Immunology and Infectious Disease Commons^™

Fundamental Differences In The B Cell Locus, V(D)J Repertoire, And Marburg Virus Epitope Recognition Of The Egyptian Rousette Bat That May Allow For Asymptomatic Presentation, Maggie Linn Bartlett

Theses & Dissertations

Marburg virus (MARV) causes a hemorrhagic fever in humans but is asymptomatic in a known reservoir, the Egyptian rousette bat (Rousettus aegyptiacus, ERB). Understanding the mechanisms that drive these different outcomes could potentially advance the development of therapeutics. The immunoglobulin (Ig) response to MARV infection in ERBs in known to serve a roll in protection. The Ig germline encodes Variable (VH), Diversity (DH), and Joining (JH) genes that then recombine (V(D)J) to make up the binding site of an Ig. Understanding the gene composition of the Ig germline is critical to defining the potential B cell repertoire. We …

Flavonoid And Cannabidiol Neural Glyoxalase Pathway Enhancement Against Aging And Alzheimer’S Disease, Joel R. Frandsen

Theses & Dissertations

Alzheimer’s Disease is a neurodegenerative condition featuring neural cell death and a decline in cognitive capacity caused by elevated inflammation and production of reactive oxygen species. The glyoxalase pathway is an endogenous antioxidant system that neutralizes reactive methylglyoxal through sequential reactions. Dysfunction of the glyoxalase pathway contributes to oxidative stress and the accumulation of inflammatory metabolic byproducts. Plant-produced compounds with antioxidant activity can enhance endogenous antioxidant pathways and protect cells from elevated ROS production. We hypothesize that flavonoids and limited Cannabis Sativa-produced cannabidiol can enhance glyoxalase pathway function through regulation of antioxidant and pro-apoptotic signaling pathways to prevent methylglyoxal-mediated …

Theranostics For Antiretroviral Biodistribution And Pharmacokinetics, Brendan M. Ottemann

Theses & Dissertations

RATIONALE: Our laboratories birthed the field of human immunodeficiency virus (HIV) theranostics. The new field allows simultaneous detection (diagnostics) and treatment (therapeutic) for the identification, treatment and inevitable elimination of virus in cell and tissue compartments. By employing theranostics, antiretroviral drugs (ARVs) can be tracked in lymph nodes, gut, spleen and liver. Cellular viral reservoirs including CD4+ T cell populations and mononuclear phagocytes (MP; monocytes, macrophages, microglia and dendritic cells) along with subcellular endosomal structures can now be targeted for drug delivery bringing therapeutics to areas where virus replicates. The overarching idea rests in improving precision targeted ARV delivery. …

Role Of Astrocyte-Derived Extracellular Vesicles In Neuroinflammation Mediated By Drug Abuse, Ke Liao

Theses & Dissertations

Neuronal damage and neuroinflammation is a hallmark feature of HIV-associated neurological disorders (HANDs). Opioids abuse accelerates the incidence and progression of HAND; however, the mechanisms underlying the potentiation of neuropathogenesis by these drugs remain elusive. Extracellular vesicles (EVs) are essential conduits in HIV and drug abuse-mediated synaptodendritic injury and neuroinflammation. Findings from our group have demonstrated that astrocyte-derived EV (ADEV)-miRNA-29b mediates HIV Tat and morphine-induced neuronal injury, thus underscoring the importance of such interactions in NeuroHIV.

Besides, HIV Tat and morphine-mediated synaptodendritic injury via ADEVs, we are also interested in whether ADEVs contributes to neuroinflammation. Microglia are critical players in …

Il-17-Cxcr2 Axis Promotes Breast Cancer Metastasis And Therapy Resistance, Lingyun Wu

Theses & Dissertations

Cancer-related fatalities rank as the second leading cause of death in all ages and both genders in the United States. Moreover, breast cancer-related mortality rank as the second leading cause of death in females in the United States in 2019. The main concerns regarding breast cancer management include chemotherapy resistance and metastasis. Thus, the advanced understanding of cancer progression is required to develop improved therapeutic methods for breast cancer patients.

Recent studies demonstrate that neutrophils, as the most abundant leukocytes, play an essential role in breast progression. However, the mechanisms regarding neutrophils recruitment to the tumor sites, and the precise …

Development Of A Long-Acting Nanoformulation Of Dolutegravir For Prevention And Treatment Of Hiv-1 Infection, Brady Sillman

Theses & Dissertations

Dolutegravir (DTG) is a potent human immunodeficiency virus type 1 (HIV-1) integrase strand-transfer inhibitor (INSTI) with a high barrier to viral drug resistance. However, opportunities to improve its profile abound. These include extending the drug’s apparent half-life, increasing penetrance to “putative” viral reservoirs, and reducing inherent toxicities. These highlight, in part, the need for long-acting, slow effective release antiretroviral therapy (LASER ART) delivery schemes. A long-acting (LA) DTG was made by synthesizing a hydrophobic and lipophilic prodrug encased with poloxamer (P407) surfactant. This modified DTG (MDTG) reduced systemic metabolism and polarity, increased lipophilicity and membrane permeability, improved encapsulation, and formed …

