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The Major Histocompatibility Complex In Song Sparrows: Immunity, Signals, And Mate Choice, Joel W.G. Slade 2018 The University of Western Ontario

The Major Histocompatibility Complex In Song Sparrows: Immunity, Signals, And Mate Choice, Joel W.G. Slade

Electronic Thesis and Dissertation Repository

In recent years, sexual selection theory has redefined genetic quality to consider not only additive genetic effects on fitness but also non-additive genetic effects, such as heterozygote advantage or disadvantage. In jawed vertebrates, the major histocompatibility complex (MHC) gene family has been shown to exhibit both additive and non-additive genetic effects on fitness. MHC gene products are involved in initiating adaptive immune responses, and MHC genotype determines the range of pathogens to which an individual can respond. Therefore, parasite-mediated selection at MHC may favour locally-adapted, rare, or particular combination of alleles. Because heterozygote advantage at MHC is widespread, sexual selection ...


Severity Of Acute Infectious Mononucleosis Correlates With Cross-Reactive Influenza Cd8 T-Cell Receptor Repertoires, Nuray Aslan, Levi B. Watkin, Anna Gil, Rabinarayan Mishra, Fransenio G. Clark, Raymond M. Welsh, Dario Ghersi, Katherine Luzuriaga, Liisa K. Selin 2017 University of Massachusetts Medical School

Severity Of Acute Infectious Mononucleosis Correlates With Cross-Reactive Influenza Cd8 T-Cell Receptor Repertoires, Nuray Aslan, Levi B. Watkin, Anna Gil, Rabinarayan Mishra, Fransenio G. Clark, Raymond M. Welsh, Dario Ghersi, Katherine Luzuriaga, Liisa K. Selin

UMass Center for Clinical and Translational Science Supported Publications

Fifty years after the discovery of Epstein-Barr virus (EBV), it remains unclear how primary infection with this virus leads to massive CD8 T-cell expansion and acute infectious mononucleosis (AIM) in young adults. AIM can vary greatly in severity, from a mild transient influenza-like illness to a prolonged severe syndrome. We questioned whether expansion of a unique HLA-A2.01-restricted, cross-reactive CD8 T-cell response between influenza virus A-M158 (IAV-M1) and EBV BMLF1280 (EBV-BM) could modulate the immune response to EBV and play a role in determining the severity of AIM in 32 college students. Only ex vivo total IAV-M1 and IAV-M1+EBV-BM ...


Molecular Evolution Of Dengue Type 2 Virus In Thailand, Rebeca Rico-Hesse, Lisa M. Harrison, Ananda Nisalak, David W. Vaughn, Siripen Kalayanarooj, Sharone Green, Alan L. Rothman, Francis A. Ennis 2017 Yale University School of Medicine

Molecular Evolution Of Dengue Type 2 Virus In Thailand, Rebeca Rico-Hesse, Lisa M. Harrison, Ananda Nisalak, David W. Vaughn, Siripen Kalayanarooj, Sharone Green, Alan L. Rothman, Francis A. Ennis

Sharone Green

Dengue is a mosquito-borne viral infection that in recent years has become a major international public health concern. Dengue hemorrhagic fever (DHF), first recognized in Southeast Asia in the 1950s, is today a leading cause of childhood death in many countries. The pathogenesis of this illness is poorly understood, mainly because there are no laboratory or animal models of disease. We have studied the genetic relationships of dengue viruses of serotype 2, one of four antigenically distinct dengue virus groups, to determine if viruses obtained from cases of less severe dengue fever (DF) have distinct evolutionary origins from those obtained ...


Rapid Diagnosis Of Dengue Viremia By Reverse Transcriptase-Polymerase Chain Reaction Using 3'-Noncoding Region Universal Primers, T. Mirawati Sudiro, Hiroaki Ishiko, Sharone Green, Ananda Nisalak, David W. Vaughn, Siripen Kalayanarooj, Alan L. Rothman, Boonyos Raengsakulrach, Jurand Janus, Ichiro Kurane, Francis A. Ennis 2017 University of Massachusetts Medical School

Rapid Diagnosis Of Dengue Viremia By Reverse Transcriptase-Polymerase Chain Reaction Using 3'-Noncoding Region Universal Primers, T. Mirawati Sudiro, Hiroaki Ishiko, Sharone Green, Ananda Nisalak, David W. Vaughn, Siripen Kalayanarooj, Alan L. Rothman, Boonyos Raengsakulrach, Jurand Janus, Ichiro Kurane, Francis A. Ennis

Sharone Green

A reverse transcriptase-polymerase chain reaction (RT-PCR) method was developed as a rapid diagnostic test of dengue viremia. To detect dengue viruses in serum or plasma specimens, a pair of universal primers was designed for use in the RT-PCR. Using these primers, the 3'-noncoding region of dengue virus types 1, 2, 3, and 4 could be amplified, but not those of other flaviviruses, such as West Nile virus, Japanese encephalitis virus, and yellow fever virus, or the alphavirus Sindbis virus. The sensitivity of the RT-PCR assay was similar to that of a quantitative fluorescent focus assay of dengue viruses in ...


