Microbiology Commons^™

Role Of Integrase-Pp2a Interaction In Human T-Cell Leukemia Virus Type-1 Replication And Pathogenesis, Shayna Turbin

Senior Honors Papers / Undergraduate Theses

Human T-cell leukemia virus type-1 (HTLV-1) is an oncogenic retrovirus that causes multiple disorders, including adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. HTLV-1 retroviral integrase binds to the regulatory B’56γ subunit of the host cell Protein Phosphatase 2A (PP2A). Integrase contains a highly conserved LxxIxE motif that is essential for binding, which increases integration efficiency and facilitates HTLV-1 hijack of host cell machinery. We aim to understand how mutations introduced in the highly conserved binding site can affect viral particle production and infectivity. We transfected 729B human lymphoblastoid cells and 293T cells with mutant and wildtype virus. Mutations L213A, …

Structural Insights Into The Cl-Par-4 Protein: Ionic Requirements, Conformational Transitions, And Interaction With Cisplatin, Krishna Kumar Raut

Chemistry & Biochemistry Theses & Dissertations

Cancer continues to be the leading global cause of death, with challenges in early diagnosis, drug resistance, non-specific drug targeting, and cancer recurrence and metastasis posing formidable obstacles in cancer therapy. In this context, Prostate Apoptosis Response-4 (Par-4), a pro-apoptotic tumor suppressor protein, emerged as a promising therapeutic target due to its ability to selectively induce apoptosis in cancer cells, thereby minimizing the drug-associated adverse effects. However, a comprehensive understanding of the structural features of Par-4, specifically the caspase-cleaved fragment (cl-Par-4), is crucial for therapeutic advancements.

This dissertation investigated the effects of various ions, both monovalent and divalent, on the …

The Role Of Coagulase-Negative Staphylococcal Secreted Products On Staphylococcus Aureus And Staphylococcus Lugdunensis Infections, Denny Chin

Electronic Thesis and Dissertation Repository

The Staphylococcus genus is comprised of over 40 bacterial species. The most well-studied species in this genus is the notorious human pathogen Staphylococcus aureus, a bacterium that produces coagulase among many other virulence factors. Since S. aureus is a major health burden and causes a plethora of diseases in humans, it has received significant attention and much research has been done to understand its biology to treat diseases caused by this pathogen. However, the coagulase-negative staphylococci (CoNS) make up most of the staphylococcal species and have received less attention since they are thought to have a lesser impact on …

Investigation Of Ifnγ-Induced Control Of Intracellular Pathogens, Michael Mcallaster

Arts & Sciences Electronic Theses and Dissertations

Genes required for the lysosomal degradation pathway of autophagy play key roles in topologically distinct cellular processes with significant physiologic importance. One of the first-described of these ATG gene-dependent processes is the requirement for a subset of ATG genes in interferon-γ (IFNγ)-induced inhibition of norovirus and Toxoplasma gondii replication. In this dissertation we identified novel components that are required for or that negatively regulate this immune mechanism. Enzymes involved in the conjugation of UFM1 to target proteins including UFC1 and UBA5, negatively regulated IFNγ-induced inhibition of norovirus replication via effects of Ern1. We identified and confirmed that IFNγ-induced inhibition of …

Regulation Of Host-Microbe Interactions In Autoimmunity And Antiviral Immunity By Cytosolic Nucleic Acid Sensing And Interferon Signaling, Derek Jerome Platt

Arts & Sciences Electronic Theses and Dissertations

Cytosolic nucleic acid sensing and interferon (IFN) signaling are central to the host immune response to microbial pathogens. However, dysregulation of immunological pathways such as these can result in devastating autoimmune disease. In order to provide a robust immune response to pathogen without causing harm to self, the host immune system must engage in a delicate balancing act, interacting with microbes and determining whether they are commensal or pathogenic. The cGAS-STING pathway is a key regulator of host-microbe interactions by cytosolic nucleic sensing and IFN signaling. Loss of function in the cGAS-STING pathway leads to increased susceptibility to pathogenic threats, …

Investigating The Role Of Bladder Epithelial Stem Cells In Bladder Mucosal Remodeling And Defense Against Infection, Seongmi Kim Russell

Arts & Sciences Electronic Theses and Dissertations

Urinary tract infections (UTIs) can be highly recurrent, and the mechanism(s) governing recurrence susceptibility are mostly unknown. Here I demonstrate bladder epithelial (urothelial)-intrinsic trained immunity as part of a differential mucosal remodeling response to an initial UTI. I established urothelial stem cell (USC) lines from isogenic mice with different UTI histories (naïve, chronic, or self-resolving) and discovered 2880 differential genome-accessible regions, indicating differential epigenetic reprogramming dependent on infection history. Differentiation of USC lines in vitro resulted in polarized urothelial cultures that recapitulated distinct remodeling morphologies seen in vivo and exhibited altered gene expression, including genes involved in cell death pathways. …

