Life Sciences Commons^™

Robust Odorant Recognition In Biological And Artificial Olfaction, Nalin Katta

McKelvey School of Engineering Theses & Dissertations

Accurate detection and identification of gases pose a number of challenges for chemical sensory systems. The stimulus space is enormous; volatile compounds vary in size, charge, functional groups, and isomerization among others. Furthermore, variability arises from intrinsic (poisoning of the sensors or degradation due to aging) and extrinsic (environmental: humidity, temperature, flow patterns) sources. Nonetheless, biological olfactory systems have been refined over time to overcome these challenges. The main objective of this work is to understand how the biological olfactory system deals with these challenges, and translate them to artificial olfaction to achieve comparable capabilities. In particular, this thesis focuses …

Characterization And Function Of Islet Antigen Presenting Cells During Nod Diabetes, Stephen Thomas Ferris

Arts & Sciences Electronic Theses and Dissertations

Here we characterized the initial antigen presenting cells (APCs) within the islet of Langerhans to ascertain their identity and functional role as it pertains to autoimmune diabetes. The activation of the adaptive immune system is induced by the innate immune system, and more specifically APCs. Therefore, it is crucial to identify the APCs that are initiating T1D in order to elucidate the break in tolerance and intervene in order to inhibit progression. We have found that there is a resident macrophage that is present in all strains of mice. This islet macrophage has a distinct transcriptional profile that is unique …

Identification And Characterization Of An Interferon Stimulated Gene That Restricts Alphavirus Infection And Pathogenesis, Subhajit Poddar

Arts & Sciences Electronic Theses and Dissertations

Viral infection of host cells induces the Type I interferon (IFN) response, which is

characterized by the production of hundreds of IFN-stimulated genes (ISGs). Altogether, these

ISGs function to induce an antiviral state, hindering or blocking various steps of the viral

lifecycle. Many individual ISGs have potent and broad antiviral functions. However elimination

of a single ISG does not completely abrogate protection, suggesting that other ISGs, although

moderate or moderate when considered alone, must work cooperatively to provide optimal

antiviral activity.

In order to identify and characterize novel ISGs, an attenuated strain of the alphavirus

chikungunya (CHIKV-181/25) was tested against …

Expansion Of Microbial Virology By Impetus Of The Reduction Of Viral Dark Matter, Siddharth Ravindran Krishnamurthy

Arts & Sciences Electronic Theses and Dissertations

Modern metagenomic methods have rapidly accelerated the rate of viral discovery. Currently, to discover a novel virus, deep sequencing reads must align to a known reference virus. While alignment is effective at identifying closely related viruses, highly divergent viruses can often share no discernable sequence alignment with known viruses. Therefore, the accurate classification of viral dark matter – metagenomic sequences that originate from viruses but do not align to any reference virus sequences – is one of the major obstacles in not only discovering novel viruses, but also by extension, comprehensively defining the virome. As viral dark matter results fundamentally …

The Role Of Rna Interference In The Control Of Leishmania Rna Virus 1 Infection, Erin Acino Brettmann

Arts & Sciences Electronic Theses and Dissertations

The presence of Leishmania RNA virus 1 (LRV1) in parasites of the Leishmania (Viannia) subgenus increases the virulence of the parasite in mouse models of leishmaniasis and is correlated with treatment failure, relapse, and the development of mucocutaneous disease in humans. LRV1 is not shed or infectious; rather, the infection is persistent, and as yet it is unknown how the parasite controls virus levels. Many eukaryotic organisms use RNA interference (RNAi) to limit virus replication, and Leishmania (Viannia) parasites have an active RNAi pathway. To determine whether Leishmania are capable of using RNAi to control LRV1, we sequenced sRNAs from …

Epigenetic Activation Of The Mouse T Cell Receptor Beta Recombination Center, Jiangyang Zhao

Arts & Sciences Electronic Theses and Dissertations

Lymphocytes are the work horses of adaptive immunity. Compared to the B lymphocyte lineage, early stage progenitors of T lymphocytes maintain considerable potential for differentiation into other hematopoietic lineages. T lineage commitment requires the continuous coordination of transcription factors (TFs) by Notch1 signaling after multi-potent progenitors (MPPs) migrate to thymus. One of the first hall marks of T lineage commitment is expression of the T cell receptor β (TCRβ), which is encoded by the Tcrb locus following its assembly by V(D)J recombination, a somatic shuffling of the genome that joins one V, one D, and one J gene segment. Tcrb …