The Cxcr2-Dependent Role Of Cancer-Associated Fibroblasts In Pancreatic Ductal Adenocarcinoma, Mohammad Awaji

Theses & Dissertations

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, the fourth leading cause of cancer-related deaths in the USA with over 40,000 deaths per year. Unlike other major cancer types, the progress in dealing with PDAC is plodding, attributed mainly to the asymptomatic nature of the disease, the late diagnosis and the ineffectiveness of current therapies. A better understanding of the biology of the disease could permit the discovery of novel diagnostic and therapeutic tools. With that in mind, we present this dissertation that investigates the tumor-stromal interaction underlined by genetic alterations and inflammation. PDAC develop as …

Elucidation Of The Functions Of Neuropilin 2 In Osteoclasts In Promoting Prostate Cancer Bone Metastasis., Navatha S. Polavaram

Theses & Dissertations

Bone metastasis is one of the major clinical concerns that causes skeletal related malignancies and increased mortality. Bone is one of the preferred sites for metastatic prostate cancer. The metastatic prostate cancer cells interact with bone cells (osteoblasts and osteoclasts) resulting in an imbalance in the bone homeostasis leading to increased activation of osteoblasts over osteoclasts. Our preliminary data indicated a non-tyrosine kinase receptor Neuropilin 2 (NRP2) is expressed in osteoclasts induced by metastatic prostate cancer cells and acts as a negative regulator of osteoclast differentiation and function. We hypothesize that prostate cancer -induced NRP2 expression in osteoclasts is necessary …

Defining The Role Of Neuropilin-2 In Macrophages: Implications In Tumor Associated Macrophages In Pancreatic Cancer, Sohini Roy

Theses & Dissertations

Macrophages are extremely heterogeneous and highly plastic hematopoietic cells that reside in all tissues and act as a bridge between the innate and adaptive arms of the immune responses. Besides, they undertake a wide array of housekeeping functions like, clearance of cellular debris that arise due to regular turnover in tissues, iron homeostasis, immune surveillance as well as tissue repair processes post inflammation. They are also causally associated with several clinical conditions, including cancer where the infiltration of macrophages contribute to disease progression, metastasis and therapy resistance, and thereby poor clinical outcome.

Neuropilins (NRPs) are non-tyrosine kinase cell surface glycoproteins …

Effects Of Gm-Csf On Dendritic Cells And Regulatory T Cells In Parkinson’S Disease Patients And Models Of Parkinson’S Disease, Charles Schutt

Theses & Dissertations

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. Pathologically, loss of nigrostriatal neurons and dopamine released by these neurons are responsible for PD motor symptoms. During PD, activation of resident microglia and infiltrating lymphocytes leads to progressive neuroinflammation and reduction in the number and function of regulatory immune cells. Neuroinflammation contributes to progressive neurodegeneration and declining motor function. Reducing neuroinflammation is the target for novel PD therapeutics. Our goal is to increase the number and function of regulatory T cells (Tregs) in PD patients to decrease neuroinflammation and reduce PD symptoms. One potential therapy is granulocyte-macrophage colony stimulating …

Redirection Of The Immune Response To Staphylococcus Aureus Biofilm Infection, Anna G. Staudacher

Theses & Dissertations

Staphylococcus aureus (S. aureus) is a leading cause of community- and healthcare-associated infections and has a propensity to form biofilms. Biofilm infections are recalcitrant to host immune-mediated clearance as well as antibiotics, making them exceptionally difficult to eradicate. The biofilm environment has been shown to skew the host immune response towards an anti-inflammatory phenotype, characterized by alternatively activated macrophages, recruitment of myeloid-derived suppressor cells (MDSCs), and minimal neutrophil and T cell infiltrates. Our laboratory has attempted to redirect the host immune response towards one that would favor bacterial clearance by employing strategies to augment pro-inflammatory mechanisms. One such …

Development Of C5ar-Targeted Nanoparticles For Delivery Of Vaccines, Shailendra Bharadwaj Tallapaka Venkata Sesha

Theses & Dissertations

Since the early attempts of Benjamin Jesty at inducing immunity against smallpox and the pioneering work of Edward Jenner, vaccination has been, and continues to remain, the principal method of protection from diseases. However, most of the successful vaccines have been against pathogens that do not have major mechanisms to evade the immune system. So far, many life-threatening diseases like hepatitis C, HIV infection, malaria etc., have been resistant to existing vaccination strategies. Thus, there is an urgent need to develop new vaccination strategies that can generate long-lived protective immunity against such pathogens.