The Roles Of Capsular Polysaccharides And Diet In The Immune Response To A Bacteroides Thetaiotaomicron Antigen, Samantha Hsieh

Arts & Sciences Electronic Theses and Dissertations

The environment is well recognized to modulate immune responses within the intestinal mucosa in a general fashion. However, the connection between the effects of the environment on the immune response directed towards specific intestinal microbes is unclear. Progress in this area has been hampered by the lack of a model system in which the immune responses to a specific antigen in a gut symbiont can be examined. To this end, we developed a novel CD4+ T cell model, termed BθOM, that is specific for a dominant antigen in the gut symbiont Bacteroides thetaiotaomicron (B. theta). In this work, we use …

Suppression Of Inflammation Of Cytokine Following Induced Francisella Tularensis Infection, Nicole Renee Setzu

Open Access Theses & Dissertations

Francisella tularensis is intracellular bacteria which is the causative agent of the disease Tularemia. Highly virulent in both humans and animals, it takes only as few as 10 microorganisms to cause a lethal infection. The bacteria can enter via direct or indirect routes causing the activations of the host innate inflammatory response to ensue. The bacteria invade host dendritic cells and neutrophils but predominately macrophages. This causes a mass inflammatory response resulting in the cytokine storm. Activation of Natural Killer T (NKT) cells has been shown to suppress inflammation in in vivo studies. Development and optimization of an in vitro …

Hiv-1 Drug Resistance To Integrase Strand Transfer Inhibitors In Hiv-1 Non-B Subtypes, Emmanuel Ndashimye

Electronic Thesis and Dissertation Repository

Human immunodeficiency syndrome (HIV-1) has infected over 75 million people and over 35 million have succumbed to virus related illnesses. Despite access to a variety of antiretroviral therapy (ART) options, ART programs have been disproportionally spread in the world with low-and middle-income countries (LMICs) facing challenges to access the most potent ART options. With less potent ART remaining in use in LMICs, HIV-1 drug resistance (HIVDR) presents a growing challenge in LMICs. Since approval of the first-generation integrase strand transfer inhibitor (INSTIs), Raltegravir (RAL) in 2007, INSTIs remain the best choice as a backbone of ART. Access to second generation …

Examining Early Interactions Between Innate Airway Resident Immune Cells And Mtb-Specific Factors During Pulmonary Infection With Mycobacterium Tuberculosis, Micah D. Dunlap

Arts & Sciences Electronic Theses and Dissertations

Mycobacterium tuberculosis (Mtb) is the leading cause of death by an infectious agent in the world today, infecting roughly one quarter of humans. Despite this, the mechanisms of early pathogenesis and host protective innate immune responses remain poorly understood and uncharacterized.

Lung resident Alveolar Macrophages (AMs) are the first host contact with Mtb bacilli after inhalation and are thus key mediators of the early pulmonary immune response. AMs are generally believed to reside entirely in the airway, but it was recently demonstrated that they have the capacity to egress and enter into granulomas during pulmonary infection with hypervirulent Mtb. Furthermore, …

Characterizing The Physiology And Genetics Of Contact Dependent Growth Inhibiton Systems In Burkholderia Species, Alice Elizabeth Oates

Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics

Contact-dependent growth inhibition (CDI) systems mediate interbacterial competition. The genes encoding these systems are widespread among Gram-negative bacteria, including Burkholderia pathogens. CDI systems of Burkholderia species are composed of two-partner secretion pathway proteins and function to deliver the toxic C-terminus of a polymorphic surface-exposed exoprotein BcpA (Burkholderia CDI protein A) to the cytoplasm of neighboring recipient bacteria upon cell-cell contact. Specific outer and inner membrane proteins facilitate BcpA translocation both out of the donor bacterium and into the recipient cell cytoplasm. Most Burkholderia species-specific CDI translocation factors in recipient cells are unknown. BcpA intoxication functions as a mechanism by …

Plasmodium Impairs Antibacterial Innate Immunity To Systemic Infections In Part Through Hemozoin-Bound Bioactive Molecules., Christopher Lynn Harding

