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Innate Signaling Pathways In The Maintenance Of Serological Memory: A Dissertation, Forum M. Raval Jun 2012

Innate Signaling Pathways In The Maintenance Of Serological Memory: A Dissertation, Forum M. Raval

GSBS Dissertations and Theses

Long-term antiviral antibody responses provide protection from re-infection and recurrence of persistent viruses. Using a polyomavirus (PyV) mouse model, our lab has shown that MyD88-deficient mice generate low levels of virus-specific IgG after the acute phase of infection and that these IgG responses have a skewed isotype distribution with low levels of IgG2a/c. Moreover MyD88-deficient mice have reduced numbers of long-lived plasma cells in the bone marrow. These studies suggest an important role of MyD88-mediated signaling in long-term antiviral responses. Our lab has shown that T cell-deficient mice can also maintain long-term virus-specific IgG responses following PyV infection. The ...


The Subtype Specific And Cross-Reactive T Cell Responses To Influenza Viruses In Humans: A Dissertation, Jenny Aurielle B. Babon Apr 2012

The Subtype Specific And Cross-Reactive T Cell Responses To Influenza Viruses In Humans: A Dissertation, Jenny Aurielle B. Babon

GSBS Dissertations and Theses

Human influenza is a contagious respiratory disease resulting in substantial morbidity and mortality worldwide. With the recent cases of avian influenza infections in humans and the heightened concern for an influenza pandemic arising from these infections, it is essential to understand host responses that would confer protective immunity to influenza. The cell-mediated immune responses to influenza virus play an important role during influenza infection.

To analyze the specificity and diversity of memory T-cell responses, we performed a genome-wide screening of T cell epitopes to influenza A virus in healthy adult donors. We identified a total of 83 peptides, 54 of ...


The Role Of Heterologous Immunity In Mediating Natural Resistance To Infection In Human Subjects: A Dissertation, Levi B. Watkin Mar 2012

The Role Of Heterologous Immunity In Mediating Natural Resistance To Infection In Human Subjects: A Dissertation, Levi B. Watkin

GSBS Dissertations and Theses

Heterologous immunity is a mechanism by which immunological memory within an individual, developed in response to a previous infection, plays a role in the immune response to a subsequent unrelated infection. In murine studies, heterologous immunity facilitated by cross-reactive CD8 T-cell responses can mediate either beneficial (protective immunity) or detrimental effects (e.g. enhanced lung and adipose immunopathology and enhanced viral titers) (Selin et al., 1998; Chen et al., 2001; Welsh and Selin, 2002; Nie et al., 2010; Welsh et al., 2010). Protective heterologous immunity results in enhanced clearance of virus during a subsequent infection with an unrelated pathogen. Such ...


M.Tb Killing By Macrophage Innate Immune Mechanisms: A Dissertation, Michelle L. Hartman Sep 2011

M.Tb Killing By Macrophage Innate Immune Mechanisms: A Dissertation, Michelle L. Hartman

GSBS Dissertations and Theses

Macrophages infected with a heavy burden of M.tb Erdman undergo a cell death that initially resembles apoptosis but quickly transitions to necrosis. Unlike the previously reported TNF dependent apoptosis induced by avirulent Mycobacterium [1], this form of macrophage cell death is not microbicidal [2]. Microbicidal effects are observed however, when the heavily infected macrophage encounters an uninfected naïve macrophage. My studies describe in part, the crosstalk between the uninfected and infected macrophage that results in the killing of the intracellular M.tb Cell contact between the two cell populations is not necessary for this killing of bacilli to occur ...