Cytoplasmic Proteins As Autoantigens In The Development Of Inflammatory Heart Disease, Bharathi Yalaka 2017 University of Nebraska-Lincoln

Cytoplasmic Proteins As Autoantigens In The Development Of Inflammatory Heart Disease, Bharathi Yalaka

Dissertations & Theses in Veterinary and Biomedical Science

Inflammatory heart disease can result from infectious or non-infectious etiologies. When infectious causes are involved, autoimmune responses are commonly suspected to explain persistence of inflammation, leading to the suggestion that pathogens primarily affecting the target organs can lead to a secondary generation of autoimmune responses. In addressing this hypothesis, we had previously reported that Coxsackievirus B3 (CVB) infection accompanies the generation of cardiac myosin-specific T cells, which can transfer disease to naïve mice. This work led us to propose that the postinfectious phase of CVB infection involves the generation of autoreactive T cells with multiple antigen specificities. To this end ...


Suppression Of Systemic Autoimmunity By The Innate Immune Adaptor Sting, Shrutie Sharma, Allison M. Campbell, Jennie Chan, Stefan A. Schattgen, Gregory M. Orlowski, Ribhu Nayar, Annie H. Huyler, Kerstin Nundel, Chandra Mohan, Leslie J. Berg, Mark J. Shlomchik, Ann Marshak-Rothstein, Katherine A. Fitzgerald 2017 University of Massachusetts Medical School

Suppression Of Systemic Autoimmunity By The Innate Immune Adaptor Sting, Shrutie Sharma, Allison M. Campbell, Jennie Chan, Stefan A. Schattgen, Gregory M. Orlowski, Ribhu Nayar, Annie H. Huyler, Kerstin Nundel, Chandra Mohan, Leslie J. Berg, Mark J. Shlomchik, Ann Marshak-Rothstein, Katherine A. Fitzgerald

Katherine A. Fitzgerald

Cytosolic DNA-sensing pathways that signal via Stimulator of interferon genes (STING) mediate immunity to pathogens and also promote autoimmune pathology in DNaseII- and DNaseIII-deficient mice. In contrast, we report here that STING potently suppresses inflammation in a model of systemic lupus erythematosus (SLE). Lymphoid hypertrophy, autoantibody production, serum cytokine levels, and other indicators of immune activation were markedly increased in STING-deficient autoimmune-prone mice compared with STING-sufficient littermates. As a result, STING-deficient autoimmune-prone mice had significantly shorter lifespans than controls. Importantly, Toll-like receptor (TLR)-dependent systemic inflammation during 2,6,10,14-tetramethylpentadecane (TMPD)-mediated peritonitis was similarly aggravated in STING-deficient mice ...


Discovery Of Pf-06928215 As A High Affinity Inhibitor Of Cgas Enabled By A Novel Fluorescence Polarization Assay, Justin Hall, Douglas T. Golenbock, Eicke Latz 2017 Pfizer

Discovery Of Pf-06928215 As A High Affinity Inhibitor Of Cgas Enabled By A Novel Fluorescence Polarization Assay, Justin Hall, Douglas T. Golenbock, Eicke Latz

Open Access Articles

Cyclic GMP-AMP synthase (cGAS) initiates the innate immune system in response to cytosolic dsDNA. After binding and activation from dsDNA, cGAS uses ATP and GTP to synthesize 2', 3' -cGAMP (cGAMP), a cyclic dinucleotide second messenger with mixed 2'-5' and 3'-5' phosphodiester bonds. Inappropriate stimulation of cGAS has been implicated in autoimmune disease such as systemic lupus erythematosus, thus inhibition of cGAS may be of therapeutic benefit in some diseases; however, the size and polarity of the cGAS active site makes it a challenging target for the development of conventional substrate-competitive inhibitors. We report here the development of ...


