Life Sciences Commons^™

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

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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

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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

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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

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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

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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

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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 …