Electronic Theses and Dissertations

Despite efforts to decrease the global health burden of malaria, infections with Plasmodium species continue to cause over 200 million episodes of malaria each year which resulted in 405,000 deaths in 2018 [1]. One complication of malaria is increased susceptibility to invasive bacterial infections. Plasmodium infections impair host immunity to non-Typhoid Salmonella (NTS) through activities of heme oxygenase I (HO-I) )-induced release of immature granulocytes and myeloid cell-derived IL-10. Yet, it is not known if these mechanisms are specific to NTS. We show here, that Plasmodium yoelii 17XNL (Py) infected mice had impaired clearance of systemic Listeria monocytogenes (Lm) during …

Development, Expansion And Role Of Myeloid-Derived Suppressor Cells In Post-Sepsis Immune Suppression, Tuqa Alkhateeb

Electronic Theses and Dissertations

Myeloid-derived suppressor cells (MDSCs) numbers increase significantly in sepsis and are associated with high mortality rates. These myeloid cell precursors promote immunosuppression, especially in the late (post sepsis) stage. However, the mechanisms that underlie MDSC expansion and programming are not completely understood. To investigate these mechanisms, we used a cecal-ligation and puncture (CLP) mouse model of polymicrobial sepsis that progresses from an early/acute proinflammatory phase to a late/chronic immunosuppressive phase. Previous studies in our laboratory showed that microRNA (miR)-21 and miR-181b elevate levels of the transcription factor nuclear factor 1 (NFI-A) that promotes MDSC expansion. We report here that miR-21 …

Cognitive Recovery In The Post-Infectious Cns, Charise Joy Garber

Arts & Sciences Electronic Theses and Dissertations

Neuroinflammation plays a pivotal role in a variety of diseases of the CNS associated with cognitive impairment, including Alzheimerճ Disease, Parkinsonճ Disease with dementia, Multiple Sclerosis, anti-NMDA receptor encephalitis, and West Nile Virus Neuroinvasive disease (WNND). Despite strong evidence that infiltration of peripheral immune cells and activation of resident microglia and astrocytes occurs in these various diseases, very little is known about how this altered immune environment may influence normal cognitive function. Given that communication between the nervous and immune system is essential for normal cognitive function, the central motivation of my thesis work is to understand the mechanisms by …

Characterization Of A Plasmid-Based Dna Vaccine For Simian Immunodeficiency Virus, Priya Sanipara

Honors Theses

Described as one of the world’s worst pandemics, HIV (Human Immunodeficiency Virus) infects millions of people each year and is the cause for AIDS (Acquired Immunodeficiency Syndrome). Despite the development of vaccines for numerous infectious diseases such as polio, small pox, and influenza, a vaccine for HIV remains elusive due to the virus’s high mutation rate and ability to evade the immune system. HIV causes depletion of CD4+ lymphocytes, resulting in a weakened immune system. However, the development of a plasmid-based DNA vaccine approach may help revolutionize vaccine development for HIV due to its ability to confer cellular and humoral …

Oncolytic Viruses: Cancer Treatment Going Viral, Rhianna N. Bronson

Chancellor’s Honors Program Projects

No abstract provided.

Oral Localization Of Scardovia Wiggsiae, Graydon Ramos Carr

UNLV Theses, Dissertations, Professional Papers, and Capstones

Early childhood caries is one of the most prevalent diseases in the United States among children. The formation of caries is a complex, multifactorial process that is still being studied. Researchers have thought for years that Streptococcus mutans was the primary causative agent of early childhood caries. The recent discovery of a novel cariogenic pathogen, Scardovia wiggsiae and its significant contribution to the etiology of early childhood caries has led oral health researchers to re-evaluate this microorganism and its link to this disease. While there have been several projects undertaken within the University of Nevada, Las Vegas School of Dental …

Exosomes In Transmission And Blocking Of Arthropod-Borne Flaviviral Infection And Pathogenesis, Wenshuo Zhou

Biomedical Sciences Theses & Dissertations

Vector-borne diseases (VBDs) are human illnesses that are transmitted by vectors such as ticks, mosquitoes, and fleas. These arthropods transmit infectious pathogens such as viruses, protozoa, and bacteria, to humans during their blood-feeding. According to the estimation of the WHO, billions of people are affected by VBDs worldwide, and about 700,000 deaths are reported annually. Currently, very few reliable VBDs control approaches and vaccines available to treat various VBDs. Additionally, approaches to control arthropod’ proliferation and migration are difficult to develop. Furthermore, molecular determinants and mechanisms for the transmission are poorly understood. This work describes two studies identifying the novel …

Evaluating Historical Paradigms Of Sterility In Perinatal Microbiology And Ramifications For Pregnancy Outcomes, Jonathan Greenberg

