Immunology and Infectious Disease Commons^™

Withaferin A And Immune Checkpoint Blocker Therapy For The Treatment Of Non-Small Cell Lung Cancer, Roukiah Khalil

USF Tampa Graduate Theses and Dissertations

Lung cancer is the first cause of cancer-related deaths in both men and women with an overall five-year survival rate of 28%. Although immune checkpoint blockers (ICBs) are currently FDA-approved for the treatment of non-small cell lung cancer (NSCLC), only 17-20% of patients achieve durable responses by the induction of immunologic memory. The lack of response in most patients can be attributed to the tumor-intrinsic or tumor-extrinsic immune resistance mechanisms. A biomarker of importance is the Programmed Death Ligand-1 (PD-L1), as higher PD-L1 expression is usually associated with a better response to ICBs. Although studies have attempted to combine ICBs …

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. …

Histone Deacetylase 8 Is A Novel Therapeutic Target For Mantle Cell Lymphoma And Preserves Natural Killer Cell Cytotoxic Function, January M. Watters

USF Tampa Graduate Theses and Dissertations

This study demonstrates for the first time that HDAC8 function is critical for MCL survival, and abrogating its activity in human primary NK cells does not interfere with NK IgG antibody directed ADCC therapies ex vivo. Human NK cells, isolated from healthy donors, are highly resistant to HDAC8 inhibitor treatment with PCI-34051. Even at the highest concentration, 20uM, no toxicity was observed. Conversely, MCL cell lines representative of the aggressive MCL subtype, classical MCL, were especially sensitive to PCI-34051, an HDAC8 selective inhibitor, treatment. Blocking HDAC8 activity and/or abrogating expression through shRNA silencing induced significant DNA damage, hyperacetylation of SMC3, …

Determining The Role Of Dendritic Cells During Response To Treatment With Paclitaxel/Anti-Tim-3, Alycia Gardner

USF Tampa Graduate Theses and Dissertations

Intratumoral CD103+ dendritic cells (cDC1) are required for anti-tumor immune responses. In tumors that are poorly responsive to immunotherapeutic approaches targeting T cells, targeting cDC1 represents an alternative approach that may be useful in improving patient response rates. As such, it is critical to understand cDC1 function within tumors, and what may be preventing optimal function of cDC1. TIM-3 is a receptor that is highly expressed by cDC1 in murine and human mammary tumors, and TIM-3 blocking antibodies are currently being evaluated in clinical trials for a number of solid and hematological malignancies. In order to best design combinatorial therapeutic …

Development And Validation Of An Isothermal Amplification Assay For Eastern Equine Encephalitis Virus, Mikayla D. Maddison

USF Tampa Graduate Theses and Dissertations

Eastern Equine Encephalitis virus (EEEV) is a neurotrophic alphavirus for which there is no effective treatment or vaccine for humans. Periodic outbreaks in the Eastern United States represent an ongoing public health problem; Florida serves as the reservoir for EEEV for the rest of the country. Reverse transcription-polymerase chain reaction (RT-PCR) is the current gold standard for molecular diagnostic testing of the presence of EEEV in vectors. However, RT-PCR is technically complex and can be difficult for mosquito control districts to utilize. In order to provide a simple, cost-effective alternative for mosquito surveillance and control, a novel one step reverse …

Mechanisms And Mitigation: Effects Of Light Pollution On West Nile Virus Dynamics, Meredith E. Kernbach

USF Tampa Graduate Theses and Dissertations

Light pollution, or the presence of unnatural light at night, is a pervasive and growing problem across the globe. While often pictured in urban centers, light pollution is far reaching and can affect seemingly safe and minimally developed environments. For example, agricultural communities with artificial lighting near facilities can generate such light pollution in rural areas. Further, streetlights and illuminated billboards along roads and highways can generate light pollution far from cities. Given how pervasive this anthropogenic stressor is, it is surprising that not much is known about how artificial light at night, or ALAN, affects humans or wildlife, especially …

Defining Codes Based On The Consolidated Framework For Implementation Research In The Context Of The Implementing Universal Lynch Syndrome Screening, Jasmine A. Burton-Akright

USF Tampa Graduate Theses and Dissertations

Lynch syndrome (LS) is the most common hereditary cause of both colorectal cancer (CRC) and endometrial cancer (EC). Universal tumor screening (UTS) of newly diagnosed EC and CRC patients has been shown to be both an effective and economical approach to identify patients with LS and subsequently reduce future cancer s for patients and their family members. Despite its efficacy, LS UTS has not been consistently adopted across hospital systems and existing programs vary widely in their structure and execution. The Implementing Universal Lynch Syndrome Screening (IMPULSS) study aims to determine the critical factors necessary for successful implementation of LS …