Intranasal Colonization By Streptococcus Pneumoniae Induces Immunological Protection From Pulmonary And Systemic Infection: A Dissertation, Nang H. Maung Aug 2011

Intranasal Colonization By Streptococcus Pneumoniae Induces Immunological Protection From Pulmonary And Systemic Infection: A Dissertation, Nang H. Maung

GSBS Dissertations and Theses

Given that Streptococcus pneumoniae can cause life-threatening pulmonary and systemic infection, an apparent paradox is that the bacterium resides, usually harmlessly, in the nasopharynx of many people. Humoral immunity is thought to be the primary defense against serious pneumococcal infection, and we hypothesized that nasopharyngeal colonization of mice results in the generation of an antibody response that provides long-term protection against lung infection. We found that survival of of C57L/6 mice after intranasal inoculation with wild-type serotype 4 strain TIGR4 pneumococci required B cells but not T cells, suggesting that nasopharyngeal colonization elicited a protective humoral immune response. In ...


Nucleic Acid Sensing By The Immune System: Roles For The Receptor For Advanced Glycation End Products (Rage) And Intracellular Receptor Proteins: A Dissertation, Cherilyn M. Sirois Jul 2011

Nucleic Acid Sensing By The Immune System: Roles For The Receptor For Advanced Glycation End Products (Rage) And Intracellular Receptor Proteins: A Dissertation, Cherilyn M. Sirois

GSBS Dissertations and Theses

As humans, we inhabit an environment shared with many microorganisms, some of which are harmless or beneficial, and others which represent a threat to our health. A complex network of organs, cells and their protein products form our bodies’ immune system, tasked with detecting these potentially harmful agents and eliminating them. This same system also serves to detect changes in the healthy balance of normal functions in the body, and for repairing tissue damage caused by injury. Immune recognition of nucleic acids, DNA and RNA, is one way that the body detects invading pathogens and initiates tissue repair. A number ...


Regulation Of Humoral Immunity By Pim Kinases: A Dissertation, Kristen N. Willems Jun 2011

Regulation Of Humoral Immunity By Pim Kinases: A Dissertation, Kristen N. Willems

GSBS Dissertations and Theses

Pim (Provirus Integration site for Moloney murine leukemia virus) kinases are a family of three serine/threonine kinases involved in cell cycle, survival and metabolism. These kinases were first identified in malignant cells and are most often associated with their role in cancer. Their role in immunity and lymphocytes is less well known. To date, it has been shown that Pim 1 and/or Pim 2 are important for T lymphocyte survival and activation when the Akt signaling pathway is inhibited by rapamycin. In addition, our laboratory has shown that Pim 2 is critical for BLyS-mediated naive B lymphocyte survival ...


The Function Of Innate Γδ T Cell Subsets Is Molecularly Programmed In The Thymus In Three Stages: A Dissertation, Kavitha Narayan Mar 2011

The Function Of Innate Γδ T Cell Subsets Is Molecularly Programmed In The Thymus In Three Stages: A Dissertation, Kavitha Narayan

GSBS Dissertations and Theses

The immune system generates discrete lineages of cells that are designed to respond optimally to environmental cues and infectious agents. Two distinct lineages of T cells, distinguished by expression of either an αβ or γδ T cell receptor (TCR), arise from a common progenitor in the thymus. The type of pathogen and the cytokine milieu directs effector differentiation of αβ T cells in the periphery through the induction of specific transcriptional networks. γδ T cell development is distinct from that of αβ T cells in its ordered rearrangement of TCR genes and the pairing of Vγ and Vδ chains to ...


Immunity, Pathogenesis, And Prevention Of Poxvirus Infections: A Dissertation, Mina O. Seedhom Dec 2010

Immunity, Pathogenesis, And Prevention Of Poxvirus Infections: A Dissertation, Mina O. Seedhom

GSBS Dissertations and Theses

Vaccinia virus (VAC) is the prototypical member of the orthopoxvirus genus of the poxvirus family and the virus used for smallpox vaccinations. The following describes the testing of VAC variants designed to have similar immuno-protective profiles with decreased pathogenicity, examines the immune response to VAC after lethal infection in wild type and lupus-prone mice, and describes a method that allows for the enumeration of VAC-specific CD8+ T in naïve and VAC-immune mice.

The first part describes work examining VAC Wyeth (VAC-Wy) variants engineered to be less pathogenic in vivo. VAC-Wy variants included genes that code for three immunomodulatory proteins, an ...