Evaluation Of Il2 And Hla On The Homeostasis And Function Of Human Cd4 And Cd8 T Cells, Philip A. Durost 2017 University of Massachusetts Medical School

Evaluation Of Il2 And Hla On The Homeostasis And Function Of Human Cd4 And Cd8 T Cells, Philip A. Durost

GSBS Dissertations and Theses

Homeostasis of human T cells is regulated by many factors that control proliferation, differentiation of effector cells and generation of memory. Our current knowledge of the mechanisms controlling human T cell homeostasis in vivo is based on experiments in small animal models. However many differences exist between immune systems of mice and humans, including cell composition, function, and gene expression. Humanized mouse models have shown great value in the study of human immunobiology. I have used novel humanized mouse models to examine the role of human MHC (HLA) and human IL2 in CD8 T cell and CD4 regulatory T cell ...


Different Journeys, Same Destination: Exploring The Role Of A Pyhin Protein And Involvement Of Caspase-8 In The Regulation And Activation Of Inflammasomes, Sreya Ghosh 2017 University of Massachusetts Medical School

Different Journeys, Same Destination: Exploring The Role Of A Pyhin Protein And Involvement Of Caspase-8 In The Regulation And Activation Of Inflammasomes, Sreya Ghosh

GSBS Dissertations and Theses

Interferon-inducible PYHIN protein family includes the DNA-binding proteins, AIM2 and IFI16, which form ASC-caspase 1 dependent inflammasomes, important in immunity against cytosolic bacteria, DNA viruses and HIV. The role of other members of this family in the recognition of DNA and/or regulation of immune responses is unclear. We identified an immune regulatory function of p205, another member of the PYHIN family, in the transcriptional control of immune genes. Knockdown of p205 in macrophages revealed that inflammasome activation due to dsDNA and ligands that engage the NLRP3 inflammasome were severely compromised. Detailed mechanistic analysis showed that loss of p205 was ...


Alloimmune Responses Of Humanized Mice To Human Pluripotent Stem Cell Therapeutics, Nigel G. Kooreman, Michael A. Brehm, Dale L. Greiner, Leonard D. Shultz, Joseph C. Wu 2017 Stanford University

Alloimmune Responses Of Humanized Mice To Human Pluripotent Stem Cell Therapeutics, Nigel G. Kooreman, Michael A. Brehm, Dale L. Greiner, Leonard D. Shultz, Joseph C. Wu

Open Access Articles

There is growing interest in using embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) derivatives for tissue regeneration. However, an increased understanding of human immune responses to stem cell-derived allografts is necessary for maintaining long-term graft persistence. To model this alloimmunity, humanized mice engrafted with human hematopoietic and immune cells could prove to be useful. In this study, an in-depth analysis of graft-infiltrating human lymphocytes and splenocytes revealed that humanized mice incompletely model human immune responses toward allogeneic stem cells and their derivatives. Furthermore, using an "allogenized" mouse model, we show the feasibility of reconstituting immunodeficient mice with ...


Transient Expression Of Zbtb32 In Anti-Viral Cd8+ T Cells Limits The Magnitude Of The Effector Response And The Generation Of Memory, HyunMu Shin, Varun N. Kapoor, Gwanghun Kim, Peng Li, Hang-Rae Kim, M. Suresh, Susan M. Kaech, E. John Wherry, Liisa K. Selin, Warren J. Leonard, Raymond M. Welsh, Leslie J. Berg 2017 University of Massachusetts Medical School

Transient Expression Of Zbtb32 In Anti-Viral Cd8+ T Cells Limits The Magnitude Of The Effector Response And The Generation Of Memory, Hyunmu Shin, Varun N. Kapoor, Gwanghun Kim, Peng Li, Hang-Rae Kim, M. Suresh, Susan M. Kaech, E. John Wherry, Liisa K. Selin, Warren J. Leonard, Raymond M. Welsh, Leslie J. Berg

Open Access Articles

Virus infections induce CD8+ T cell responses comprised of a large population of terminal effector cells and a smaller subset of long-lived memory cells. The transcription factors regulating the relative expansion versus the long-term survival potential of anti-viral CD8+ T cells are not completely understood. We identified ZBTB32 as a transcription factor that is transiently expressed in effector CD8+ T cells. After acute virus infection, CD8+ T cells deficient in ZBTB32 showed enhanced virus-specific CD8+ T cell responses, and generated increased numbers of virus-specific memory cells; in contrast, persistent expression of ZBTB32 suppressed memory cell formation. The dysregulation of CD8 ...


