Immunology and Infectious Disease Commons^™

Efficacy And Resistance Potential Of Jpc-3210 In Plasmodium Falciparum, Siobhan Marie Flaherty

USF Tampa Graduate Theses and Dissertations

Combating drug resistant malaria has been historically challenging, and remains so today. Recent reports from Southeast Asia show that Plasmodium falciparum is developing resistance to even our best defenses; artemisinin-based therapies. This development threatens to become a significant challenge in controlling malaria infections worldwide, making research into developing and characterizing new antimalarial drugs increasingly important. The purpose of this study was to characterize the resistance potential of novel antimalarial compound JPC-3210 in vitro using P. falciparum clones. JPC-3210 is a new long acting drug with potential to be used in combination with fast-acting drugs like artemisinins to cure drug resistant …

Altered Intraerythrocytic Development Phenotypes Of Artemisinin-Resistant Plasmodium Falciparum Confer A Fitness Advantage, Amanda Hott

USF Tampa Graduate Theses and Dissertations

Resistance to artemisinin combination therapies (ACTs) has emerged in southeast Asia threatening the most widely used treatment against antimalarial-resistant Plasmodium falciparum worldwide. Artemisinin resistance has been associated with a reduced rate of parasite clearance following treatment with an ACT and is attributed to increased survival of ring-stage parasites. Single nucleotide polymorphisms (SNPs) in kelch gene (K13) has been associated with delayed in vivo clearance half-life of artemisinin-resistant P. falciparum and is the only known molecular marker of resistance. The absence of reliable in vitro phenotypes for artemisinin resistance has limited our understanding of the resistance mechanism(s) and fitness costs, therefore …

Development Of Orally Bioavailable 4(1H)-Quinolones And 1,2,3,4-Tetrahydroacridin-9(10H)-Ones With Potent Anti-Malarial Activity, Jordany Richarlson Maignan

USF Tampa Graduate Theses and Dissertations

Although Malaria rates are on the decline due to the efforts of the World Health Organization and other organizations dedicated to the eradication of this disease, a relaxed attitude towards the development of new antimalarial entities would be flawed. Due to the emergence of resistance in the parasite, the almost 50% world-wide reduction in malarial death rates that have been produced over the past 15 years are threatening to be lost

New drugs are urgently needed and our approach focuses on the re-evaluation and optimization of the historic antimalarial ICI 56,780. Due to its causal prophylactic activity, along with its …

A Novel Role For Nf-Κb In Proximal T Cell Signaling, Crystina Bronk Watson

USF Tampa Graduate Theses and Dissertations

The interrogation of T cell signaling over the past fifty years has led to the discovery of amazingly intricate cascade networks and elaborate descriptions of individual proteins' domains and functions. A complex landscape has been rendered in which proteins relay messages from the extracellular ligation of the TCR by a cognate peptide loaded MHC via changes in sub-cellular location, phosphorylation, and binding affinities and partners to enact nuclear localization of three key transcription factors required for cellular effector function and proliferation: AP-1, NF-AT, and NF-κB. Dogma has favored activation of each of these transcription regulating elements to be a linear …

Implications Of Human Umbilical Cord Blood Cells: An Immunotherapeutic Strategy For Alzheimer's Disease, Donna Darlington

USF Tampa Graduate Theses and Dissertations

ABSTRACT

Alzheimer's disease (AD) is the most common progressive age related dementia and the fourth major cause of mortality in the elderly in the United States. AD is pathologically characterized by deposition of amyloid beta (Aβ) plaques in the brain parenchyma and neurofibrillary tangles (NFTs) within the neuronal soma. While pharmacological targets have been discovered, current strategies for the symptomatic or disease-modifying treatment of AD do not significantly slow or halt the underlying pathological progression of the disease. Consequently, more effective treatment is needed. One possibility for amelioration is using human umbilical cord blood cell (HUCBC) therapy. HUCBCs comprise a …

Pathogenic Mechanisms And Signaling Pathways In Plasmodium Falciparum, Jennifer L. Sedillo

USF Tampa Graduate Theses and Dissertations

Plasmodium falciparum is a human intracellular parasite that is the causative agent of a deadly form of malaria. This species alone is responsible for 200 million cases of malaria annually resulting in over 1 million deaths worldwide. The excessive mortality due to P. falciparum infection is due to its ability to cause severe pathogenesis through hyperparasitemia and cytoadherence defined as the ability of infected red blood cells to adhere to host vasculature. Cytoadherence is mediated through the export of parasite proteins to the surface of the infected red blood cell (RBC). Exported proteins have been identified but the pathway for …

