Expanding Inducible Epithelial Resistance Against Pneumonia: Novel Virus, Novel Receptor, Michael Longmire

Dissertations and Theses (Open Access)

Pneumonia is the leading infectious cause of death worldwide and presents a continuing risk among immunocompromised patients. Our work has been focused for many years on the phenomenon of inducible epithelial resistance, where activation of the innate immune response in the airway epithelium is necessary and sufficient to produce a pathogen-killing but self-protective environment to prevent severe disease. Inducible resistance is pathogen-agnostic and has been demonstrated against an array of respiratory infections. We achieve this using a combination of pattern recognition receptor agonists – Pam2CSK4 and ODN M362 being the current formulation – which produce synergistic levels of pathogen reduction …

Comprehensive Investigation Into The Molecular Mechanisms Driving The Emergence Of Emm4 Group A Streptococcus, Chioma Odo, Samuel A Shelburne, Anthony R. Flores, Steven J Norris, Anna Konovalova, Blake Hanson

Dissertations and Theses (Open Access)

Abstract

Comprehensive Investigation into the Molecular Mechanisms Driving the Emergence of emm4 Group A Streptococcus

Chioma Modeline Odo, M.S.

Advisory Professor: Samuel A. Shelburne, MD, Ph.D.

The major gram-positive bacterium group A Streptococcus (GAS) is a model organism for studying microbial epidemics as it is well known to cause infections that occur in waves. GAS strains are grouped based on the composition of the N-terminal sequence of the M protein which is encoded by the emm gene. With the advent of large-scale whole genome sequencing, GAS clonal emergence events in emm1, emm3, and emm89 types have been identified …

Characterizing The Regulation Of Candida Albicans Hyphal Morphogenesis In The Context Of Host Macrophages, Hannah Wilson

Dissertations and Theses (Open Access)

Candida albicans is a commensal fungus that resides on the skin, mucosal surfaces, and in the gut of an estimated 80% of individuals. Though generally harmless, C. albicans is capable of causing uncomfortable mucosal infections as well as deadly disseminated infections depending on the immune status of the host. Although antifungal therapeutics exist, the mortality rate associated with disseminated disease still lingers around 50%. Further, C. albicans is the fourth most common cause of all bloodstream infections and continues to present as a major clinical issue with less than satisfactory treatment options. For this reason, it is imperative to understand …

Molecular Mechanisms Behind Sars-Cov-2 Induced Host Genome Restructuring, Erin Simpson

Dissertations and Theses (Open Access)

Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) has caused unprecedented morbidity and mortality worldwide. There are two pathophysiological hallmarks associated with severe patient outcomes after SARS-CoV-2 acute infection, namely delayed/weakened interferon production and overactive inflammatory responses. Our previous work has shown that these altered immune responses are due, at least in part, to significant alterations in 3D genome organization and epigenetic landscape following SARS-CoV-2 infection that are distinct from and more severe than changes caused by other viral infections or immune stimulants. While these changes at the chromatin level are important for understanding the immune dysregulation seen in some cases …

Investigating The Roles Of Lung Epithelial Stat3 In Therapeutically Inducible Resistance To Acute Bacterial Pneumonia., Vikram V. Kulkarni, Vikram V. Kulkarni

Dissertations and Theses (Open Access)

Investigating the roles of lung epithelial STAT3 in therapeutically inducible resistance to acute bacterial pneumonia.

Vikram Vitthal Kulkarni, M.S.

Advisory Professor: Scott Evans, MD.

The lung epithelium is a dynamic tissue capable of displaying structural and functional plasticity in response to pathogenic challenges. Our lab has demonstrated that it is possible to therapeutically exploit the lung epithelium’s versatility by inducing resistance to lethal pneumonias caused by viruses, bacteria and fungi. An inhaled combination of a TLR2/6 agonist and a TLR9 agonist (Pam2ODN) results in robust protection against otherwise lethal pneumonia caused by Pseudomonas aeruginosa. Pam2ODN-mediated protection requires key signaling …

Enhancement Of Hiv Persistence By Adipose Tissue, Jacob Couturier

Dissertations and Theses (Open Access)

A major challenge for HIV eradication is the persistence of cellular and anatomic viral reservoirs. The primary cellular reservoirs for HIV, memory CD4 T cells and macrophages, traffic into various tissues where most viral replication occurs, or in the case of virally-suppressed antiretroviral-treated patients, the virus becomes dormant and protected from drugs and immune responses. The major tissue reservoirs for HIV include lymphoid tissues such as lymph nodes, bone marrow, and gastrointestinal lymphoid tissues, but adipose tissues could potentially harbor HIV as well. Adipose tissues are ubiquitous connective tissues and major sites of infiltration and immune activity by T cells …

The Effect Of Activation Induced Cytidine Deaminase Phosphorylation And Herpes Virus Uracil Dna Glycosylase On Antibody Diversification, Marc Macaluso

Dissertations and Theses (Open Access)

Activation-induced cytidine deaminase (AID) is a mutagenic enzyme that is expressed in mammalian B-cells and initiates the antibody diversification processes of somatic hypermuntation (SHM) and isotype class switch recombination (CSR). AID is targeted to the immunoglobulin gene locus where it deaminates cytosines to generate uracil residues in DNA. This generates guanine-uracil (U:G) mismatch lesion which are recognized by uracil DNA glycosylase (UNG), a DNA repair enzyme that removes uracil from DNA and triggers downstream repair of the lesion. While UNG is a ubiquitously expressed DNA repair enzyme, its recognition and removal of AID introduced uracils is essential in both SHM …