The purpose of this thesis is to …

Requirement Of Ehd Family Of Endocytic Recycling Regulators For T-Cell Functions, Fany M. Iseka

Theses & Dissertations

T-cells use the endocytic pathway for key cell biological functions, including receptor turn-over and maintenance of the immunological synapse. Some of the established players include the Rab GTPases, SNARE complex proteins, and others which in non-T-cell systems function together with Eps15 Homology Domain-containing (EHD) proteins. To date, the role of the EHD protein family in T-cell function remains unexplored. We generated conditional EHD1/3/4 knockout mice using CD4-Cre and crossed these with mice bearing a myelin oligodendrocyte glycoprotein (MOG)-specific TCR transgene. We found that CD4⁺ T-cells from these mice exhibited a reduced antigen-driven cell proliferation and IL-2 secretion in vitro. …

Staphylococcus Aureus Biofilms Interfere With Macrophage Antimicrobial Responses Through Differential Gene Regulation, Toxin Production, And Purine Metabolism, Tyler D. Scherr

Theses & Dissertations

Staphylococcus aureus (S. aureus) is an opportunistic pathogen that is a leading cause of both nosocomial and community-associated infections. Armed with a myriad of virulence factors and the propensity to form a biofilm on native tissues and implanted medical devices alike, S. aureus infections represent a very real public health threat, the treatment of which results in an excessive economic burden. S. aureus biofilm infections are notoriously recalcitrant to antibiotic therapy and adept at evading and neutralizing the host immune antimicrobial response. Previous studies from our laboratory have shown that S. aureus biofilms are able to cause persistent …

Role Of Cbl-Family Ubiquitin Ligases As Critical Negative Regulators Of T Cell Activation And Functions, Benjamin Goetz

Theses & Dissertations

Adaptive T cell immunity is essential for defense against foreign antigens and immune surveillance against cancer. Tight regulation of T cell activation is required to avoid autoimmunity to self-antigens or protracted inflammation after foreign antigens are cleared. Incomplete or inappropriate stimulation leads to an active shutdown of T cell activation called anergy. The Casitas B-lineage Lymphoma (CBL)-family of ubiquitin ligases (E3s) are essential negative regulators of T cell activation that impinge on thymic selection as well as anergy induction programs. Single gene studies show that CBL is critical during T cell development while CBL-B plays an essential role in peripheral …

Defining The Role Of Interferon Regulatory Factor 4 In Chronic Lymphocytic Leukemia., Vipul Shukla

Theses & Dissertations

Chronic Lymphocytic Leukemia (CLL) represents the most common adult leukemia in the Western hemisphere. Despite considerable progress in our current understanding of CLL, this disease remains incurable and the molecular events underlying the complex pathogenesis of CLL are not fully elucidated. Interferon Regulatory Factor 4 (IRF4) belongs to the IRF superfamily of transcription factors that has been shown to play critical roles at multiple stages of B cell development. Interestingly, a Genome Wide Association Study identified Single Nucleotide Polymorphism (SNP) mediated IRF4 down regulation, as a major predisposing genetic event during the development of CLL. However, whether low levels of …

Compensatory Mechanisms And T Cell Migration In Mouse Models Of Dopaminergic Loss, Kristi M. Anderson

Theses & Dissertations

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and second most common neurodegenerative disorder. PD is characterized by the selective loss of dopaminergic neurons and dopamine neurotransmitter within the substantia nigra and termini in the striatum. Progressive loss of dopaminergic neurons occurs over many years in PD, and by the time movement disorder symptoms manifest, up to 50-70% of dopaminergic neurons have been lost. Several aspects of PD pathology have been described in detail, but a better understanding of PD progression is needed to develop more efficient treatments.

Motor symptoms associated with PD do not manifest until significant …

Myeloid-Derived Suppressor Cells Contribute To The Subversion Of Innate Immunity During Staphylococcus Aureus Biofilm Infection, Cortney E. Heim

Theses & Dissertations

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature monocytes and granulocytes that are potent inhibitors of T cell activation. A role for MDSCs in bacterial infections has only recently emerged, and our laboratory was the first to demonstrate a functional role for MDSCs during Staphylococcus aureus (S. aureus) biofilm infection. Biofilm infections often lead to significant morbidity due to their recalcitrance to antibiotics and ability to subvert immune-mediated clearance by skewing the immune response toward an anti-inflammatory, pro-fibrotic phenotype. Therefore, we examined whether MDSCs could play a role in this process. CD11b⁺Gr-1⁺ MDSCs …

Role Of Macrophages In Muscle Transfection With Pdna/Pluronic Formulation, Vivek Mahajan

Theses & Dissertations

Non-ionic amphiphilic block copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), Pluronics, arranged in a tri-block structure PEO-PPO-PEO, have raised a considerable interest in skeletal muscle Gene Therapy. Previous studies have demonstrated that co-administration of Pluronics with naked plasmid DNA (pDNA) by direct i.m. injection enhanced transgene expression not only in muscle but also in distal lymphoid organs (spleen and lymph nodes) and this response was strain-dependent; not observed in athymic (BALB/c nu/nu) mouse; suggesting a role of immune cells in gene transfer to skeletal muscles. Therefore, we first evaluated the role of inflammation and inflammatory cells, on muscle …