Dissecting The Role Of Innate Pattern Recognition Receptors And Interferon Regulatory Factor-5 In The Immune Response To Human Metapneumovirus And Other Pathogens: A Dissertation, Zhaozhao Jiang Aug 2010

Dissecting The Role Of Innate Pattern Recognition Receptors And Interferon Regulatory Factor-5 In The Immune Response To Human Metapneumovirus And Other Pathogens: A Dissertation, Zhaozhao Jiang

GSBS Dissertations and Theses

The Innate immune system is the first line of defense against invading microbial pathogens. It is a fast-acting and non-antigen-specific defense system, which employs germline encoded surveillance systems capable of responding to a broad-spectrum of pathogens. The innate immune system involves a variety of immune cells, which express different profiles of surveillance or detection receptors. Upon sensing pathogens, these receptors trigger cell signalling to turn on transcription of inflammatory cytokines, chemokines, anti-microbial peptides and type I Interferons. These effectors have direct effects on the control of pathogen load and also activate the adaptive immune system, which is ultimately required to ...


Endocytosis, Phagocytosis, And Innate Immune Responses: A Dissertation, Christine A. St. Pierre Jul 2010

Endocytosis, Phagocytosis, And Innate Immune Responses: A Dissertation, Christine A. St. Pierre

GSBS Dissertations and Theses

In this dissertation, the roles of endocytosis and phagocytosis pathways in a variety of clinically relevant scenarios were examined. These scenarios include antibody-mediated internalization of cell surface proteins, titanium wear-particle uptake in failed joint replacements, and polymeric microparticle uptake and immune responses for drug delivery or adjuvant use.

The use of antibodies specific for cell surface proteins has become a popular method to deliver therapeutics to target cells. As such, it is imperative to fully understand the ability of antibodies to mediate internalization and endosomal trafficking of the surface protein that it recognizes, so that drug delivery can be optimized ...


Pathogenesis Of The Helicobacter Induced Mucosal Disease: A Dissertation, Calin Stoicov Jun 2010

Pathogenesis Of The Helicobacter Induced Mucosal Disease: A Dissertation, Calin Stoicov

GSBS Dissertations and Theses

Helicobacter pylori causes chronic gastritis, peptic ulceration and gastric cancer. This bacterium is one of the most prevalent in the world, but affects mostly the populations with a lower socioeconomical status. While it causes gastric and duodenal ulcers in only 20% of infected patients, less then 1% will develop gastric adenocarcinoma. In fact, H. pylori is the most important risk factor in developing gastric cancer. Epidemiological studies have shown that 80% of gastric cancer patients are H. pylori positive. The outcome of the infection with this bacterium depends on bacterial factors, diet, genetic background of the host, and coinfection with ...


Regulation Of Immune Pathogenesis By Antigen-Specific Cd8 T Cells Following Sequential Heterologous Infections: A Dissertation, Alex T. Chen Apr 2010

Regulation Of Immune Pathogenesis By Antigen-Specific Cd8 T Cells Following Sequential Heterologous Infections: A Dissertation, Alex T. Chen

GSBS Dissertations and Theses

Previously, our lab demonstrated that heterologous immunity could result in either gain or loss of protective immunity and alteration in immune pathology following infection by a second un-related pathogen. One of the prototypical models to study T cell-mediated heterologous immunity involves two distantly related arenaviruses, namely lymphocytic choriomeningitis virus (LCMV) and Pichinde virus (PV). Each virus encodes a cross-reactive CD8 epitope that has six out of eight in amino acid (aa) similarity with respect to its counterpart at the position 205-212 of the nucleoprotein (NP205). Heterologous challenge between LCMV and PV results in 1) expansion of the cross-reactive NP205-specific CD8 ...