Pathways Involved In Recognition And Induction Of Trained Innate Immunity By Plasmodium Falciparum, Jacob E. Schrum 2017 University of Massachusetts Medical School

Pathways Involved In Recognition And Induction Of Trained Innate Immunity By Plasmodium Falciparum, Jacob E. Schrum

GSBS Dissertations and Theses

Malarial infection in naïve individuals induces a robust innate immune response, but our understanding of the mechanisms by which the innate immune system recognizes malaria and regulates its response remain incomplete. Our group previously showed that stimulation of macrophages with Plasmodium falciparum genomic DNA (gDNA) and AT-rich oligodeoxynucleotides (ODNs) derived from this gDNA induces the production of type I interferons (IFN-I) through a STING/TBK1/IRF3-dependent pathway; however, the identity of the upstream cytosolic DNA receptor remained elusive. Here, we demonstrate that this IFN-I response is dependent on cyclic GMP-AMP synthase (cGAS). cGAS produced the cyclic dinucleotide 2’3’-cGAMP ...


Interleukin-36beta Provides Protection Against Hsv-1 Infection, But Does Not Modulate Initiation Of Adaptive Immune Responses, Katelynn A. Milora, Siva R. Uppalapati, Julio Sanmiguel, Wei Zou, Liselotte E. Jensen 2017 Temple University

Interleukin-36beta Provides Protection Against Hsv-1 Infection, But Does Not Modulate Initiation Of Adaptive Immune Responses, Katelynn A. Milora, Siva R. Uppalapati, Julio Sanmiguel, Wei Zou, Liselotte E. Jensen

Open Access Articles

Interleukin-36 (IL-36) represents three cytokines, IL-36alpha, IL-36beta and IL-36gamma, which bind to the same receptor, IL-1RL2; however, their physiological function(s) remain poorly understood. Here, the role of IL-36 in immunity against HSV-1 was examined using the flank skin infection mouse model. Expression analyses revealed increased levels of IL-36alpha and IL-36beta mRNA in infected skin, while constitutive IL-36gamma levels remained largely unchanged. In human keratinocytes, IL-36alpha mRNA was induced by HSV-1, while IL-1beta and TNFalpha increased all three IL-36 mRNAs. The dominant alternative splice variant of human IL-36beta mRNA was isoform 2, which is the ortholog of the known mouse ...


Finding A Link Between Circadian Rhythms And The Immune System Of Captive Zebra Finches (Taeniopygia Guttata), Amber Bishop 2017 Western Kentucky University

Finding A Link Between Circadian Rhythms And The Immune System Of Captive Zebra Finches (Taeniopygia Guttata), Amber Bishop

Honors College Capstone Experience/Thesis Projects

Circadian rhythms are commonplace in organisms and are normally controlled by a master clock. More recent evidence suggests that autonomous clocks operate in various systems in the body, including the immune system. This study looks for such a connection between the circadian rhythm and the immune system. In this study, captive zebra finches (Taeniopygia guttata) were exposed to different light and dark cycles and blood samples were taken every six hours. Birds were exposed to 12 hours of light and then 12 hours of darkness (LD), 24 hours of darkness (DD), or 48 hours of DD. After collecting whole blood ...


Phenomenological And Molecular Basis Of The Cnidarian Immune System, Tanya Brown 2017 Florida International University

Phenomenological And Molecular Basis Of The Cnidarian Immune System, Tanya Brown

FIU Electronic Theses and Dissertations

Coral reefs are one of the most diverse ecosystems on the planet due partially to the habitat structure provided by corals. Corals are long lived organisms that can live for hundreds of years and as a result growth of many species is very slow. As a result of this, recovery of corals from disease outbreaks is very slow and difficult and therefore the ecosystem is deteriorating rapidly. Due to this increase in disease and its detrimental effect on coral reefs, it has become imperative to study how corals respond to disease outbreaks. The response of the coral to pathogens is ...


The Antiviral Rna Interference Response Provides Resistance To Lethal Arbovirus Infection And Vertical Transmission In Caenorhabditis Elegans, Don B. Gammon, Takao Ishidate, Lichao Li, Weifeng Gu, Neal S. Silverman, Craig C. Mello 2017 University of Massachusetts Medical School

The Antiviral Rna Interference Response Provides Resistance To Lethal Arbovirus Infection And Vertical Transmission In Caenorhabditis Elegans, Don B. Gammon, Takao Ishidate, Lichao Li, Weifeng Gu, Neal S. Silverman, Craig C. Mello

Neal Silverman

The recent discovery of the positive-sense single-stranded RNA (ssRNA) Orsay virus (OV) as a natural pathogen of the nematode Caenorhabditis elegans has stimulated interest in exploring virus-nematode interactions. However, OV infection is restricted to a small number of intestinal cells, even in nematodes defective in their antiviral RNA interference (RNAi) response, and is neither lethal nor vertically transmitted. Using a fluorescent reporter strain of the negative-sense ssRNA vesicular stomatitis virus (VSV), we show that microinjection of VSV particles leads to a dose-dependent, muscle tissue-tropic, lethal infection in C. elegans. Furthermore, we find nematodes deficient for components of the antiviral RNAi ...