Selection Methods For Genetically-Modified T Cells: In Support Of Translational Therapy, David Rushworth

Dissertations and Theses (Open Access)

T cells are blood cells which organize the immune system of the host. These cells are necessary for the host to respond appropriately to threats from foreign organisms and cancerous growth. However, in the case of certain infections and cancer, T cells are unable to respond appropriately to a threat and establish immunity. This leads to disease when the infection or cancer is not sufficiently eliminated. On the other hand, T cells can lack tolerance for healthy tissue and perceive healthy tissue as infected. The ensuing over-reactive immune response also leads to disease. A delicate balance must exist between immunity …

The Role Of Dual Specificity Phosphatase -11 In Innate And Adaptive Immune Responses, Kalyan Chakravarthy Nallaparaju

Dissertations and Theses (Open Access)

THE ROLE OF DUAL SPECIFICITY PHOSPHATASE -11 IN INNATE AND ADAPTIVE IMMUNE RESPONSES

Kalyan Chakravarthy Nallaparaju, M.S.

Supervisory Professor: Chen Dong, Ph.D.

Dual-specificity phosphatases (DUSPs) constitute a subfamily of protein tyrosine phosphatases characterized by their ability to dephosphorylate both phosphotyrosine and phosphoserine/phosphothreonine residues within a substrate, typically among members of the MAP kinase family. DUSPs have been shown to play a critical role in the regulation of various cellular processes including signal transduction, cell cycle regulation and cellular proliferation via modulation of MAP kinase activities. Also, many members of this family have been demonstrated to be potent immune regulators. …

The Role Of The C5a Receptor In Host Defense Against Listeria Monocytogenes, Daniel Calame

Dissertations and Theses (Open Access)

Listeria monocytogenes (Lm) is a major cause of mortality resulting from food poisoning in the United States. While the complement component C5 is known to be protective in listeriosis, it is unknown how its cleavage fragment C5a participates. Here we show in a model of systemic Lm infection that the C5a receptor is essential for host defense. C5aR-/- mice have reduced survival and increased bacterial burden in the liver and spleen in comparison to WT mice. Surprisingly, C5aR-/- mice also have a dramatic reduction in splenocyte numbers resulting from elevated cell death as indicated by TUNEL staining and caspase 3 …

C-Jun N-Terminal Kinases Regulate Adenovirus-Mediated Autophagy And Antigen Presentation, Sarah R. Klein

Dissertations and Theses (Open Access)

Targeted immunotherapy with recombinant, oncolytic adenoviruses is under investigation for the treatment of cancer. Evidence indicates adenoviruses induce autophagy that is required for oncolysis, but the molecular regulation of autophagy in infected cells remains under investigation. Our data suggested the canonical pathway regulating starvation-induced autophagy was not implemented in adenovirus-induced autophagy; however, adenovirus infection triggered phosphorylation of c-Jun N-terminal kinases (JNK) that was essential for autophagy. Adenoviral replication within the host cell elicited JNK pathway activation leading to B cell lymphoma-2 (Bcl-2) phosphorylation. JNK-dependent Bcl-2 phosphorylation stimulated the dissociation of Bcl-2/beclin 1 heterodimers, enabling beclin 1 to initiate autophagy. Moreover, …

Regulation Of To Xin Synthesis By Clostridium Difficile, Charles Darkoh

Dissertations and Theses (Open Access)

Clostridium difficile is the leading definable cause of nosocomial diarrhea worldwide due to its virulence, multi-drug resistance, spore-forming ability, and environmental persistence. The incidence of C. difficile infection (CDI) has been increasing exponentially in the last decade. Virulent strains of C. difficile produce either toxin A and/or toxin B, which are essential for the pathogenesis of this bacterium. Current methods for diagnosing CDI are mostly qualitative tests that detect the bacterium, the toxins, or the toxin genes. These methods do not differentiate virulent C. difficile strains that produce active toxins from non-virulent strains that do not produce toxins or produce …

Role Of Vitamin-D3 And Retinoic Acid In A Human Thp-1 Macrophage Model Of Mycobacterium Tuberculosis Infection, Jaymie L. Estrella

Dissertations and Theses (Open Access)

Mycobacterium tuberculosis (Mtb) replicates within the human macrophages and we investigated the activating effects of retinoic acid (RA) and vitamin D3 (VD) on macrophages in relation to the viability of Mtb. A combination of these vitamins (RAVD) enhanced the receptors on THP-1 macrophage (Mannose receptor and DC-SIGN) that increased mycobacterial uptake but inhibited the
subsequent intracellular growth of Mtb by inducing reactive oxygen species (ROS) and autophagy. RAVD also enhanced antigen presenting and homing receptors in THPs that suggested an activated phenotype for THPs following RAVD treatment. RAVD mediated activation was also associated with a marked phenotypic change in Mtb …

The Role Of Mucosal Epithelial Cells In Hiv-1 Infection, Danielle Fontenot

Dissertations and Theses (Open Access)

The predominant route of human immunodeficiency virus type 1 (HIV-1) transmission is infection across the vaginal mucosa. Epithelial cells, which form the primary barrier of protection against pathogens, are the first cell type at these mucosal tissues to encounter the virus but their role in HIV infection has not been clearly elucidated. Although mucosal epithelial cells express only low levels of the receptors required for successful HIV infection, productive infection does occur at these sites. The present work provides evidence to show that HIV exposure, without the need for productive infection, induces human cervical epithelial cells to produce Thymic Stromal …