Medicine and Health Sciences Commons^™

The Role Of Intracellular Growth During The Systemic Spread Of Listeria Monocytogenes, Jamila S. Tucker

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

Listeria monocytogenes is a facultative intracellular pathogen transmitted through the consumption of contaminated food products. Typically, infections range from mild, self-limiting gastroenteritis to life-threatening systemic infections; however, the events that occur in the gut to allow for this spread are unclear.

The focus of my thesis aims to determine how L. monocytogenes escape the mesenteric lymph nodes (MLN), the final barrier to systemic spread for both commensal and pathogenic bacteria in the gut. I have shown that intracellular replication of L. monocytogenes in an as-yet-unidentified cell type is essential for the colonization and dissemination of the bacteria from the MLN. …

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 …

Elucidating The Complex Signaling Events Driving Intestinal Stem Cell Plasticity Following Injury, Evan Lynch

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

Signaling events governing intestinal stem cell (ISC) homeostasis maintain the delicate balance of active self-renewal and passive differentiation to replenish intestinal epithelial cells (IEC) every 3-5 days. However, under certain contexts, ISC function is irreversibly compromised—requiring committed IEC lineages to dedifferentiate and regain “stemness”. In the current studies, we examine the signaling events driving epithelial cell responses to injury to expose pathologic failures in the healing response. Our specific goal is to tease out the cellular contexts that promote dedifferentiation to design effective therapeutics for disease conditions compromising ISC function.

First, we generated a novel transgenic animal using the epithelial-specific …

Mast Cells As Novel Effector Cells In The Pathogenesis Of Chronic Graft-Versus-Host Disease, Ethan Strattan

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

Hematopoietic stem cell transplantation (HSCT) is most commonly a treatment for inborn defects of hematopoiesis or acute leukemias. Widespread use of HSCT, a potentially curative therapy, is hampered by onset of graft-versus-host-disease (GVHD), a condition wherein the donor cells recognize the patient tissues as non-self. GVHD can manifest anywhere from weeks to decades post-transplant and is classified as either acute or chronic GVHD, both of which are significant causes of transplant-related morbidity and mortality.

However, GVHD is a complex, multifactorial, and enigmatic disease. The factors driving GVHD at the cellular and molecular level are incompletely understood. Immunosuppression targeting T-cells has …

The Role Of Cd8 T Cell Immunodominance And Regulatory T Cells In Neonatal Immunity To Influenza Virus, Luke Heil

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

Neonates are more susceptible to influenza virus infection than adults, resulting in increased morbidity and mortality as well as delayed clearance of the virus. Efforts to improve influenza infection outcomes in neonates typically center on prevention, although current vaccines fall short of complete protection and can only be administered in humans after 6 months of life. We propose that as the neonatal immune system responds differently than the adult immune system, interventions that are efficacious or tolerable in adults cannot be guaranteed to perform the same in neonates. T cell vaccines that target conserved influenza virus epitopes have been proposed …

The Role Of Pro-Inflammatory Mediators Ifnβ And Prostaglandin E2 In Suppression Of Innate Immunity To Listeria Monocytogenes, Michelle G. Pitts

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

As a foodborne pathogen, Listeria monocytogenes (Lm) encounters many barriers to invasion and dissemination in the host that may change the nature of host response. Lm has been most commonly studied using intravenous (i.v.) inoculation, however, a method that delivers a bolus of bacteria directly to the bloodstream. Thus, little is known about what systemic and local mediators are triggered during the natural course of infection and how these may impact susceptibility. Our laboratory used foodborne transmission of Lm in mice to assess whether the method of transmission and the specific organ microenvironment could affect infection-induced secretion of …

Role Of Intracellular Growth During The Gastrointestinal Stage Of Listeria Monocytogenes Infection, Grant Steven Jones

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

Listeria monocytogenes is a facultative intracellular bacterium that causes foodborne disease in humans. L. monocytogenes invade the gut mucosa and then disseminate, causing systemic infections associated with high mortality rates in immunocompromised individuals. It is unknown how L. monocytogenes traffic to the mesenteric lymph nodes, which represent an important bottleneck for systemic spread. In addition, little is known about the gastrointestinal stage of infection due to the general resistance of mice to oral infection with L. monocytogenes. Our laboratory developed a novel foodborne mouse model of listeriosis utilizing a murinized strain of L. monocytogenes to investigate the gastrointestinal stage …

