Life Sciences Commons^™

Evaluation Of The Humoral Immune Responses To Plasmodium Vivax Circumsporozoite Protein (Csp)-Based Pre-Erythrocytic Vaccine Candidates, Jack Esquenazi

USF Tampa Graduate Theses and Dissertations

Malaria, caused by the apicomplexan Plasmodium spp. , is a major public health issue that impacts over one-third of the world’s population ,with Plasmodium vivax accounting for over 130 million clinical cases annually. The circumsporozoite protein (CSP) is the most abundant molecule on the surface of Plasmodium sporozoites and is considered a leading pre-erythrocytic stage vaccine candidate. CSP is essential for sporozoite maturation, migration, and invasion. Anti-CSP antibodies interrupt sporozoite migration and infection of hepatocytes thus reducing liver-stage burden. P. vivax CSP is composed of three subdomains: a highly polymorphic immunodominant central repeat region (CRR), conserved N-terminal ,and C-terminal subdomains. …

Genomics And Transcriptomics Approaches To Understanding Drug Resistance Mechanisms In The Malaria Parasite Plasmodium Falciparum, Justin Allan Gibbons

USF Tampa Graduate Theses and Dissertations

The malaria parasite Plasmodium falciparum is responsible for about 500,000 deaths a year and is evolving resistance to the front-line treatment of artemisinin-based combination therapy. Resistance is currently confined to South East Asia, however millions of lives will be at risk if resistance spreads to Africa. Understanding the mechanism of resistance to artemisinins would aid containment strategies to prevent the spread of artemisinin resistance. There is also an urgent need to accelerate drug discovery since drug resistance has already been documented to all existing antimalarials. Here, I report on our efforts to understand the function of the gene k13, the …

Synthesis, In Vitro Characterization And Applications Of Novel 8-Aminoquinoline Fluorescent Probes, Adonis Mcqueen

USF Tampa Graduate Theses and Dissertations

Malaria is a parasitic disease that is caused by the plasmodium parasite. Plasmodium infection has affected man for thousands of years. With advances in drug discovery over the past century, malaria has evolved to possess resistance to most mainline therapeutics. This war of drug discovery vs plasmodium evolution continues to be fought to this very day, with attempts to eradicate malaria worldwide. Frontline treatments such as chloroquine, artemisinin, and atovaquone/proguanil have all seen parasitic resistance in strains of P. vivax as well as P. falciparum. While plasmodium possesses resistance to most classes of anti-malarials, the 8-aminoquinoline (8-AQ) class has …

Analysis Of Antibody-Induced Plasmodium Falciparum Sporozoites Through Scanning Electron Microscopy, Sagorika Bera

USF Tampa Graduate Theses and Dissertations

Malaria is a devastating disease that continues to affect millions of people worldwide every year. Specifically, Plasmodium falciparum is the most common human malaria parasite, particularly in sub-Saharan Africa. P. falciparum causes the most malignant and debilitating symptoms with the highest mortality and complication rates. Even with the worldwide efforts of many researchers and organizations, the road to discovering a vaccine has been difficult and challenging. Due do to the improvements in in vitro liver stage assays as well as rodent models of mammalian malaria, pre-erythrocytic stages of malaria have become a more accessible target for experimental studies. These vaccine …

The Effects Of Phytohormones And Isoprenoids In Dihydroartemisinin-Induced Dormancy In The Erythrocytic Stages Of Plasmodium Falciparum, Marvin Duvalsaint Duvalsaint

USF Tampa Graduate Theses and Dissertations

Our ability to control malaria has been challenged by increasing antimalarial resistance. Plasmodium falciparum undergoes dormancy in the blood stages which is hypothesized to be a means by which they are able to survive under drug pressure. This helps select for resistant parasites which grow following removal of drug. The mechanisms behind dormancy and the subsequent recrudescence are not fully understood but translating knowledge from related organisms which undergo a similar phenomenon might shed some light. Higher plants utilize dormancy during the early development stages to survive under unfavorable conditions, increasing fitness of the seedling and ensuring viability when this …

Mitochondrial Heteroplasmy Contributes To The Dynamic Atovaquone Resistance Response In Plasmodium Falciparum, Sasha Victoria Siegel

USF Tampa Graduate Theses and Dissertations

Of the considerable challenges researchers face in the control and elimination of malaria, the development of antimalarial drug resistance in parasite populations remains a significant hurdle to progress worldwide. Atovaquone is used in combination with proguanil (Malarone) as an antimalarial treatment in uncomplicated malaria, but is rendered ineffective by the rapid development of atovaquone resistance during treatment. Previous studies have established that de novo mutant parasites confer resistance to atovaquone with a substitution in amino acid 268 in the cytochrome b gene encoded by the parasite mitochondrial genome, yet much is still unknown about how this resistance develops, and whether …

Antimalarial Exoerythrocytic Stage Drug Discovery And Resistance Studies, Lynn Dong Blake