Mitochondrial Dynamics Controls T Cell Fate Through Metabolic Programming, Michael Buck

Arts & Sciences Electronic Theses and Dissertations

Activated effector T (TE) cells augment anabolic pathways of metabolism, such as aerobic glycolysis, while memory T (TM) cells engage catabolic pathways, like fatty acid oxidation (FAO). However, signals that drive these differences remain unclear. Mitochondria are metabolic organelles that actively transform their ultrastructure. Therefore, we questioned whether mitochondrial dynamics controls T cell metabolism. We show that TE cells have punctate mitochondria, while TM cells maintain fused networks. The fusion protein Opa1 is required for TM, but not TE cells after infection, and enforcing fusion in TE cells imposes TM cell characteristics and enhances antitumor function. Our data suggest that, …

The Role Of Bhlhe40 In Autoimmune Neuroinflammation And Mycobacterial Infection, Chih-Chung Lin

Arts & Sciences Electronic Theses and Dissertations

The mammalian immune system is composed of innate and adaptive compartments, which cooperate with each other to maintain homeostasis and protect the host from the invasion by a variety of pathogens. The tight control of immune responses is extremely important for all individuals. Here, we discovered that the transcription factor basic helix-loop-helix family, member e40 (Bhlhe40) is a critical protein that regulates the autoimmune ("against self") and anti-microbial ("against non-self") responses of myeloid cells and T lymphocytes. Multiple sclerosis (MS) is a human neuroinflammatory disease in the central nervous system with an autoimmune etiology. We have reported that Bhlhe40 positively …

The Role Of Histidine Rich Protein Ii In Cerebral Malaria, Priya Pal

Arts & Sciences Electronic Theses and Dissertations

Human malaria is caused by five species of Plasmodium. Of these, P. falciparum is the deadliest and is the only species that causes cerebral malaria (CM). CM is a disease of the vascular endothelium characterized by parasite sequestration, increased inflammatory cytokine production, vascular leakage and leukocyte infiltration. A distinguishing feature of P. falciparum infection is the parasite’s production and secretion of histidine-rich protein II (HRPII). HRPII accumulates to high concentrations (up to 100 µg/ml) in serum, which correlates with disease severity. Due to high serum levels of this protein, HRPII has classically been considered a biomarker for P. falciparum infection. …

Defining The Ontogeny And Functions Of Macrophages In Pancreatic Ductal Adenocarcinoma, Yu Zhu

Arts & Sciences Electronic Theses and Dissertations

The immune system plays an essential role in protecting the host organisms against both foreign invaders and self-attacks arisen within the host, such as tumors. Instead of promoting the long-term fitness of the organism, the immune system is often suppressed or hijacked by tumor cells to accelerate the progression of malignancies. Among the key drivers of immune suppression, macrophages are one of the most abundant immune cells present in tumor tissues. High levels of macrophage infiltration in the malignant tissues correlate with negative patient outcome in many types of cancers, including pancreatic ductal adenocarcinoma (PDAC), one of the most lethal …

Role Of Atg16l1 In Uropathogenic E. Coli Pathogenesis, Jane Symington

Arts & Sciences Electronic Theses and Dissertations

Urinary tract infections (UTIs) are among the most common infectious diseases and are primarily caused by uropathogenic E. coli (UPEC). Given the greater incidence of antibiotic resistance among UPEC isolates, it is vital to determine factors and pathways important for an effective host response to UPEC in order to improve therapeutic options for combating UTIs. Autophagy is a cellular degradation pathway that plays important roles in pathogen control and modulation of innate immunity. One essential autophagy protein, ATG16L1, has been further implicated in controlling inflammation due to a common variant of ATG16L1 being associated with increased risk of Crohns disease, …

Granulocyte-Colony Stimulating Factor Reprograms The Bone Marrow Microenvironment To Suppress B Lymphopoiesis, Ryan Brent Day

Arts & Sciences Electronic Theses and Dissertations

The production of hematopoietic cells in the bone marrow is tightly and dynamically regulated in response to environmental stimuli. In response to infection, the bone marrow increases granulopoiesis at the expense of lymphopoiesis. The mechanisms mediating this shift are poorly understood. We show that treatment with granulocyte-colony stimulating factor (G-CSF), which is often induced during infection, results in marked decline of B lymphocytes at multiple stages of bone marrow B cell development. Transgenic mouse models show that G-CSF acts in a non-cell intrinsic fashion through cells of the monocyte-macrophage lineage to suppress B lymphopoiesis by downregulating important B trophic factors …