Adenovirus Prime, Env Protein Boost Vaccine Protects Against Neutralization-Resistant Sivsme660 Variants In Rhesus Monkeys, Brandon F. Keele, Wenjun Li, Erica N. Borducchi, Joseph P. Nkolola, Peter Abbink, Bing Chen, Michael S. Seaman, Dan H. Barouch 2017 Frederick National Laboratory for Cancer Research

Adenovirus Prime, Env Protein Boost Vaccine Protects Against Neutralization-Resistant Sivsme660 Variants In Rhesus Monkeys, Brandon F. Keele, Wenjun Li, Erica N. Borducchi, Joseph P. Nkolola, Peter Abbink, Bing Chen, Michael S. Seaman, Dan H. Barouch

Open Access Articles

Previous studies have shown that DNA prime, Ad5 boost vaccines protect against neutralization-sensitive but not neutralization-resistant virus variants within the SIVsmE660 swarm. Here we show that Ad prime, Env protein boost vaccines protect against neutralization-resistant SIVsmE660 variants. We perform two studies in rhesus monkeys with Ad35/Ad26 vectors expressing SIVmac239 Gag/Pol/Env with or without an AS01B-adjuvanted SIVmac32H gp140 protein boost. In a repetitive, low-dose challenge study, we observe robust protection against acquisition of infection by both Ad Alone and Ad/Env vaccines. In a single, high-dose challenge study, only the Ad/Env vaccine affords significant protection against acquisition ...


B7h6: A Cancer Biomarker For The Development Of Novel Immunotherapy Approaches, Mariana Phillips 2017 Seton Hall University

B7h6: A Cancer Biomarker For The Development Of Novel Immunotherapy Approaches, Mariana Phillips

Seton Hall University Dissertations and Theses (ETDs)

Cancer-based immunotherapy has led the evolution of biologics that can stimulate immune responses towards tumor eradication. The synthesis of small to intermediate size molecules with the targeting and effector functions of mAb may represent a novel class of immunotherapeutics that may overcome the limitations of their biological counterparts.Towards this objective, B7H6 has been identified as a protein ligand localized on the cell surface of transformed tumor cells. B7H6 binds specifically to the activating receptor NKp30, constitutively expressed on all resting and active NK cells. Upon ligand:receptor binding, B7H6 triggers NK cell activation and release of chemokines and pro-inflammatory ...


Developing Novel Approaches To Improve Response To T Cell Based Cancer Immunotherapy, Rina M. Mbofung 2017 The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences

Developing Novel Approaches To Improve Response To T Cell Based Cancer Immunotherapy, Rina M. Mbofung

UT GSBS Dissertations and Theses (Open Access)

Recently, T cell based immunotherapies have moved to the forefront of cancer immunotherapy with the success of Adoptive T cell therapy (ACT) and Immune checkpoint blockade.ACT, where patients are treated with tumour infiltrating T cells (TILs), conferred a clinical response rate of ~50%. Treatment with anti-CTLA4 and anti –PD1 therapy, conferred response rates of up to 50%, greatly improving the overall survival of patients with advanced melanoma amongst other cancer types. Despite the encouraging outcomes, there are relatively low response rates coupled with the delay of weeks to months before tumour shrinkage can be appreciated. Thus, understanding what tumour ...


Characterization Of Murine Breast Cancer Cell Lines For Anti-Cancer Vaccine, Haven N. Frazier 2017 University of Arkansas, Fayetteville

Characterization Of Murine Breast Cancer Cell Lines For Anti-Cancer Vaccine, Haven N. Frazier

Biological Sciences Undergraduate Honors Theses

Breast cancer is the most commonly diagnosed cancer in women and the second leading cause of cancer death among women in the United States (1). While treatments involving radiation and chemotherapy currently exist, disease must be detected early in order for the treatments to be somewhat effective, and there is no effective treatment after metastasis occurs (2). Additionally, current therapies do not mitigate tumor immunosuppression. Decreasing the tumor-associated immunosuppressive conditions while activating antitumor immunity could prevent recurrence and metastasis, possibly leading to an effective treatment for cancer (3). Tumor cell vaccines could possibly address this issue and have become a ...


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