Wayne State University Dissertations

Next-generation sequencing technologies, especially 16S rRNA gene and metagenomic sequencing have allowed investigations of low microbial biomass tissues of the human body. While these sequencing methodologies have provided large amounts of reliable data for higher microbial biomass sites, such as the mouth, intestine, and vagina, tissues of low microbial biomass sites are subject to specific caveats that were not appropriately considered in early investigations of these sites. Low microbial biomass sites of particular interest have included those of the reproductive and urinary systems. Utilization of DNA sequencing methodologies have allowed researchers to challenge existing paradigms of sterility around these sites …

Tick-Borne Infections In New Hampshire: An Evaluation Of The Diagnostic Process In A Local Patient Population, Katherine Anderson

Honors Theses and Capstones

Overall, approximately 95 percent of reported cases of vector-borne disease were associated with ticks, making these the most medically important group of arthropods in the United States.¹ Despite the prevalence of tick-borne infections, the process for the diagnosis of this condition is not well studied. This study aims to analyze data from a pool of 100 patients who underwent testing for tick-borne disease in the same institution in Dover, New Hampshire during the most recent peak tick season of 2019. Information utilized in this study included: patient age, sex, location of testing (inpatient versus outpatient), diagnostic testing methods used …

The Transcription Factor Bhlhe40 Regulates Tissue-Resident Macrophages And Type 2 Immunity, Nicholas N. Jarjour

Arts & Sciences Electronic Theses and Dissertations

Transcriptional control of gene expression is essential for life, tailoring protein production to development and environment to maintain organismal homeostasis. A limited set of proteins termed transcription factors are critical to this process. As our understanding of these central regulators has improved, new aspects of cell and organismal biology have been revealed. Herein, we demonstrate the importance of the transcription factor Bhlhe40 to tissue-resident macrophages, T helper type 2 cells, and type 2 immune responses, revealing novel transcriptional control of macrophages and unexpected cytokine regulation of helminth infection. We find that Bhlhe40 is cell-intrinsically required for normal proliferation of large …

Role Of Regulatory T Cells In The Development And Progression Of Lyme Disease In Balb/C Mice, Kaitlyn Nielsen

Theses and Dissertations

Lyme disease, caused by Borrelia burgdorferi, is an increasingly important public health concern, with tens of thousands of new cases being diagnosed each year, even in previously non-endemic areas. It is known that symptoms of Lyme disease are caused by an inflammatory immune response initiated to aid in clearance of the pathogen. Left unchecked, these inflammatory responses can potentially increase tissue damage, leading to increased disease severity. Mechanisms responsible for the control of the inflammatory response to infection with B. burgdorferi are not entirely understood. Evidence exists that regulatory T (Treg) cells, a population of Foxp3-expressing CD4+ T cells known …

Secretory Iga Enhances Gut B Cells Priming And Systemic Igg Responses Towards Commensals, You Zhou

Arts & Sciences Electronic Theses and Dissertations

IgA is the primary antibody response at mucosal surfaces and is reported to inhibit adaptive immune responses against gut bacteria. Here, we utilize an in vitro system to expand and screen IgA memory B cells for their ability to recognize gut bacteria in the context of secretory IgA (sIgA) deficiency in polymeric Ig receptor (Pigr–/–) mice. Contrary to the prevailing hypothesis that IgA provides an immune exclusionary function, we found that mice lacking sIgA showed decreased anti-bacterial IgA specificities as assessed using flow cytometry. IgA B cell responses against certain taxa such as those of order Bacteriodales showed greater dependence …

Dissemination Of The Apicomplexan Parasite, Toxoplasma Gondii, Lisa L. Drewry

Arts & Sciences Electronic Theses and Dissertations

The parasitic protist Toxoplasma gondii is a common pathogen of rodents and felines that also infects humans. The most severe clinical manifestations of toxoplasmosis in humans derive from the systemic dissemination of T. gondii, during which the parasite penetrates biological barriers and accesses protected host compartments such as the central nervous system. T. gondii dissemination is enabled by the intrinsic gliding motility of extracellular parasites, which allows for travel to new host cells and tissues, and also powers the invasion of diverse host cells including migratory leukocytes. Dissemination is further advanced when migrating infected leukocytes shuttle intracellular parasites to new …

Adaptation Of The Streptococcal Collagen-Like Protein 1, Scl1, Of Group A Streptococcus To Recognize Fibronectin Type Iii Repeats, Dudley H. Mcnitt