Omcp Mediated Cowpox Virulence And Its Dependence On The Immune Receptors Nkg2d And Fcrl5., Michel Muzi Sun

Arts & Sciences Electronic Theses and Dissertations

Viruses with large DNA genomes, such as cowpox virus, encode many open-reading frames involved in the modulation of the host immune system, facilitating escape from immune detection or downregulation of specific aspects of the host immune response. Investigation of virally-encoded immunoevasins has been instrumental in understanding host-pathogen interactions. Here, we focus on the cowpox virus immunoevasin Orthopoxvirus MHC Class I-like Protein (OMCP) and demonstrate for the first time that OMCP facilitates cowpox virus virulence in vivo. We have previously documented that OMCP binds the activating receptor NKG2D on NK cells as well as the orphan receptor FCRL5 on innate B …

Iron Regulation Of Macrophage Responses To Uropathogenic E. Coli, Nana Kwame Owusu-Boaitey

Arts & Sciences Electronic Theses and Dissertations

Uropathogenic E. coli (UPEC) are the principal cause of urinary tract infections (UTIs), one of the most common infections globally. Given the rising incidence of antibiotic resistance among UPEC strains, there is an increasing need to better understand the host response to UPEC and to develop ways to harness the bladder innate immune response that clears infection. In response to infection, the host attempts to limit the ability of UPEC to access iron, a metal critical to UPEC survival. Innate immune cells known as macrophages are known to regulate iron homeostasis through the production of pro-inflammatory cytokines, though it remains …

Understanding The Interactions Of Developing Thymocytes And Antigen Presenting Cells In The Thymic Medulla, Justin Shaun Arnold Perry

Arts & Sciences Electronic Theses and Dissertations

Various thymic APC subsets have been invoked in deletional tolerance and Treg cell induction, but previous studies either assessed total T cell numbers or used TCR transgenic lines, obscuring roles that individual thymic APC subsets might serve for particular antigen-specific T cell populations. Utilizing T cell receptor sequencing, we found that medullary thymic epithelial cells (mTECs) and bone marrow-derived (BM) APCs delete or select unique conventional and Treg cell TCR repertoires, demonstrating distinct roles for these APCs. We show that BM APCs and mTECs each contribute to Aire-dependent T cell tolerance development, albeit through either cooperative or autologous antigen presentation …

The Resolution Phase Of Nk Cell Proliferation And Ifn Production Following Viral Infection Are Highly Regulated Processes., Leslie Abigail Fogel

Arts & Sciences Electronic Theses and Dissertations

In response to MCMV infection, NK cells undergo three distinct phases of proliferation: the non-specific phase mediated by pro-proliferative cytokines; the specific phase mediated by recognition of an MCMV-encoded protein by an NK cell activating receptor, Ly49H; and the resolution phase, whose mechanism is unknown. MCMV infection of RAG mice, which lack all adaptive immune cells, results in prolonged proliferation of NK cells despite similar viral titers compared to wildtype mice. Interestingly, there are different kinetics for Ly49H+ and Ly49H- NK cells. We have identified several additional markers that may distinguish NK cells that have been specifically activated through their …

Structural Mechanism Of Orthopoxvirus Sabotage Of Mhci Antigen Presentation, William Howard Mccoy Iv

All Theses and Dissertations (ETDs)

Immunomodulatory proteins that subvert major histocompatibility complex class I: MHCI) antigen presentation can help viruses to evade cytotoxic T-lymphocyte: CTL) detection and clearance. Cowpox virus, like other orthopoxvirus family members, is a large DNA virus, whose genomic termini encode numerous immunomodulatory genes, including two ER-resident MHCI saboteurs: CPXV012 and CPXV203). CPXV012 inhibits peptide loading of MHCI within the peptide-loading complex: PLC), while CPXV203 inhibits surface expression of both murine and human MHCI through the use of a C-terminal ER-retention sequence: KTEL). An association: direct or indirect) between CPXV203 and MHCI was first demonstrated in pull-down experiments. This doctoral work explores …

A Role For Interferon Stimulated Gene-15 (Isg15) During Chikungunya Virus Infection, Scott Werneke

All Theses and Dissertations (ETDs)

Abstract of the Dissertation

A Role for Interferon Stimulated Gene-15: ISG15) During Chikungunya Virus Infection