Molecular Evidence For Vector Implication Of Onchocerca Lupi In Los Angeles County, Ca, Shanna June Bolcen

USF Tampa Graduate Theses and Dissertations

Onchocerca is a genus of roundworm most commonly associated with the human infection onchocerciasis, or river blindness. While typically a zoonotic infection of ungulate populations, canine cases (Onchocerca lupi) have been identified in the United States and Greece. In 2012, Los Angeles County, Veterinary Public Health Program identified 3 cases of Onchocerca spp. infections in domestic canines. Samples from the ensuing blackfly collections were sent to the Global Health Infectious Disease Research Unnasch Laboratory for parasite isolation and vector species identification. Species-specific primers were designed and optimized for O. lupi using a non- specific cytochrome oxidase (COI) gene target (689bp) …

Combined Metal-Enhanced Fluorescence-Surface Acoustic Wave (Mef-Saw) Biosensor, Samuel Morrill

USF Tampa Graduate Theses and Dissertations

Immunofluorescence assays are capable of both detecting the amount of a protein and the location of the protein within a cell or tissue section. Unfortunately, the traditional technique is not capable of detecting concentrations on the nanoscale. Also, the technique suffers from non-specific attachment, which can cause false-positives, as well as photobleaching when detecting lower concentrations is attempted. There is also a time constraint problem since the technique can take from many hours to a few days in some cases.

In this work, metal-enhanced fluorescence (MEF) is used to lower the detection limit and reduce photobleaching. Unfortunately, MEF also increases …

Achievement Of Transplantation Tolerance: Novel Approaches And Mechanistic Insights, Joseph Pidala

USF Tampa Graduate Theses and Dissertations

Current immune suppressive strategies fail to induce donor-recipient immune tolerance after allogeneic hematopoietic cell transplantation. Accordingly, patients suffer morbidity and mortality from graft vs. host disease (GVHD) and prolonged immune suppressive therapy. Biologic insight into transplantation tolerance is needed, and translation of such insight to novel clinical strategies may improve clinical outcomes. We report original investigation at seminal phases of this process including initial prophylactic immune suppression, onset of acute graft vs. host disease, and ultimate immune suppression discontinuation: In a controlled randomized clinical trial, we demonstrate that sirolimus-based immune suppression reduces risk for acute GVHD, ameliorates the severity of …

Immature Myeloid Cells Promote Tumor Formation Via Non-Suppressive Mechanism, Myrna Lillian Ortiz

USF Tampa Graduate Theses and Dissertations

ABSTRACT

Although there is ample evidence linking chronic inflammation with cancer, the cellular mechanisms involved in early events leading to tumor development remain unclear. Myeloid cells are an intricate part of inflammation. They consist of mature cells represented by macrophages, dendritic cells and granulocytes and a population of Immature Myeloid Cells (IMC), which in healthy individuals are cells in transition to mature cells. There is a substantial expansion of IMC in cancer and many other pathological conditions which is associated with pathologic activation of these cells. As a result, these cells acquire the ability to suppress immune responses and are …

Relationship Between Dysphoric Moods, Risk-Taking Behaviors, And Toxoplasma Gondii Antibody Titers In Female Veterans, Allyson Radford Duffy

USF Tampa Graduate Theses and Dissertations

The number of female veterans is increasing daily. Previous research conducted on veterans has focused primarily on males or with small samples of females. Depression and suicidality are becoming increasingly evident in returning veterans. Toxoplasma gondii is an intracellular parasite that is common in the Middle East and has been reported to cause changes in personality and behavior.

The purpose of the current study was to examine relationships between T. gondii antibody titer and socioeconomic variables, dysphoric moods, and risk-taking behaviors in a sample of 70 female veterans. Blood samples were collected and analyzed for T. gondii antibody titer and …

Understanding Amphibian Decline: The Role Of Pesticides And The Pathogenic Chytrid Fungus On Amphibians And Aquatic Communities, Taegan A. Mcmahon

USF Tampa Graduate Theses and Dissertations

Amphibians are the most threatened taxon on the planet. Declines have been associated with over-exploitation, habitat loss, pollution, and pathogenic diseases, but of these factors, pollution and disease have been relatively under-studied. Here, I investigated: 1) the impacts of commonly used pesticides on aquatic communities, 2) the effect of these pesticides on amphibian susceptibility to the pathogenic chytrid fungus, Batrachochytrium dendrobatidis (Bd), and 3) whether there are non-amphibian hosts of Bd and 4) how to best quantify the survival of Bd through ontogeny of the host.