Graduate Theses, Dissertations, and Problem Reports

Background: Group A Streptococcus (GAS) is responsible more than 700 million infections worldwide each year. Most of these infections start with initial colonization of the throat and skin, which is augmented by surface adhesins. The streptococcal collagen-like protein 1 (Scl1) is a major adhesin expressed by GAS that contains an N-terminal sequence-variable (V) domain, protruded away from the cell surface by the collagen domain. The Scl-V domain is comprised of three pairs of anti-parallel α-helices interconnected by surface-exposed loops. For attachment, GAS adhesins require a portal of entry, such as a wound or breach in the epithelium, to enter …

A Recombinant Virus And Reporter Mouse System To Study Chronic Chikungunya Virus Pathogenesis, Alissa Roxanne Young

Arts & Sciences Electronic Theses and Dissertations

Chikungunya virus (CHIKV) is an arthritogenic alphavirus that during acute disease causes fever as well as severe joint and muscle pain. Chronic joint and muscle pain persists in a significant subset of patients, yet we still have a poor understanding of what drives this chronic disease. While replicating virus has not been detected in the joints of patients with chronic arthritis or in various animal models at chronic time points, persistent viral RNA can be detected for months after acute infection.

To identify the cells that could be contributing to chronic CHIKV pathogenesis, we developed recombinant viruses that express Cre …

The Role Of Non-Neuronal Acetylcholine In Urogenital Chlamydial Infection, Jessica R. Lockhart

Electronic Theses and Dissertations

Chlamydia trachomatiscauses a bacterial sexually transmitted infection, Chlamydia, that is often chronic and casues reproductive complications in women. We hypothesized that Chlamydia infection increases local acetylcholine (ACh) production, which regulates the host’s inflammatory response to the infection. Female mice infected with C. muridarumwere sacrificed at days 3, 9, 15, and 21 post-infection, genital tract tissues harvested, and immunohistochemistry performed to enumerate ACh-producing cells. Infection increased the number of ACh-producing cells in cervical tissue at days 3,15, and 21 post-infection (pi), uterine tissue at day 3 and 9 pi, and ovarian tissue day 3, 15, and 21 pi. These …

Mechanisms Adopted By Dengue-2 Viruses To Induce Autophagy In Mammalian Cells, Sounak Ghosh Roy

Dissertations, Theses, and Capstone Projects

Dengue, the most rapidly spreading flavivirus, threatens to affect almost half of the human global population. We previously showed that dengue-2 protects canine kidney cells (MDCK) from cytotoxic chemicals. We showed, independently, that cell protection, as well as viral replication and maturation, are positively regulated by PI3K-dependent autophagy. However, we had not identified the specific pathway that induces autophagy in infected cells. The current study explores the role of a specific branch of the endoplasmic reticulum (ER) stress-mediated Unfolded Protein Response (UPR), the PERK/eIF2α/ATF4 pathway in the induction of autophagy by …

Viral Mhc Class I Evasion Affects Anti-Viral T Cell Development And Responses, Elvin James Lauron

Arts & Sciences Electronic Theses and Dissertations

Cytotoxic CD8+ T cells (CTLs) play a critical role in protective immunity against viruses, a fact underscored by the evolution of viral CTL evasion mechanisms. For instance, many viruses commonly target the major histocompatibility complex class I (MHCI) antigen presentation pathway to prevent CTLs from recognizing infected cells. A striking example of this is cowpox virus (CPXV), which interferes with MHCI antigen presentation through two distinct mechanisms. One mechanism of CPXV-mediated MHCI inhibition is to retain MHCI molecules in the endoplasmic reticulum (ER). The second mechanism is to prevent antigen peptide loading onto MHCI molecules. When combined these mechanisms result …

Identification Of Bhlhe40 And Irg1 As Essential Regulators Of The Inflammatory Response To Mycobacterium Tuberculosis, Jeremy Peter Huynh

Arts & Sciences Electronic Theses and Dissertations

Protective immune responses to Mycobacterium tuberculosis (Mtb) must induce bactericidal functions while minimizing damage to the lung. Such responses require precise control of pro- and anti-inflammatory factors to regulate the recruitment and function of protective immune cells but the mechanisms by which this control is exerted remain incompletely defined. Basic helix-loop-helix family, member e40 (Bhlhe40) is a transcription factor known to regulate production of pro- and anti-inflammatory cytokines that affect protective immunity to Mtb. Immune-responsive Gene 1 (Irg1) is an enzyme that generates itaconate, a metabolite with potential anti-inflammatory and antibacterial roles during Mtb infection. The impact of Bhlhe40 and …