A View Of The Imd Pathway From The Rhim, Kamna Aggarwal Mar 2010

A View Of The Imd Pathway From The Rhim, Kamna Aggarwal

GSBS Dissertations and Theses

Innate immunity is the first line of defense against invading pathogens. It functions to eliminate pathogens and also to control infections. The innate immune response is also important for the development of pathogen-specific adaptive immune responses. As a result, the study of innate immune signaling pathways is crucial for understanding the interactions between host and pathogen. Unlike mammals, insects lack a classical adaptive immune response and rely mostly on innate immune responses.

Innate immune mechanisms have been widely studied in the fruit fly, Drosophila melanogaster. The genetic and molecular tools available in the Drosophila system make it an excellent model ...


Caspase Mediated Cleavage, Iap Binding, Ubiquitination And Kinase Activation : Defining The Molecular Mechanisms Required For Drosophila Nf-Кb Signaling: A Dissertation, Nicholas Paul Paquette Nov 2009

Caspase Mediated Cleavage, Iap Binding, Ubiquitination And Kinase Activation : Defining The Molecular Mechanisms Required For Drosophila Nf-Кb Signaling: A Dissertation, Nicholas Paul Paquette

GSBS Dissertations and Theses

Innate immunity is the first line of defense against invading pathogens. Vertebrate innate immunity provides both initial protection, and activates adaptive immune responses, including memory. As a result, the study of innate immune signaling is crucial for understanding the interactions between host and pathogen. Unlike mammals, the insect Drosophila melanogasterlack classical adaptive immunity, relying on innate immune signaling via the Toll and IMD pathways to detect and respond to invading pathogens. Once activated these pathways lead to the rapid and robust production of a variety of antimicrobial peptides. These peptides are secreted directly into the hemolymph and assist in ...


Respiratory Syncytial Virus (Rsv) Induces Innate Immunity Through Toll-Like Receptors And Acquired Immunity Via The Rsv G Protein: A Dissertation, Matthew R. Murawski Jul 2009

Respiratory Syncytial Virus (Rsv) Induces Innate Immunity Through Toll-Like Receptors And Acquired Immunity Via The Rsv G Protein: A Dissertation, Matthew R. Murawski

GSBS Dissertations and Theses

Respiratory syncytial virus (RSV) causes a common infection that is associated with a range of respiratory illnesses from common cold-like symptoms to serious lower respiratory tract illnesses such as pneumonia and bronchiolitis. RSV is the single most important cause of serious lower respiratory tract illness in children < 1 year of age. Host innate and acquired immune responses activated following RSV infection have been suspected as contributing to RSV disease. Toll-like receptors (TLRs) activate innate and acquired immunity and are candidates for playing key roles in the host immune response to RSV. Leukocytes express TLRs including TLR2, TLR6, TLR3, TLR4, and TLR7 that can potentially interact with RSV and promote immune responses following infection. Using knockout mice, we have demonstrated that TLR2 and TLR6 signaling in leukocytes can activate innate immunity against RSV by promoting TNF-α, IL-6, CCL2 (MCP-1), and CCL5 (RANTES) production. As previously noted, TLR4 also contributed to cytokine activation (71, 90). Furthermore, we demonstrated that signals generated following TLR2 and TLR6 activation were important for controlling viral replication in vivo. Additionally, TLR2 interactions with RSV promoted neutrophil migration and dendritic cell activation within the lung. Collectively, these studies indicate that TLR2 is involved in RSV recognition and subsequent innate immune activation and may play a role in modulating acquired immune responses through DCs.

Despite the fact that RSV is the single ...


The Humanized Mouse Model: The Study Of The Human Alloimmune Response: A Dissertation, Marie A. King May 2008

The Humanized Mouse Model: The Study Of The Human Alloimmune Response: A Dissertation, Marie A. King

GSBS Dissertations and Theses

The transplantation of allogeneic cells and tissues for the treatment of human disease has been a life-saving procedure for many thousands of patients worldwide. However, to date, neither solid organ transplantation nor bone marrow transplantation have reached their full clinical potential. Significant limitations to the advancement of clinical transplantation stem from our current inability to prevent the rejection of allogeneic tissues by the immune system of the host. Similarly, in patients that receive allogeneic bone marrow transplants, we cannot permanently prevent the engrafted immune system from mounting a response against the patient. This problem, termed graft versus host disease is ...