In my first research chapter, I quantified the effects of environmentally relevant concentrations of …

Innate Immune Responses To Respiratory Syncytial Virus: Age-Associated Changes, Terianne Maiko Wong

USF Tampa Graduate Theses and Dissertations

Respiratory syncytial virus (RSV) infection causes ~64 million cases of respiratory disease and 200,000 deaths annually worldwide, yet there is no broadly effective prophylactic or treatment regimen. RSV can produce acute respiratory illness in patients of all ages but strikes the age extremes, infants and the elderly, with highest frequency presumably due to innate immune deficiencies. A higher morbidity and mortality has been reported for the elderly above 65 years of age, which has been attributed to immune senescence. Efforts to generate an effective vaccine have thus far been unsuccessful.

The innate immune system provides the first line of defense …

Histone Deacetylases As Targets For Melanoma Immunotherapy, David Michael Woods

USF Tampa Graduate Theses and Dissertations

Cancer represents the second leading cause of death in the United States. For many malignancies, currently available treatment options offer little long-lasting survival benefits to patients. However, recent studies have shown immunotherapeutic approaches to be an attractive strategy to cancer treatment. While many current immunotherapeutic strategies convey durable responses, such responses are only seen in a minority of patients. An increased understanding of the mechanisms governing tumor immunogenicity and the biology of immune responses is crucial to improving upon the efficacy of current and future cancer immunotherapies. Histone deacetylases (HDACs), enzymes classically associated with regulation of gene expression, have been …

The Inflammatory Response Initiated By The Spleen To Ischemic Stroke, Hilary Seifert

USF Tampa Graduate Theses and Dissertations

The peripheral immune system plays a role in delayed neural injury after stroke. This response originates from the spleen as splenectomy prior to middle cerebral artery occlusion (MCAO) in rats significantly reduces infarct volume in the brain. This research is based on the hypothesis that inhibiting the splenic response will reduce neurodegeneration after stroke. Studies in animals have implicated lymphocytes as the immune cell type that is detrimental following MCAO. Interferon gamma (IFNγ) has been identified as a pro-inflammatory cytokine that is also detrimental following stroke. IFNγ is important because it activates microglia and macrophages in a pro-inflammatory nature that …

Prenatal Stress, Depression, And Herpes Viral Titers, Pao-Chu Hsu

USF Tampa Graduate Theses and Dissertations

Recent studies suggest that some cases of prenatal depression may be associated with reactivation of latent infections of the herpesvirus family. The possible relationships among stress, prenatal depression, and herpes viral reactivation in pregnancy are understudied and the molecular pathways such as the neuroimmune biogenic amine pathway are unidentified. Chronic stress shifts the T helper-1 cell (Th1) cytokine profile to a Th2 profile, which favors virus induced pathogenesis and survival. Pregnancy is also associated with a similar Th2 dominance. In non-pregnant individuals, exposure to psychological or physical stress may be associated with latent herpes viral reactivation and could result in …

Phenotypic And Genotypic Analysis Of In Vitro Selected Miltefosine Resistant Leishmania Donovani, Brian A. Vesely

USF Tampa Graduate Theses and Dissertations

Abstract

Visceral leishmaniasis is a devastating neglected parasitic disease caused by infection with Leishmania donovani. It life cycle has two stages with promastigote (insect stage) and amastigote (animal stage) morphologies. Miltefosine is currently the only commercially available oral drug available to treat leishmaniasis and recent evidence suggests clinical resistance has emerged. Due to the importance of this drug and the scarcity of new drugs in the pipeline, work has been done on understanding the mechanism(s) of miltefosine, yet the mechanism of action for resistance is still not known.

In previous studies investigators generated miltefosine resistance on the insect vector stage …

Epigenetic Modifiers To Augment The Immunogenicity Of Chronic Lymphocytic Leukemia, Jason A. Dubovsky

USF Tampa Graduate Theses and Dissertations

Cancer cells employ a litany of immunosuppressive and immunevasive strategies to avoid detection and elimination by the various arms of the innate and adaptive immune system. Many hematologic and solid tumors progressively develop a specialized microenvironment which promotes tissue restructuring inflammation while masking the immune signature of the tumor cells themselves. Chronic lymphocytic leukemia, a malignancy of mature B lymphocytes must constantly balance on the precipice of immune recognition. A mature antigen presenting cell themselves, CLL clonal growth is dependent on the very interactions which, if effective, could potentially lead to their demise. To circumvent this, CLL clones set up …

Analysis Of Variable Effects On Presence Of Cryptosporidium Oocysts And Giardia Cysts In Effluent Water From Wastewater Treatment Utilities In Florida From 1998 To 2010, Katherine Jane Barkan