Suppression Of Anti-Tumor Immunity In Chronic Lymphocytic Leukemia Via Interleukin-10 Production, Sara Alhakeem

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

The most common human leukemia is B-cell chronic lymphocytic leukemia (B-CLL), which is characterized by a progressive accumulation of abnormal B-lymphocytes in blood, bone marrow and secondary lymphoid organs. Typically disease progression is slow, but as the number of leukemic cells increases, they interfere with the production of other important blood cells, causing the patients to be in an immunosuppressive state. To study the basis of this immunoregulation, we used cells from the transgenic Eμ-TCL1 mouse, which spontaneously develop B-CLL due to a B-cell specific expression of the oncogene, TCL1. Previously we showed that Eμ-TCL1 CLL cells constitutively …

Prion Characterization Using Cell Based Approaches, Vadim Khaychuk

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

Prions are the causative agents of a group of lethal, neurodegenerative conditions that include sheep scrapie, bovine spongiform encephalopathy (BSE), and human Creutzfeldt-Jakob disease (CJD). Prions are derived from the conversion of a normal, primarily alpha-helical, cellular prion protein (PrP^C), to an infectious, beta sheet-rich conformer (PrP^Sc). Many unresolved issues surround the process of PrP conversion, and we know very little about cellular responses to these unique pathogens. Our lack of knowledge relates, in part, to the difficulty of infecting cells in vitro with prions. While expression of PrP^C is an absolute requirement for prion …

Signaling Mechanisms Involved In The Generation Of Human Peripheral Itregs, Mary Catherine Reneer

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

Maintaining balance in the human immune system is critical for the body’s ability to discriminate between foreign and self-antigens. This balance is achieved, in part, by a subpopulation of T cells known as induced regulatory T cells (iTregs). Dysregulation of this population may contribute to the onset and progression of cancer, chronic inflammation and autoimmune diseases. Therefore, manipulation of iTreg development holds promising therapeutic potential; however, studying this vital population has proven difficult due to low numbers, heterogeneous cell populations, substantial phenotypic differences between mouse and human cells, and the high plasticity seen in iTregs. These current limitations have prevented …

Crosstalk Between Gastrointestinal Epithelial Cells And Resident Microbiota Promotes Immune Homeostasis, Eric William Rogier

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

The gastrointestinal tract houses one of the most dense and diverse communities of bacteria on the planet. The mutualistic relationship between the host and commensal microbe permits the microbe an ideal environment to grow and provides the host with increased caloric intake, maturation of the adaptive immune system, and resistance against invading pathogens. To maintain a system in which both parties benefit, the epithelium has evolved numerous strategies to ensure epithelial cells respond to microbes appropriately and that potentially hazardous commensals remain distanced from the soma proper. Breakdown of these propitiating mechanisms elicits unchecked inflammation and can lead to pathology …

Role Of The Immune System And Bioactive Lipids In Trafficking Bone Marrow-Derived Stem Cells In Patients With Ischemic Heart Disease, Ahmed Abdel-Latif

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

Acute myocardial infarction (AMI) triggers the mobilization of stem/progenitor cells from bone marrow (BMSPCs) into peripheral blood (PB). The underlying mechanisms orchestrating this mobilization and subsequent homing of BMSPCs to the myocardium are poorly understood. While the role of traditional chemokines in the mobilization and homing of hematopoietic stem cell (HSCs) to BM niches is undisputed, their role in directing BMSPCs to the highly proteolytic environment of the ischemic myocardium is debatable and other redundant mechanism may exist. Based on our observation that bioactive lipids, such as sphingosine-1 phosphate (S1P) and ceramide-1 phosphate (C1P), play an important role in regulating …

Regulation Of Hepatic Gene Expression During Liver Development And Disease, Hui Ren

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

My first project was to investigate the role of Hepatocyte Nuclear Factor 1 (HNF1) and Nuclear Factor I (NFI) on alpha-fetoprotein (AFP) promoter activity during liver development. AFP is highly expressed in the fetal liver, silenced at birth, and remains at very low levels in the adult liver. A GA substitution located at -119 of the human AFP promoter is associated with hereditary persistence of AFP (HPAFP) expression in the adult liver (Hum Molec Genet, 1993, 2:379). The -120 region harbors overlapping binding sites for HNF1 and NFI. While it has been shown that the GA substitution increases HNF1 binding, …