameworks To Unravel The Immune Landscape, Shan He

Dissertations and Theses (Open Access)

Recent advances in immunotherapy, including immune checkpoint blockade (ICB) and adoptive cell therapy, face challenges such as resistance and immune-related adverse events, partly due to our limited understanding of the immune signaling pathways. While high- throughput genomic data provide unprecedented resolution into these immune pathways, their full potential is limited by the lack of well-annotated, context-specific immune gene sets. To address this need, I developed a workflow to construct immune gene sets by integrating RNA- seq datasets and performing decomposition. Using this approach, I constructed 28 immune- specific gene sets from 83 bulk RNA-seq datasets and 12 Natural Killer (NK) …

Studies Of The Mechanisms Of Reverse Signaling By Cd40l, Barbara M. Nassif Rausseo

Dissertations and Theses (Open Access)

CD40 ligand (CD40L) is a transmembrane protein expressed on activated CD4 T cells, traditionally known for its role in forward signaling by engaging CD40 on antigen- presenting cells to promote immune activation. While this pathway is well characterized, there is evidence that CD40L also mediates reverse signaling, acting as a signaling receptor on T cells which enhances T cell function. However, the extent, consequences, and mechanism of CD40L-mediated reverse signaling in CD4 T cells remain poorly defined. This dissertation investigates the mechanisms and effects of CD40L reverse signaling on T cell function using both primary human T cells and the …

Ecoimmunology Of Dirty Physella Acuta Snails, Kevin Arthur Mcquirk

Biology ETDs

Research on Physella acuta, an invasive freshwater snail, reveals insights into its parasitology, fitness, and molecular biology. Morphological and molecular analyses revealed two distinct mitogenomic lineages, local (B) and invasive (A) strains of native P. acuta, both having comparable trematode infection rates, suggesting that the low infection rates observed from A in invaded regions result from "enemy release" rather than immune incompatibility. Fitness assessments showed that while lineages A and B performed similarly under laboratory conditions, rewilding experiments revealed significantly higher fitness in lineage A. Transcriptomic profiling supported these differences, with A snails showing greater immune-related gene expression and …

Immune Regulation In Fungal Airway Inflammation And Host Defense, Ruoning Wang

Biomedical Sciences ETDs

Asthma is a chronic inflammatory disease of the lungs characterized by complex pathophysiological mechanisms and diverse endotypes, primarily categorized as T helper type 2 cell (Th2)-high and Th2-low asthma. Despite significant advances in understanding asthma pathogenesis, the mechanisms governing the pulmonary immune system’s response to external challenges have not been fully understood. To address these gaps, this comprehensive project was designed to investigate the interplay between fungal infections and specific CD4⁺ T cell populations in asthma. Our findings suggest that fungal infections can contribute to neutrophilic asthma by promoting the migration of platelet-myeloid aggregates into the lungs. We also …

Macrophage Heterogeneity And Function In The Lung, Xin Li

Dartmouth College Ph.D Dissertations

Macrophages are critical custodians of the lung, orchestrating immune surveillance, maintaining tissue homeostasis, and coordinating both innate and adaptive responses. This dissertation examines their heterogeneity and specialized functions, focusing on IMs, which reside in the lung interstitium, and AMs, which occupy the airspace. Through comprehensive single-cell transcriptomic profiling of murine and human samples, we identify multiple IM and AM subsets defined by distinct chemokine, cytokine, receptor, and innate immune gene signatures. These subsets display clear divisions of labor, contributing to immune cell recruitment, tertiary lymphoid structure formation, and alveolar homeostasis.

In IMs, coordinated chemokine programs not only recruit inflammatory cells …

Developing A Murine Model To Investigate The Mechanisms Of Peanut, Cashew, Shrimp Multifood Allergy, Aaron Wilson

NYMC Student Theses and Dissertations

Approximately 32 million people in the United States have food allergies, which is approximately 10 percent of the population. Food allergies can be mild, moderate, or even severe, resulting in anaphylaxis. The most predominant food groups that trigger food allergies include peanuts, tree nuts, fish, and shellfish. Peanuts and tree nuts have some similarities in protein structure. Shellfish is not associated with the protein properties of peanuts or tree nuts, it is the leading cause of adult anaphylaxis and often co-exist with peanut and tree nut allergies Currently, there are few studies that have established a murine model for allergy …