USF Tampa Graduate Theses and Dissertations

The concern of a Cryptosporidium or Giardia waterborne outbreak due to treated wastewater has had water treatment utilities using some of the highest water cleansing technologies available. Cryptosporidiosis and Giardiasis are severe diarrheal diseases which can lead to death, thus it is important that appropriate steps are taken to assure these parasites are not present in the effluent of treated wastewater. This study examined the results of 863 assays for Giardia and Cryptosporidium on the effluent of wastewater treatment facilities and found that county of collection, watershed of collection, and laboratory analyzing the sample have the most significant impact on …

Enhancing The Immune Response Through Ikkbeta-Induced Activation Of Nf-Kappab, Emily Hopewell

USF Tampa Graduate Theses and Dissertations

Nuclear factor-κB (NF-κB) is one of the main regulators of inflammatory and immune responses. It is a family of transcription factors composed of five members: RelA, RelB, cRel, NF-κB1 (p105/p50), and NF-κB2 (p100/p52). Homo- and hetero-dimers of family members are inhibited by inhibitor of &klappaB (IκB) family members and activated by IκB kinase (IKK) family members. The IKK family is comprised of IKKα, IKKΒ, and IKKγ. The focus of my dissertation delves into the role of NF-κB activation by IKKΒ in both an immunotherapy setting and its role in T cell mediated anti-tumor immune responses.

A central focus of immunotherapy …

Regulation Of Natural Killer Cells: Ship-1, 2b4, And Immunomodulation By Lenalidomide, Nicole Renee Fortenbery

USF Tampa Graduate Theses and Dissertations

Natural Killer cells (NK) are critical components of the innate immune system. Often referred to by their morphology, these large granular lymphocytes (LGLs) are bone marrow-derived lymphocytes and can be found throughout the body. NK cells reside in the liver, lymph nodes, spleen, thymus, and mucosal-associated lymphoid tissues (MALT). Importantly, NK cells also circulate throughout the blood where they function as surveyors of the body and are armed to eliminate malignant, infected, damaged, or foreign cells.

NK cells function by a dual receptor system. That is, NK receptors are broadly categorized as inhibitory or activating. It is a fine balance, …

The Role Of Tumor Suppressors, Ship And Rb, In Immune Suppressive Cells, Michelle Marie Collazo Ruiz

USF Tampa Graduate Theses and Dissertations

Regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC) have been extensively studied in the past 30-40 years. Their potent suppressive capacity shown in several pathological and clinical settings, such as cancer and transplantation, has made it evident that better understanding their development and function is critical.

Specifically, Tregs play a pivotal role in preventing autoimmunity, graft-versus-host disease (GvHD), and organ graft rejection. We previously demonstrated that germline or induced SH2 domain-containing inositol 5-phosphatase (SHIP) deficiency in the host abrogates GvHD. Here we show that SHIP-deficiency promotes an increase of FoxP3+ cells in both the CD4+CD25+ and the CD4+CD25- T …

Therapeutic Peptide-Based Vaccination Strategies Against Hpv-Induced Cancers, Kelly Barrios Marrugo

USF Tampa Graduate Theses and Dissertations

There is an urgent need for the development of an effective therapeutic vaccine against cancer caused by human papilloma virus (HPV). We focused on HPV-induced malignancies because of their high worldwide prevalence (e.g., cervical carcinoma and head & neck cancer). A successful therapeutic vaccine could prevent the 250 000 deaths/year worldwide and the 2.25 billion dollars that

are expended in related care in the US.

We used an HPV-induced mouse cancer model to test vaccines

composed of a CD8 T cell peptide epitope administered with potent adjuvants designed to generate vast numbers of high avidity cytotoxic T lymphocytes specific for …

Behavioral And Immunological Phenotypes Of Transgenic Mice Overexpressing Human Secreted Amyloid Precursor Protein Alpha: Implications For Autism, Antoinette R. Bailey

USF Tampa Graduate Theses and Dissertations

Autism is a heterogeneous neurodevelopmental disorder that is characterized by impaired social interaction and communication as well as restricted and repetitive behaviors and focused interests. In addition to the cardinal behavioral characteristics observed for diagnosis, autistic individuals exhibit a number of comorbid conditions as well as a variety of aberrant immunological features. Recent studies report that plasma from autistic children contained elevated levels of secreted amyloid precursor protein alpha (sAPP-á), the á-secretase cleavage product of the amyloid precursor protein (APP) which is ubiquitously expressed in the brain, spleen, thymus and other organs. Interestingly, the sAPP-á fragment functions as a neurotrophic …

Lenalidomide Targets The T-Cell Co-Stimulatory Pathway To Mediate Immune Modulation, Jessica Marie Mcdaniel

USF Tampa Graduate Theses and Dissertations

T-cells are lymphocytes that make up part of the adaptive arm of the immune system, and are essential for efficient protection from and eradication of viruses and pathogens. T-cells not only play an important role in protection from external agents, but also regulate and prevent activation towards self-peptides and detect and remove erratically growing cells. Alterations in T-cell activation and suppression contribute to auto-immunity, immunocompromised disorders, and cancer progression.