The Impact Of Myeloid-Mediated Co-Stimulation And Immunosuppression On The Anti-Tumor Efficacy Of Adoptive T Cell Therapy, Pasquale Patrick Innamarato

USF Tampa Graduate Theses and Dissertations

Adoptive T cell therapy (ACT) in combination with lymphodepleting chemotherapy is an effective strategy to induce the eradication of tumors, providing long-term regression in cancer patients. However, only a minority of patients that receive ACT with tumor infiltrating lymphocytes (TILs) exhibit durable benefit. Thus, there is an urgent need to define strategies that potentiate anti-tumor activity conducted by adoptively transferred T cells. In these studies, we aimed to identify novel strategies to enhance the therapeutic efficacy of ACT. Accordingly, we describe the disparate roles of myeloid cells in the context of ACT characterized by the augmentation of TIL proliferation in …

Non-Invasive Sex Determination And Genotyping Of Transgenic Brugia Malayi Larvae, Santiago E. Hernandez Bojorge

USF Tampa Graduate Theses and Dissertations

Lymphatic filariasis is a very painful and disfiguring helminth disease caused by the tissue nematodes Wuchereria bancrofti, Brugia malayi, and Brugia timori. This parasitosis is considered a Neglected Tropical Disease and it is a major public health burden for 72 tropical countries of Africa, Southeast Asia, the Caribbean, and South America. Despite the effectiveness of many control programs, there remains the need to develop new pharmacological agents to treat lymphatic filariasis, as most programs rely on a limited variety of drugs that are expensive, logistically difficult to obtain, and can lead to drug resistance. The Clustered Regularly Interspaced Short Palindromic …

Understanding The Role Of Cereblon In Hematopoiesis Through Structural And Functional Analyses, Afua Adutwumwa Akuffo

USF Tampa Graduate Theses and Dissertations

The discovery and implementation of immunomodulatory drugs (IMiD®s) has revolutionized the treatment of many hematological malignancies due to the plethora of IMiD®-induced clinical responses that include anti-angiogenesis, anti-inflammation, and anti-tumor effects, as well as enhanced erythropoiesis, immune modulation and improved metabolism. More ground-breaking was the identification of cereblon as the target of IMiD®s. Upon binding to thalidomide and other immunomodulatory drugs, the E3 ligase substrate receptor cereblon (CRBN) promotes proteosomal destruction of neo-substrates by engaging the DDB1-CUL4A-Roc1-RBX1 E3-ubiquitin ligase in human cells but not in mouse cells suggesting that sequence variations in CRBN may cause its inactivation. Therapeutically, CRBN engagers …

Investigating Mechanisms Of Immune Suppression Secondary To An Inflammatory Microenvironment, Wendy Michelle Kandell

USF Tampa Graduate Theses and Dissertations

The immune system plays a dynamic role in cancer progression. The theory of immunoediting suggests that the relationship between the tumor cell and the immune cell is one that is in flux: initially highly active and responsive to tumor antigen to one that has escaped immune responsiveness. Once the tumor has formed and effectively “escaped”, there are multiple mechanisms that work against a conventional immune response. The tumor cell clones that have escaped the elimination phase are those that are less immunogenic. These clones downregulate MHC, have increased apoptosis through DAMP-driven mechanisms, and suppressive cell phenotypes are driven through cytokine-driven …

A Novel Cytokine Response Modulatory Function Of Mek Inhibitors Mediates Therapeutic Efficacy, Mengyu Xie

USF Tampa Graduate Theses and Dissertations

Despite the recent success of immune-checkpoint blockade therapy for late-stage non-small cell lung cancer (NSCLC), lung cancer is still the leading cause of cancer deaths worldwide. One of the most important characteristics of lung cancer in therapeutic decision-making are the targetable molecules, including EGFR, ALK, BRAF, and MEK. The excitement of immune-checkpoint blockade therapy has triggered concerted efforts that focus on exploring combinations of immune checkpoint therapy with other approved therapeutic regimens aiming at further augmenting positive outcomes and survival. However, the lack of understanding of underlying mechanisms and evidence-based clinical testing has hindered the progress to a cure. Hence, …

Enhancing Immunotherapeutic Interventions For Treatment Of Chronic Lymphocytic Leukemia, Kamira K. Maharaj