USF Tampa Graduate Theses and Dissertations

Malaria is a devastating global health issue that affects approximately 200 million people yearly and over half a million deaths are caused by this parasitic protozoan disease. Most commercially available drugs only target the blood stage form of the parasite, but the only way to ensure proper elimination is to treat the exoerythrocytic stages of the parasite development cycle. There is a demand for the discovery of new liver stage antimalarial compounds as there are only two current FDA approved drugs for the treatment of liver stage parasites, one of which fails to eliminate dormant forms and the other inducing …

Drivers Of Immune Cost And Implications For Host Protection From Parasites, Amber Jasmine Brace

USF Tampa Graduate Theses and Dissertations

Among species, populations, and individuals, there exists a tremendous amount of variation in how hosts respond to, and are thus protected from parasites. Such variation inevitably affects host-parasite dynamics and ultimately how parasites will move through and evolve in communities. A likely factor in the diversity of immune responses seen in nature are the costs associated with activation of the immune system upon exposure to parasites. Costs can manifest in many ways, including changes in resource usage or metabolism, self-damage from inflammatory reactions, lost opportunities (e.g., foraging reproduction), and often as tradeoffs with other physiological processes. However, we do not …

A Forward Genetic Screen Identifies Factors Associated With Fever Pathogenesis In Plasmodium Falciparum, Phaedra J. Thomas

USF Tampa Graduate Theses and Dissertations

Infectious diseases that spread from person-to-person and continent-to-continent are a cause for concern for any health entity. One such disease is malaria, a mosquito-borne infection instigated by the protozoan parasite, Plasmodium falciparum. Hundreds of millions of people are affected annually and it is responsible for nearly 1 million deaths. It is the most fatal species causing malaria and proliferates in human red blood cells with a life cycle occurring every 48 hours. At this time, the parasite’s late stage form or schizont bursts from the erythrocyte releasing immune-inducing particles and infective forms (merozoites) into the bloodstream. The merozoites go …

Mmv Malaria Box Activity Screening In Dormant Plasmodium Falciparum Phenotypes, Sandra Galusic

USF Tampa Graduate Theses and Dissertations

The causative agent of malignant tertian malaria, Plasmodium falciparum undergoes an arrested growth phenotype of its erythrocytic stage when under drug-stress. Recent artemisinin treatment failures seem to be indicative of such induction followed by recrudescence rather than actual therapeutic failure. Likewise, P. vivax hypnozoites are the prototypic dormants and the latent infections for which they are responsible prove most difficult to treat. Dihydroartemisinin, an artemisinin-derivative, can be used to exploit this mechanism by inducing a dormant state in ring-stage P. falciparum parasites and in turn, their recovery may be used as a screening period for compounds that inhibit or foster …

Immunological Characterization Of Duffy Binding Protein Of Plasmodium Vivax, Miriam Thankam George

USF Tampa Graduate Theses and Dissertations

Plasmodium vivax Duffy binding protein (DBP) is an essential ligand for reticulocyte invasion making it a premier asexual blood stage vaccine candidate. However, strain-specific immunity due to DBPII allelic variation may complicate vaccine efficacy, suggesting that an effective DBPII vaccine needs to target immune responses to conserved epitopes that are potential targets of strain-transcending neutralizing immunity. Anti DBPII monoclonal antibodies, which were previously characterized by COS7 cell binding assay as inhibitory and non-inhibitory to DBPII-erythrocyte binding, were mapped to DBPII gene fragment libraries using phage display. Inhibitory mAb 3C9 binds to a conserved conformation-dependent epitope in subdomain 3 while non-inhibitory …

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 …

Host-Parasite Interactions In An Invasive Songbird, Courtney A.C. Coon

USF Tampa Graduate Theses and Dissertations

Introduced species are the greatest threat to biodiversity after habitat loss. Understanding the processes that permit organisms to become successful invaders may provide opportunities to prevent or limit their dispersal and establishment and thereby alleviate some of their harmful effects. The goal of my dissertation research has been to investigate whether invasive species have distinctive interactions with parasites, and some of the mechanisms that may underlie that variation. I used one of the world's most successful vertebrate invaders as a case study: the house sparrow (Passer domesticus; Introduction).

Previous research in the house sparrow suggested that loss of …

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 …

Design Of Novel Inhibitors For Infectious Diseases Using Structure-Based Drug Design: Virtual Screening, Homology Modeling And Molecular Dynamics, Divya Ramamoorthy

USF Tampa Graduate Theses and Dissertations

The main aim of the study in this thesis was to use structure-based protocols to design new drugs for enzymes, DXS and DXR in the non mevalonate pathway. Another aim of this study was to identify the dimer interface in E.coli FabH as an allosteric binding site for designing new class of anti-infective drugs. We have attempted to identify potential inhibitors for DXS by docking the NCI Diversity set compounds, compound libraries available from GSK-MMV and St. Jude's Children's research center. FabH dimer interface has been identified as a potential target using SiteMap, Alanine mutagenesis and docking studies.

The first …