The Effect Of 1,25-Dihydroxyvitamin D3 Supplementation On Humoral Immunity Against Bacterial Chondronecrosis With Osteomyelitis Lameness In Broiler Chickens, Bailey Herberger

Animal Science Undergraduate Honors Theses

Bacterial chondronecrosis with osteomyelitis (BCO) lameness, the most predominant locomotive illness in fast-growing broilers, causes substantial animal well-being issues and affects broiler production, leading to huge financial losses. Several strategies, including feed supplementations using organic trace minerals, vitamin D, probiotics, and prebiotics, have been utilized to alleviate BCO lameness incidences in broiler chickens. Previous studies have indicated that feeding an additive of Panbonis^®-G-1,25(OH)₂D₃ from Solanum glaucophyllum containing 1 µg/kg G-1,25(OH)₂D₃ to broilers for the first 28 days of their production cycle reduced BCO lameness by more than 50%. In this study, we …

Impact Of Temperature And Microbial Infection On The Honey Bee Hemocytes, Michael E. Oeth

Master's Theses

Introduction

Honey bees (Apis mellifera) rely on hemocytes for immunity, wound healing, and hemolymph homeostasis. While 32°C reflects optimal hive conditions, suboptimal temperatures (22°C) and stressors like pathogens (Varroa destructor, bacteria) or pesticides impair hemocyte function. Using clodronate liposomes (CLD) to deplete hemocytes, we assessed how immune suppression interacts with these stressors.

Methods

Newly emerged (5-day-old) and older (15-day-old) bees were assigned to: CLD, control liposomes (LP), PBS, injection wound, or no treatment. Cohorts were exposed to 32°C (optimal) or 22°C (stressful for non-immunosuppressed bees). Fifteen-day-old bees were challenged with Escherichia coli or Staphylococcus aureus. Survival, hemolymph volume, and hemocyte …

Expanding Inducible Epithelial Resistance Against Pneumonia: Novel Virus, Novel Receptor, Michael Longmire

Dissertations and Theses (Open Access)

Pneumonia is the leading infectious cause of death worldwide and presents a continuing risk among immunocompromised patients. Our work has been focused for many years on the phenomenon of inducible epithelial resistance, where activation of the innate immune response in the airway epithelium is necessary and sufficient to produce a pathogen-killing but self-protective environment to prevent severe disease. Inducible resistance is pathogen-agnostic and has been demonstrated against an array of respiratory infections. We achieve this using a combination of pattern recognition receptor agonists – Pam2CSK4 and ODN M362 being the current formulation – which produce synergistic levels of pathogen reduction …

Exploring Veto Activity: Dnam-1-Cd155 Axis In Overcoming Nk Cell-Mediated Allo-Rejection And Applications For Car-T Cell Therapy, Wei-Hsin Liu

Dissertations and Theses (Open Access)

As Miller et al. defined veto activity, it enables cells to target host cytotoxic T lymphocyte (CTL) precursors specific to veto cells' antigens, selectively eliminating anti- donor T cell clones without inducing rejection. By leveraging this unique immune property, two key research aims were proposed: “Exploration of the Impact of Veto Activity on Natural Killer (NK) Cell-Mediated Allo-rejection” and “Development of Off-the- shelf Chimeric Antigen Receptor (CAR)-T Therapy: Engineering Anti-Viral Veto CD8+ T Cells”. As demonstrated in our previous research, in a murine model with mild conditioning, anti-third-party central memory CD8+ veto T cells (veto Tcm) can prevent T cell- …

Mhc Class I Tyrosine Phosphorylation Site Y320 Augments Cd8+ T Cell Priming, Effector Function, And Memory Response, Yimo Sun, Gregory A Lizee, Yitao Tang, Priscilla Ortiz, R Eric Davis

Dissertations and Theses (Open Access)