USF Tampa Graduate Theses and Dissertations

Chronic lymphocytic leukemia (CLL) is the most common leukemia in developed countries. It is characterized by the accumulation of CD5+ B lymphocytes in the peripheral blood, bone marrow, and lymphoid tissues of affected patients. Patients experience lymphadenopathy, fatigue, and are severely immunocompromised. Management of disease and symptoms is possible with chemo-immunotherapy for higher risk patients; however, CLL remains incurable unless bone marrow transplant is performed. Identification of novel targets and optimization of current therapeutics is therefore still necessary. The new targeted therapies are at the forefront of development for CLL treatment, but it remains challenging to maximize their efficacies while …

Understanding Immunometabolic And Suppressive Factors That Impact Cancer Development, Rebecca Swearingen Hesterberg

USF Tampa Graduate Theses and Dissertations

The immune system is responsible for surveillance against pathogens and malignancies and adoptive transfer of antigen-specific T is a powerful new cancer treatment option. There is a clinical need to understand more about the normal regulatory processes that prevent immunosurveillance and how to manipulate this for clinical benefit. This project aims to understand T cells from three different angles. First, the biological role of the negative regulator cereblon (CRBN) was investigated in CD8+ T cells and my studies showed that higher levels of specific derivatives downstream of the amino acid glutamine may be beneficial to T cells in the immune …

Identification Of Novel Hits Against, Ala A. Azhari

USF Tampa Graduate Theses and Dissertations

Leishmaniasis is a disease caused by obligate intracellular parasites of the genus Leishmania, including 20 species that are pathogenic to humans. Female sand fly is the known vector that can transmit the disease. Visceral leishmaniasis is the severe form of the disease that affects internal organs and can be fatal with inappropriate diagnosis or treatment. Leishmania donovani is the causative agent of visceral leishmaniasis. Approximately 350 million in 89 countries are at risk of infection. Around 2 million new cases are reported annually with 500,000 of these are visceral leishmaniasis. Current drug therapies are inadequate due to their toxicity, high …

A Multivariate Approach For An Improved Assessment Of Pre-Erythrocytic Stage Therapies Targeting Plasmodium Vivax And Plasmodium Falciparum, Alison E. Roth

USF Tampa Graduate Theses and Dissertations

The malaria pre-erythrocytic stages have been identified as an ideal therapeutic target, but complex in vitro models for Plasmodium vivax and Plasmodium falciparum lack the efficiency needed for rapid screening and evaluation of new vaccines and drugs, especially targeting the P. vivax hypnozoite. To address this challenge, we employed a multi-parameter approach using “omics’” to identify pre-erythrocytic targets and biomarkers, guide phenotypic therapeutic screening, and study parasite functionality with innovative bioassays using highcontent screening. Herein, we discuss three novel bioassays formatted in 384-well plate systems with utilization of commercially-available materials and application of high-content imaging for rapid bio-image analysis. To …

Angiostrongylus Cantonensis: Epidemiologic Review, Location-Specific Habitat Modelling, And Surveillance In Hillsborough County, Florida, U.S.A., Brad Christian Perich

USF Tampa Graduate Theses and Dissertations

Angiostrongylus cantonensis is a parasitic nematode endemic to tropical and subtropical regions and is the leading cause of human eosinophilic meningitis. The parasite is commonly known as rat lungworm because the primary host in its lifecycle is the rat. A clinical overview of rat lungworm infection is presented, followed by a literature review of rat lungworm epidemiology, risk factors, and surveillance projects. Data collected from previous snail surveys in Florida was considered alongside elevation, population per square kilometer, median household income by zip code territory, and normalized difference vegetation index specific to the geographic coordinates from which the snail samples …

Novel Role Of Histone Deacetylase 11 (Hdac11) In Regulating Normal And Malignant Hematopoiesis, Jie Chen

USF Tampa Graduate Theses and Dissertations

During hematopoiesis, multilineage progenitor cells and the precursors are committed to individual hematopoietic lineages. In normal myelopoiesis, the immature myeloid cells (IMCs) differentiate into macrophages, neutrophils or dendritic cells. However, under tumor burden, these IMCs differentiate into myeloid derived suppressor cells (MDSCs) result in an up-regulation of immune suppressive factors and pro-tumor effect. The development of normal or malignant is tightly controlled by endogenous signals such as transcription factors and epigenetic regulations. HDAC11 is the newest identified members of the histone deacetylase (HDAC) family. Previous study in our group had identified HDAC11 as a negative regulator of interleukin 10 (IL-10) …

Cost-Effectiveness Analysis Of Targeted Herpes Zoster Vaccination In Adults 50-59 At Increased Cardiovascular Risk, Kathleen M. Glassner

