Medicine and Health Sciences Commons^™

A Mechanistic And Genomic Analysis Of Molluscum Contagiosum Virus Immune Evasion, Ian Benjamin Harvey

Arts & Sciences Electronic Theses and Dissertations

Molluscum contagiosum virus (MCV) is a common human-specific poxvirus with a proclivity for

infecting children and the immune-compromised. A characteristic MCV infection is restricted to

the epidermal layers of the skin and can persist for weeks to years in an otherwise healthy

individual. The high clinical burden of MCV is at odds with our limited knowledge regarding how

it successfully evades the human immune response, which is in part due to the lack of an animal

model or cell line to propagate the virus. Through this dissertation, we have uncovered and

characterized a novel mechanism by which MC80, a protein …

Mechanisms Of Cross-Presentation By Cdc1s, Derek James Theisen

Arts & Sciences Electronic Theses and Dissertations

Classical dendritic cells (cDCs) are specialized antigen presenting cells that can be divided into distinct subsets based on the types of pathogens they respond to and the type of immune response they generate. The cDC1 subset is specialized in priming CD8 T cell responses through the process of cross-presentation. During cross-presentation, exogenous protein antigens are taken up by cDC1 and presented on MHCI molecules, allowing for the priming of CD8 T cells during conditions when DCs themselves are not directly infected. The ability to cross-present in vivo is unique to cDC1, and is essential for anti-viral responses and rejection of …

Mechanisms Of Sting-Associated Vasculopathy And Immunodeficiency, Brock Gordon Bennion

Arts & Sciences Electronic Theses and Dissertations

STING N153S in mice and STING N154S in humans cause spontaneous autoimmunity. Specifically, these mutations reduce the numbers of T cells and NK cells, and cause lung disease. However, mice develop perivascular lung inflammation that is distinct from the pulmonary fibrosis observed in human patients. Viral infections are known to exacerbate autoimmunity and foment pulmonary fibrosis. Therefore, we hypothesized that exposure to a virus may influence STING N153S disease in mice. To test this, we infected STING N153S animals with the gammaherpesvirus family member, gHV68, and found that 14 days post infection pulmonary fibrosis was readily observed by histological staining. …

Dendritic Cell Development And Function, Vivek Durai

Arts & Sciences Electronic Theses and Dissertations

Dendritic cells (DCs) are a group of immune cells that include both classical dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs). cDCs are further comprised of two distinct subsets, cDC1s and cDC2s, which play critical roles in the initiation of innate and adaptive immune responses. Understanding how these lineages develop and function is therefore paramount. All DCs require the receptor tyrosine kinase Flt3 and its ligand Flt3L for their development, but the loss of Flt3L in mice leads to a more severe DC deficiency than does the loss of Flt3. This has led to speculation that Flt3L can bind to …

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 …

Epigenetic And Signaling Pathways Regulating The Maintenance Of Cd8 T Cell Identity And Function, Daniel Verbaro

Arts & Sciences Electronic Theses and Dissertations

In response to infection, antigen specific CD4 and CD8 T cells rapidly divide to provide help to the immune system and promote cytotoxicity of infected cells, respectively. Through this rapid division, CD4 and CD8 T cells maintain silencing of the opposing lineage’s genes, which is essential to acutely eliminating pathogens. However, not all pathogens are acutely eliminated even when silencing is maintained, and the pathogen persists in the presence of activated CD8 T cells. CD8 T cells chronically exposed to antigen are phenotypically different than CD8 T cells acutely exposed to antigen, but CD8 T cell still exert control over …

Effects Of Toxoplasma Gondii Infection On Nk Cells And Ilc1s, Eugene Park

Arts & Sciences Electronic Theses and Dissertations

Natural killer cells and Type I innate lymphoid cells (ILCs) are subsets of ILCs. In C57BL/6 mice, they share expression of the surface markers NK1. 1 and NKp46, and can produce the cytokine interferon-gamma. These similarities led to the initial classification of natural killer cells and Type I ILCs together under the category of Group 1 ILCs. However, more recent studies found that natural killer cells and ILC1s develop from distinct progenitor cells and utilize transcription factor in distinct manners. Whereas ILC1s require Tbet for their development and are Eomes-independent, natural killer cells require Tbet only for terminal maturation and …

In Vivo Mechanisms Of Natural Killer Cell Tolerance, Michael Bern

Arts & Sciences Electronic Theses and Dissertations

Natural killer (NK) cells are cytotoxic innate immune cells that provide protection from pathogens and tumors. To carry out these functions, NK cells must distinguish between healthy and unhealthy self-cells. Inability to recognize stressed cells would lead to a failure of NK-cell immunity whereas inability to identify healthy cells could lead to NK-cell autoimmunity. It remains unclear, however, how NK cells are able to distinguish healthy and unhealthy self-cells with a limited repertoire of germline-encoded receptors. The "missing-self" hypothesis proposes that NK cells identify stressed cells by their reduced expression of MHC class I (MHC-I) that is almost ubiquitously expressed …