The cytoplasmic domain of MHC class I (MHC-I) molecules contains a single, highly conserved tyrosine residue (Y320). In previous work, we found that mice expressing a Y320F-mutated form of H-2K^b had reduced capacity to generate K^b-restricted cytotoxic T lymphocyte (CTL) responses following viral infection, due (at least in part) to defects in endolysosomal trafficking of H-2K^b and antigen cross-presentation by dendritic cells (DCs). In this study, we investigated whether there are additional, post-presentation dependencies on Y320 for T-cell priming. We engineered both human- and mouse-derived antigen-presenting cells (APCs) to express either wild-type MHC-I or variants of …

Mechanisms Of Macrophage Metabolic Activation And Paracrine Wnt Signaling In The Pathogenesis Of Systemic Sclerosis, Emily Ann Morris

Dartmouth College Ph.D Dissertations

Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown etiology. We have previously shown that macrophages (MØs) play a critical role in its pathogenesis; however, the mechanisms driving MØ activation in SSc remain poorly understood. This dissertation investigates the molecular signaling pathways and biochemical mechanisms underlying profibrotic MØ activity in SSc.

First, I identify a novel MØ-specific effect of mycophenolate mofetil (MMF), the standard-of-care treatment for SSc. While MMF is a well characterized lymphostatic, my findings demonstrate that its active metabolite, mycophenolic acid (MPA), is also capable of directly inhibiting myeloid viability and profibrotic MØ activation by suppressing de …

The Role Of Gsk-3Α Inhibition In Attenuating Lps-Induced Inflammation In Raw 264.7 Cells, Oluwaseyi Oyewole

Theses and Dissertations

Glycogen synthase kinase-3 (GSK-3), an enzyme that modulates glucose metabolism, has been recognized as an essential target in major inflammatory diseases based on its great specificity in substrate recognition. GSK-3β has been connected to cancer, obesity, liver diseases, and neurological diseases. Nonetheless, the other GSK-3 isoform, GSK-3α, is much less studied. Previous studies from our laboratory showed that inhibiting GSK-3α potentially confers an anti-inflammatory response when tested on microglia. However, little has been documented regarding the exact mechanism by which GSK-3α exerts its effect. One of the potential mechanisms involving its anti-inflammatory effect could be partially attributed to activating the …

Genetic Analysis Of Methionine Restriction-Associated Mitochondrial Unfolded Protein Response Signaling., Josh D. Dodge

Biology Dissertations - Archive

The lifespan of an organism is dictated by various genetic and environmental factors. One such determinant is the health of mitochondria which are organelles that mediate various critical cell functions including a significant role in generating the vast supply of cellular energy. Indeed, the gradual decline of mitochondrial function is believed to be a hallmark and possible cause of aging. Paradoxically, mild mitochondrial dysfunction early in life extends lifespan in various model organisms. Cells use diverse approaches to promote mitochondrial homeostasis, including the transcriptional reprogramming of cells by mitochondrial unfolded protein response (UPRmt) to mitigate mitochondrial stress. Consistently, UPRmt activation …

The Role Of Sodium Butyrate As An Inflammatory Regulator And Its Effect On Long Noncoding Rnas In Neuroinflammation, Angel Covarrubias

Chemistry & Biochemistry Theses - Archive

Inflammation is a crucial homeostatic process that contributes to both the elimination of foreign invaders and tissue repair. Inflammation at sites of tissue injury or infection is initiated by the detection of a harmful stimulus, triggering vital inflammatory immune signaling pathways and a cascade of cytokines and inflammatory mediators. The dysregulation of this process, however, can result in inappropriate inflammatory responses manifesting in tissue damage and compromised cell function. Dysregulation of the inflammatory response is seen frequently in many human diseases such as Diabetes, Cancer, cardiovascular disease, and neurodegenerative diseases.

In the context of the Central Nervous system, inflammation is …

The Impact Of Maternal Environmental Exposures On The Immune Landscape Of The Maternal-Fetal Interface, Heather E. True

Theses and Dissertations--Pharmacy

Maternal environmental exposures and inflammation are known to impact fetal development in utero as well as increase the risk for chronic diseases later in life. Therefore, it is essential that we understand how the maternal environment alters placental structure and immune function.