Regulation Of The Nf-Кb Precursor Relish By The Drosophila I-Кb Kinase Complex: A Dissertation, Deniz Erturk Hasdemir May 2008

Regulation Of The Nf-Кb Precursor Relish By The Drosophila I-Кb Kinase Complex: A Dissertation, Deniz Erturk Hasdemir

GSBS Dissertations and Theses

The innate immune system is the first line of defense against infectious agents. It is essential for protection against pathogens and stimulation of long-term adaptive immune responses. Therefore, deciphering the mechanisms of the innate immune system is crucial for understanding the integrated systems of host defense against microbial infections, which is conserved from insects to humans.

Despite lacking a conventional adaptive immune system, insects can mount a robust immune response against a wide array of microbial pathogens. These innate immune mechanisms have been widely studied in Drosophila melanogaster, because of the model system’s powerful genetic, genomic and molecular tools ...


Serotype Cross-Reactive Cd8+ T Cell Response To Heterologous Secondary Dengue Virus Infections In Humans: A Dissertation, Hema Sundara Bashyam Oct 2006

Serotype Cross-Reactive Cd8+ T Cell Response To Heterologous Secondary Dengue Virus Infections In Humans: A Dissertation, Hema Sundara Bashyam

GSBS Dissertations and Theses

The generation of memory T cells following primary exposure to a pathogen is a critical feature of the vertebrate immune system which has evolved as a protective mechanism in order to defend the host against repeated assaults by the patnogen. Memory T cells are long-lived, undergo rapid proliferation upon re-activation, mediate a robust secondary response and clear the pathogen much more efficiently. These aspects have made the generation of memory T cells an attractive goal for the production of both prophylactic and therapeutic vaccines. However, the degeneracy of the T cell receptor, whereby a given T cell recognizes more than ...


Analysis Of Toll-Like Receptor 4 Signal Transduction And Irf3 Activation In The Innate Immune Response: A Dissertation, Daniel C. Rowe Jun 2006

Analysis Of Toll-Like Receptor 4 Signal Transduction And Irf3 Activation In The Innate Immune Response: A Dissertation, Daniel C. Rowe

GSBS Dissertations and Theses

Over the last decade, the innate immune system has been the subject of extensive research. Often overlooked by the robustness and specificity of the adaptive immune system, the innate immune system is proving to be just as complex. The identification of several families of pattern recognition receptors (PRRs) has revealed an ancient yet multifaceted system of proteins that are responsible for initiating host defense. A wide array of pathogens, from virus to bacteria, is detected using this assortment of receptors. One such family, the Toll-like receptors (TLRs), has been at the forefront of this research. To date, 10 TLRs have ...


Macrophages Directly Prime NaïVe Cd8+ T Cells: A Dissertation, Lu-Ann M. Pozzi Sep 2004

Macrophages Directly Prime NaïVe Cd8+ T Cells: A Dissertation, Lu-Ann M. Pozzi

GSBS Dissertations and Theses

Professional antigen presenting cells (APCs) represent an important link between the innate and adaptive immune system. Macrophages (MΦs) and dendritic cells (DCs) serve as sentinels in the periphery collecting samples from their environment and processing this information. These cells then present antigenic fragments to T cells in the context of self-MHC molecules. Although a clear role for both of these APCs in the stimulation of already activated or memory T cells has been established, the ability of MΦs to activate naive T cells is still unknown. In this thesis the ability of bone marrow-derived MΦs and DCs to prime naive ...