The immune system, and T-cells in particular, provides daily surveillance, recognition and destruction of aberrant cells. Although the immune system is proficient at suppressing malignant progression, tumor cells acquire various methods …

Cloning Of The Gene, Purification As Recombinant Protein And Functional Characterization Of Leishmania Mexicana Cytochrome B5 Reductase, Ala Azhari

USF Tampa Graduate Theses and Dissertations

Leishmania are protozoan parasites that are transmitted by a sand fly vector. These parasites affect not only humans but also wild animals including domestic dogs and rodents, which form an additional challenge and public health problem to control the disease. Leishmaniasis is an important disease with worldwide distribution, including Saudi Arabia, the Middle East, and other tropical and subtropical areas around the world. Due to the expansion of irrigation and agricultural activities, more exposure to sand fly occurs, which leads to the expansion of leishmaniasis infections as newly emerging disease.

Emerging drug resistance in leishmaniasis is an additional problem, contributed …

Characterization Of The Serologic Responses To Plasmodium Vivax Dbpii Variants Among Inhabitants Of Pursat Province, Cambodia, Samantha Jones Barnes

USF Tampa Graduate Theses and Dissertations

The Plasmodium vivax Duffy Binding Protein (DBP) is the ligand in the major pathway for P. vivax invasion of human reticulocytes, making it an appealing vaccine candidate. Region II of DBP (DBP-RII) is the minimal portion of the ligand that mediates recognition of the Duffy Antigen Receptor for Chemokines (DARC receptor) on the reticulocyte surface and constitutes the primary vaccine target. Analysis of natural variation in the coding sequences of DBP-RII revealed signature evidence for selective pressure driving variation in the residues of the putative receptor-binding site. We hypothesize that anti-DBP immunity in P. vivax infections is strain-specific and hindered …

The Role Of Hiv-1 Proteins In Alzheimer's Disease Pathology, Brian Nelson Giunta

USF Tampa Graduate Theses and Dissertations

Prevalence of HIV-associated cognitive impairment is rising, the worst form of which is HIV-associated dementia (HAD). The disease is fuiled by a chronic innate type pro-inflammatory response in the brain which is highly dependent upon the activation of microglia. We first created an in vitro model of HAD composed of cultured microglial cells synergistically activated by the addition of IFN-gamma and the HIV-1 coat glycoprotein, gp120. This activation, as measured by TNF-alpha and NO release, is synergistically attenuated through the alpha7nAChR and p44/42 MAPK system by pretreatment with nicotine, and the cholinesterase inhibitor, galantamine. As these medications have been FDA …

Generation And Application Of Antigen-Specific Induced Regulatory T Cells In Allogeneic Bone Marrow Transplantation, Kenrick Semple

USF Tampa Graduate Theses and Dissertations

CD28 co-stimulation is required for the generation of naturally occurring regulatory T cells (nTregs) in the thymus through Lck-signaling. However, high level of CD28 suppresses the generation of induced Tregs (iTregs) from naïve CD4 T cells, although underlying mechanism(s) has not been defined. Here we investigated the role of CD28-mediated signaling pathways in the suppression of Treg generation. We used a series of transgenic (Tg) mice on CD28-deficient background that bears WT CD28 or mutated CD28 in its cytosolic tail incapable of binding to Lck, PI3K or Itk. Regardless of exogenous IL-2, strong CD28 costimulation suppressed iTreg generation through Lck …

Novel Roles For The Transcriptional Repressor Prdm1 In Human Natural Killer Cells And Identification Of An Inhibitor Of Its Interacting Methyltransferase G9a, Matthew Adams Smith

USF Tampa Graduate Theses and Dissertations

The studies presented within this dissertation provide the first description of PRDM1 (also known as Blimp-1 or PRDI-BF1) function in natural killer cells. NK cells are major effectors of the innate immune response via antigen-independent cytotoxicity and link to the adaptive immune response through cytokine release. Molecular mechanisms mediating NK activation are relatively well-studied; however, much less is known about the mechanisms that restrain activation.

In the first study, the transcriptional repressor PRDM1 is shown to be a critical negative regulator of NK function. Microarray analysis was used to characterize transcriptional changes associated with cytokine-mediated activation. PRDM1 is expressed at …