Therefore, we isolated fetal (chorionic villous) tissues from the placentas of healthy pregnant participants (control) and those with inflammatory conditions, including SARS-COV-2 infection, pregravid obesity, and opioid use disorder. Isolated placental leukocytes were subjected to a series of assays to uncover the phenotypic, functional, and transcriptional (single-cell RNA-sequencing) landscape of placental immune cells. Additional placental tissues were subjected …

Toxin-Like Proteins In The Venom Of Drosophila Parasitoids, Lady V. Cardenas

Dissertations and Theses

The figitid parasitoid wasps of Drosophila are gaining importance in agriculture due to their ability to kill the resilient soft-fruit pest Drosophila suzukii. Their success and infection strategies vary, and the mechanisms underlying these differences are largely unknown. Some of their venom proteins have been shown to be important in suppressing host defense. Here, we report that Ganaspis brasiliensis, a parasitoid of D. suzukii survives well on Drosophila yakuba, a host species with a strong cellular immunity, and infected flies are unable to mount a strong immune response. To predict possible toxin-like proteins in Ganaspis venoms that might suppress cellular …

Explorations Of Dna-Single-Walled Carbon Nanotube Interactions To Develop Multiplexed Molecularly Specific Biosensors For Inflammation, Amelia K. Ryan

Dissertations and Theses

Inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-12 (IL-12) are central regulators of immune signaling and key biomarkers of disease, yet existing assays for their detection remain slow, invasive, and lack multiplexing ability. This dissertation advances the development of single-walled carbon nanotube (SWCNT) optical nanosensors capable of real-time, multiplexed, and molecularly specific cytokine detection through innovative use of single-stranded DNA (ssDNA) interfaces.

First, an IL-6-specific DNA aptamer was employed as both a dispersing agent and recognition probe for SWCNT fluorescence sensing. Sequence modifications, including anchor domains, truncations, and thermally induced refolding, were systematically tested to optimize sensitivity and selectivity. The …

Novel Infection By Mucor Hiemalis Kills Caenorhabditis Hosts Through Intestinal Perforation, Jay Ni

West Chester University Graduate Theses, Dissertations, and Final Projects

The nematode Caenorhabditis elegans has emerged as a popular model system to investigate cell biology and host-pathogen interactions. Presently, C. elegans is studied as a natural host of intracellular pathogens such as microsporidia and Orsay virus along with extracellular bacterial and fungal pathogens. The use of C. elegans as a model in host-pathogen research is limited by the number of naturally occurring pathogens to the organism. Through a sampling project to identify new pathogens of C. elegans, we identified the fungus Mucor hiemalis as a pathogen of Caenorhabditis species. We observed the fungus in the intestinal lumen of wild-caught …

Dickkopf1(Dkk1): A Novel Endogenous Ligand To Prime Nlrp3 Inflammasome Via Tlr4, Theingi Aung

Theses and Dissertations

Dickkopf1(DKK1) is a quintessential Wnt antagonist and immunomodulator in various inflammatory diseases. The underlying molecular mechanisms of DKK1-mediated immunomodulation remain elusive. Here, we identified TLR4 as a new receptor for DKK1 to activate NFκΒ pathway-mediated gene expression and pyroptosis via NLRP3 inflammasome in human and mouse macrophages.

DKK1 employed TLR4 to initiate NFκB signaling cascade via MyD88. MyD88-TAK1-NFκΒ pathway activation by DKK1 increased HIF1α, NFκB, and NLRP3 protein expression levels, leading to pyroptosis. Unlike LPS, DKK1 did not induce IRAK4 phosphorylation, while the interaction between MyD88 and IRAK4 was maintained for downstream signaling activation. DKK1 did not induce IRF3 phosphorylation …

Immune Pathway Modulation In Melanoma Using Chitosan Nanoparticle-Mediated Dsrna Delivery, Bethel C. Iwuji

Theses and Dissertations (Comprehensive)

Cancer is a group of diseases characterized by abnormal and uncontrolled cell division, which typically results in the formation of tumours. Even with advances in treatments, cancer remains one of the leading causes of death globally. Melanoma is an aggressive form of skin cancer which is highly malignant, develops in the pigment-producing cells of the skin, melanocytes, and in the late stages of the disease poses a significant challenge for therapeutic intervention due to its multidrug resistance. The innate immune system is the first line of defence against invading pathogens, including viruses, bacteria, and fungi, and can recognize and destroy …