Signaling Mechanisms In Adaptive Immunity, Saravanan Raju

Arts & Sciences Electronic Theses and Dissertations

The adaptive immune response consists of interplay between CD4 T cells, CD8 T cells, and B cells which function in control of pathogen in the host. T cells responding via their TCR express cytokines and costimulatory molecules that support direct effector activity and also promote high-affinity antibody generation through augmenting of B cell responses. However, the molecular components that contribute T cell function to balance viral control and the potential for host damage are incompletely understood. In this work, we establish a role for the adaptor molecule CD2AP in modulation of CD4 T cell responses to chronic LCMV infection in …

Regulation And Function Of Trem2-Dependent Pathways In Neurodegeneration, Wilbur Madison Song

Arts & Sciences Electronic Theses and Dissertations

Carriers of the R47H allele of the microglia-specific lipid receptor TREM2 have a greatly increased risk of developing Alzheimerճ disease. The objective of this dissertation is to develop further mechanistic knowledge about how TREM2 is regulated and how TREM2 mutations affect microglia and neurodegeneration. Using an in vitro reporter assay, we find that several AD risk-associated TREM2 mutations decrease ligand-dependent activation. Using humanized TREM2 mice, we find that in vivo, the R47H mutation leads to reduced microglia activation and response to A_, as well as decreased shedding of soluble TREM2. These results suggest that TREM2 is protective during disease. We …

Metabolic Requirements Of Nk Cell Responses To Viral Infection, Annelise Yoo Mah-Som

Arts & Sciences Electronic Theses and Dissertations

In recent years, the field of immunometabolism – the study of how specific changes in cellular metabolism regulate the function of diverse immune cell types—has grown exponentially. Several in vitro studies have examined the metabolic regulation of natural killer (NK) cells, which are first responders for viral infection and malignant transformation; however, much less is known regarding the role of metabolism in directing NK cell responses in vivo, such as during viral infection. In order to examine how NK cell antiviral function is regulated in vivo, we used a wellcharacterized infection with murine cytomegalovirus (MCMV) to assess NK cell cytokine …

The Enzymatic Function Of The Tir Domain: From Axon Degeneration To Innate Immunity, Kow Essuman

Arts & Sciences Electronic Theses and Dissertations

The Toll/Interleukin-1 Receptor (TIR) domain is an evolutionarily ancient protein domain conserved from bacteria to eukaryotes, and is an essential signaling component of innate immunity pathways. In animal innate immunity, TIR domains have primarily been described for their scaffolding function in assembling protein complexes in host defense. In plant immunity, TIR domains are key components of the intracellular Nucleotide Binding Leucine rich repeat (NLR) immune receptors that confer resistance to pathogens. These NLR receptors trigger cell death and an immune response upon activation, but their mechanism has remained elusive. In bacteria, TIR domain proteins have been suggested to function as …

Effects Of Agonistic Anti-Cd137 Antibody On Chikungunya Virus Infection And B Cell Responses, Jun Hong

Arts & Sciences Electronic Theses and Dissertations

CD137, a member of the tumor necrosis factor receptor superfamily of cell surface proteins, acts as a costimulatory receptor on T cells, natural killer cells, B cell subsets, and some dendritic cells. Agonistic anti-CD137 monoclonal antibody (MAb) therapy has been combined with other chemotherapeutic agents in human cancer trials. Based on its ability to promote tumor clearance, we hypothesized that anti-CD137 MAb might activate immune responses and resolve chronic viral infections. We evaluated anti-CD137 MAb therapy in a mouse infection model of chikungunya virus (CHIKV), an alphavirus that causes chronic polyarthritis in humans and is associated with reservoirs of CHIKV …

Identification And Characterization Of A Novel Non-Homologous End Joining Factor Mri, Putzer Joseph Hung

Arts & Sciences Electronic Theses and Dissertations

Non-homologous end joining (NHEJ) is the predominant DNA double-strand break (DSB) repair pathway in G1-phase cells. In particular, developing lymphocytes utilize NHEJ to repair physiologic DSBs generated during the processes of antigen receptor gene assembly and class-switch recombination (CSR). Thus, proper regulation of NHEJ is important not only for immune repertoire diversification, but also for the prevention of chromosomal translocations or deletions that can arise from misrepaired DSBs. The XRCC4-like factor (XLF) has been strongly implicated in promoting NHEJ, presumably by tethering broken DNA ends together in a sleeve-like complex, but its necessity appears to be cell context-dependent. While XLF …