The Function Of The Tyrosine Kinase, Itk, In Cd4+ T Cell Differentiation And Death: A Dissertation, Andrew Todd Miller Jul 2003

The Function Of The Tyrosine Kinase, Itk, In Cd4+ T Cell Differentiation And Death: A Dissertation, Andrew Todd Miller

GSBS Dissertations and Theses

The Tec family tyrosine kinase, Itk, plays an important role in signal transduction following T cell receptor engagement. Several prior studies have established the importance of Itk in immune system processes, such as T cell development and T cell activation. Additional biochemical studies have found that Itk specifically functions within a multi-molecular signalosome complex, which ultimately functions to provide a platform by which Itk can phosphorylate and activate PLC-γ1, a crucial step in T cell activation. To further study how Itk regulates distinct immune outcomes via T cell effector processes within the peripheral immune system, and to further understand how ...


Activation And Role Of Memory Cd8 T Cells In Heterologous Antiviral Immunity And Immunopathology In The Lung: A Dissertation, Hong Chen Dec 2002

Activation And Role Of Memory Cd8 T Cells In Heterologous Antiviral Immunity And Immunopathology In The Lung: A Dissertation, Hong Chen

GSBS Dissertations and Theses

Each individual experiences many sequential infections throughout the lifetime. An increasing body of work indicates that prior exposure to unrelated pathogens can greatly alter the disease course during a later infection. This can be a consequence of a phenomenon known as heterologous immunity. Most viruses invade the host through the mucosa of a variety of organs and tissues. Using the intranasal mucosal route of infection, the thesis focused on studying modulation of lymphocytic choriomeningitis virus (LCMV)-specific memory CD8 T cells upon respiratory vaccinia virus (VV) infection and the role of these memory CD8 T cells in heterologous immunity against ...


Cytotoxic T-Lymphocyte Responses During Acute Epstein-Barr Virus Infection, Brian L. Beaulieu May 1996

Cytotoxic T-Lymphocyte Responses During Acute Epstein-Barr Virus Infection, Brian L. Beaulieu

GSBS Dissertations and Theses

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus which causes acute infectious mononucleosis and is etiologically associated with malignant lymphoproliferative disorders including Burkitt's lymphoma, nasopharyngeal carcinoma, B-cell lymphomas in immunocompromised hosts, Hodgkin's disease, T cell lymphomas, and smooth muscle tumors in allograft recipients. The medical significance of EBV is underscored by its potent growth transforming effects on human B-lymphocytes in-vitro and the potentially oncogenic consequences of infection in-vivo. The majority of EBV-associated malignancies occur in the setting of chronic infection and strong virus-specific humoral immunity, suggesting that cellular immunity is primarily responsible for preventing the outgrowth of EBV-transformed ...


Analysis Of Low Zone Tolerance In Normal And B Cell-Deficient Mice, Allison Michelle Baird Apr 1996

Analysis Of Low Zone Tolerance In Normal And B Cell-Deficient Mice, Allison Michelle Baird

GSBS Dissertations and Theses

This thesis investigates the role of B cells as antigen-specific antigen-presenting cells (APC) in self tolerance to low concentrations of soluble self proteins and in acquired tolerance to low doses of soluble foreign protein antigens. Experiments were performed in normal and B cell-deficient animals, and tolerance induction was measured by T cell proliferation assays. T cell proliferation was reduced in B cell-deficient mice, indicating that B cells may be involved in efficient activation of naive T cells in response to protein antigen both in vivo and in vitro. To study acquired tolerance induced by low doses of soluble foreign protein ...


Role Of Recurrent Hydrophobic Residues In Catalyzing Helix Formation By T Cell-Presented Peptides: A Thesis, Shan Lu Dec 1990

Role Of Recurrent Hydrophobic Residues In Catalyzing Helix Formation By T Cell-Presented Peptides: A Thesis, Shan Lu

GSBS Dissertations and Theses

The overall objective of this study was to understand the mechanisms that control antigen processing and binding of peptides to major histocompatibility complex (MHC) molecules. Towards this goal I investigated (a) the structural features of T cell-presented peptides with a focus on the role of recurrent hydrophobic residues in catalysis of helix formation by these peptides and (b) the biochemical events that determine the fates of the invariant chain molecule (Ii) in its various post-translational processing pathways.

In the structural studies, I tested the hypothesis that the recurrence of hydrophobic amino acids in a polypeptide at positions falling in an ...