USF Tampa Graduate Theses and Dissertations

Background: Over the last twenty years the incidence of herpes zoster (HZ) infection, also known as shingles, has been increasing among adults for unknown reasons. The economic burden of HZ is currently estimated at over $1 billion per year in the United States (U.S.) and is expected to increase as the susceptible adult population ages. HZ is caused by a re-activation of the varicella zoster virus (VZV), chicken pox, and more than 95% of adults living today carry the virus with a lifetime risk of 1 in 3 for developing HZ. In 2006 the FDA approved a vaccine for the …

Evaluation Of A Microsphere-Based Immunoassay (Mia) In Measuring Diagnostic And Prognostic Markers Of Dengue Virus Infection, Jason H. Ambrose

USF Tampa Graduate Theses and Dissertations

Infections with dengue viruses (DENV) constitute both a global problem as well as locally in Florida. DENV comprise four distinct serotypes of single-stranded RNA viruses and belong to the family Flaviviridae. DENV are among the most medically important arboviruses in the world and cases may currently exceed 400 million per annum. Additionally, dengue established its first recorded endemic transmission cycle in the state of Florida in over a half century, first within the Florida Keys during 2009-10 followed by an unrelated outbreak in Martin County in 2013. The clinical profile of DENV infections ranges from a mild febrile illness …

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 …

Role Of Viruses Within Metaorganisms: Ciona Intestinalis As A Model System, Brittany A. Leigh

USF Tampa Graduate Theses and Dissertations

Marine animals live and thrive in a literal sea of microorganisms, yet are often able to maintain specific associations that are largely dictated by the environment, host immunity and microbial interactions. Animal-associated microbiomes include bacteria and viruses that vastly outnumber host cells, especially in the gut environment, and are considered to be integral parts of healthy, functioning animals that act as a metaorganism. However, the processes underlying the initial establishment of these microbial communities are not very well understood. This dissertation focuses on the establishment of a well-known developmental animal model, Ciona intestinalis (sea squirt), to study the establishment and …

Pollen Forecasting In Sarasota, Florida, Daniel J. Gessman

USF Tampa Graduate Theses and Dissertations

Current predictions of pollen levels rely strictly on historical Averages, regardless of environmental factors that might affect the timing of pollen release by different plants. For this thesis, the goal was to develop a statistical model that will accurately forecast pollen levels by correlating those daily counts to atmospheric and meteorological conditions. This project used ARIMA modeling on IBM’s SPSS Statistics 24 of daily pollen count information for multiple allergenic pollens in the Sarasota County, Florida area over a 11-year period. The pollen species in question for this project are oak and cypress trees, grass, and ragweed pollens; and Alternaria …

The Effect Of Antigen Polymorphisms On Serological Antibody Detection Assays Based Upon The, Kristi M. Miley

USF Tampa Graduate Theses and Dissertations

Onchocerca volvulus is a filarial parasite transmitted to humans by female Simulium spp. black flies. Infection with this parasite can cause blindness and severe skin disease among humans in Africa and the Americas. Enzyme-linked Immunosorbent Assay serological testing of OV-16 antigen is a diagnostic tool for determining effective elimination of the parasite. Programs typically rely on OV–16 ELISA to evaluate the progress towards interruption and/or elimination of disease by mass drug distribution of ivermectin and vector larvicidal control efforts. As elimination grows closer, monoclonal antibody positive controls for OV-16 ELISA become important to develop for Onchocerca testing due to the …

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 …

Development Of Tools For Stable Transfection In The Human Filarial Parasite Brugia Malayi Via The Piggybac Transposon System, Johan Chabanon

USF Tampa Graduate Theses and Dissertations

Brugia malayi is one of three species of nematode known to cause lymphatic filariasis (LF) in humans. LF infects over 120 million people, causing debilitating disease. Various global programs have been launched in the past 20 years to eliminate LF. These programs have greatly scaled up the resources and efforts allocated to halting the transmission and reducing disease burden. Only a few drugs are used to treat LF, and resistance is thus a devastating possibility. Research aimed at identifying new drug targets could therefore prove essential in elimination of LF.

Genetic manipulation of B. malayi has been limited to transient …

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 …

Respiratory Syncytial Virus-Infected Mesenchymal Stem Cells Regulate Immunity Via Interferon-Beta And Indoleamine-2,3-Dioxygenase, Michael B. Cheung

USF Tampa Graduate Theses and Dissertations

Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory tract infection in young children worldwide, accounting for an estimated 33.8 million cases of respiratory disease, over 3 million of which require hospitalization, and between 66,000 and 199,000 deaths in this susceptible population. Additionally, severe RSV infection early in life is associated with an increased risk of wheeze and other airway disorders later in life. Despite this, there is currently no vaccine or economically reasonable prophylactic regimen to prevent infection. While disease is typically more severe in infancy RSV can infect throughout the lifespan repeatedly as the …