By

Scott William Werneke

Doctor of Philosophy in Biology and Biomedical Science

(Immunology)

Washington University in St. Louis, 2013

Professor Deborah J. Lenschow, Chairperson

Chikungunya fever is caused by Chikungunya virus: CHIKV), an infectious disease that is characterized by severe joint and muscle pain in humans. The latest outbreak of CHIKV, which began in 2005, has affected millions of people across India, Singapore, and the Indian Ocean Island region. Type I interferon: IFN), which mediates protection against many different viruses through the upregulation of interferon …

Tumor Antigens Revealed By Exome Seqeuncing Drive Editing Of Tumor Immunogenicity, Matthew David Vesely

All Theses and Dissertations (ETDs)

Accumulated data from animal models and human cancer patients strongly support the concept that immunity cannot only function as an extrinsic tumor suppressor, but also shape tumor immunogenicity. These observations led to the development of the cancer immunoediting hypothesis that stresses the dual host-protective and tumor-sculpting actions of immunity on developing cancers. We previously demonstrated important roles for lymphocytes and type I: IFN-α/β) and type II: IFN-γ) interferons in cancer immunoediting. In the present work, we confirmed the role of IFN-γ in sculpting tumor immunogenicity and provide evidence that antigens expressed by tumors drive the destructive or sculpting actions of …

Genetic And Epigenetic Interactions In In Vivo And In Vitro Reprogramming, Margaret Ashley Young

All Theses and Dissertations (ETDs)

In cancer pathogenesis and induced pluripotent stem: iPS) cell production, an essential step for reprogramming is acquisition of self-renewal. In hematopoietic cells, HOX genes are partially responsible for self-renewal, and HOX gene dysregulation commonly occurs in acute myeloid leukemia: AML). HOX dysregulation is seen in AML with translocations involving HOX genes themselves: e.g. NUP98-HOXA9) and with other disease-initiating translocations: e.g. MLL translocations and inv(16)). However, HOX genes are also highly expressed in many AML samples without translocations; the mechanism that causes "dysregulation" in these cases is unknown. Whole genome sequencing of 45 de novo AML genomes showed that recurrent mutations …

Batf3-Deficient Mice: Susceptibility To Toxoplasma Gondii And Responses To Il-12 Treatment In Vivo, Mona Mashayekhi

All Theses and Dissertations (ETDs)

CD8α+ dendritic cells are important in vivo for cross-presentation of antigens derived from intracellular pathogens and tumors. Additionally, stimulation of IL-12 production by CD8α+ DCs has suggested a role for these cells in response to Toxoplasma gondii antigens, although no experiments have yet shown an in vivo requirement for these cells against T. gondii infection. Towards this goal, we examined T. gondii infection of Batf3-/- mice, which selectively lack only lymphoid-resident CD8α+ DCs and related peripheral CD103+ DCs. Batf3-/- mice were extremely susceptible to T. gondii infection, with defective priming of CD8+ T cells, and decreased production of IL-12 and …

Mechanisms Of Protective Activity Of West Nile Virus Anti-Envelope Antibodies In Vitro And In Vivo, Matthew Raymond Vogt

All Theses and Dissertations (ETDs)

West Nile virus: WNV) is a neurotropic flavivirus capable of causing severe disease and death in humans. Studies in mice have demonstrated that the humoral immune response against WNV limits primary infection and protects against a secondary challenge. Accordingly, passive transfer of immune serum or monoclonal antibodies: MAb) against the envelope: E) protein either prior to WNV infection or shortly thereafter is sufficient to protect mice from disease. The E protein is an immunodominant antigen in the antibody response to WNV infection, and the most potent neutralizing MAbs recognize an epitope on the lateral ridge of domain III: DIII-LR) of …

The Molecular Basis Of Antibody Mediated Neutralization Of Hepatitis C Virus, Michelle Catherine Sabo

All Theses and Dissertations (ETDs)

Hepatitis C virus: HCV) is positive strand, blood-borne, hepatotropic RNA virus that causes chronic infection in ~170 million people worldwide and is the leading cause of liver transplantation in the United States. HCV entry and attachment is mediated by the envelope protein E2 through interaction with several cellular receptors including CD81, scavenger receptor B1: SRB-1), claudin-1, and occludin, although the exact mechanism by which these receptors facilitate infection remains unclear, largely due to the absence of a structural model of E2. The production of neutralizing antibodies against E2 is thought to be important for controlling HCV infection, likely by blocking …