Medical Immunology Commons^™

Pten Signaling In Regulatory T Cells And Inflammatory Disease, Sharad Krishna Shrestha

Theses and Dissertations (ETD)

Regulatory T (Treg) cells suppress CD4+ T cell responses during homeostasis and inflammation to prevent autoimmunity and other immune disorders. Although the transcriptional and epigenetic programs impacting Treg cell function have been extensively studied, the signaling and metabolic pathways underlying Treg stability and function are not fully understood. In this study, we determined the role of the phosphatase PTEN in Treg cells. We found that specific depletion of PTEN in Treg cells results in excessive TH1 and T follicular helper cells (TFH) responses, associated with elevated germinal center (GC) B cells and spontaneous development of autoimmune and lymphoproliferative disease in …

Friendly Fire: Biological Functions And Consequences Of Chromosomal Targeting By Crispr-Cas Systems, Gary E. Heussler, George A. O'Toole

Dartmouth Scholarship

Clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) systems in bacteria and archaea target foreign elements, such as bacteriophages and conjugative plasmids, through the incorporation of short sequences (termed spacers) from the foreign element into the CRISPR array, thereby allowing sequence-specific targeting of the invader. Thus, CRISPR-Cas systems are typically considered a microbial adaptive immune system. While many of these incorporated spacers match targets on bacteriophages and plasmids, a noticeable number are derived from chromosomal DNA. While usually lethal to the self-targeting bacteria, in certain circumstances, these self-targeting spacers can have profound effects in regard to microbial biology, including functions …

Vaccination Of Gerbils With Bm-103 And Bm-Ral-2 Concurrently Or As A Fusion Protein Confers Consistent And Improved Protection Against Brugia Malayi Infection., Sridhar Arumugam, Junfei Wei, Zhuyun Liu, David Abraham, Aaron Bell, Maria Elena Bottazzi, Peter J Hotez, Bin Zhan, Sara Lustigman, Thomas R Klei

Department of Microbiology and Immunology Faculty Papers

BACKGROUND: The Brugia malayi Bm-103 and Bm-RAL-2 proteins are orthologous to Onchocerca volvulus Ov-103 and Ov-RAL-2, and which were selected as the best candidates for the development of an O. volvulus vaccine. The B. malayi gerbil model was used to confirm the efficacy of these Ov vaccine candidates on adult worms and to determine whether their combination is more efficacious.

METHODOLOGY AND PRINCIPLE FINDINGS: Vaccine efficacy of recombinant Bm-103 and Bm-RAL-2 administered individually, concurrently or as a fusion protein were tested in gerbils using alum as adjuvant. Vaccination with Bm-103 resulted in worm reductions of 39%, 34% and 22% on …

A Subset Of Latency-Reversing Agents Expose Hiv-Infected Resting Cd4+ T-Cells To Recognition By Cytotoxic T-Lymphocytes., R. Brad Jones, Stefanie Mueller, Rachel O'Connor, Katherine Rimpel, Derek D Sloan, Allison S. Thomas, Sara Karandish, Szu-Han Huang, +13 More

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Resting CD4+ T-cells harboring inducible HIV proviruses are a critical reservoir in antiretroviral therapy (ART)-treated subjects. These cells express little to no viral protein, and thus neither die by viral cytopathic effects, nor are efficiently cleared by immune effectors. Elimination of this reservoir is theoretically possible by combining latency-reversing agents (LRAs) with immune effectors, such as CD8+ T-cells. However, the relative efficacy of different LRAs in sensitizing latently-infected cells for recognition by HIV-specific CD8+ T-cells has not been determined. To address this, we developed an assay that utilizes HIV-specific CD8+ T-cell clones as biosensors for HIV antigen expression. By testing …

Treatment And Prevention Of Human Rotavirus (Hrv) In Developing Countries: The Potential Of Avian Immunoglobulin Y, Christa Brown

Senior Honors Theses

Rotavirus gastroenteritis is a leading cause of childhood mortality, killing ~1400 children younger than five daily, primarily through severe diarrheal dehydration. Eighty-five percent of this mortality occurs in developing countries where rotavirus vaccines are not widely implemented and are only partially effective. In those countries, it has proven difficult to implement the recommended supportive therapies like oral rehydration therapy (ORT) on a wide scale due to lack of both medical infrastructure and private economic investment combined with cultural bias against ORT. IgY targeting human rotavirus (anti-HRV IgY) shows potential as a passive immunotherapy that reduces rotavirus-associated morbidity and mortality, augments …

Dissecting The Novel Roles Of Trim56 In Antiviral Innate Immunity, Baoming Liu

Theses and Dissertations (ETD)

The tripartite motif-containing (TRIM) proteins have emerged as a new class of host antiviral restriction factors, with several demonstrating roles in regulating innate antiviral responses. Of >70 known TRIMs, TRIM56 inhibits replication of bovine viral diarrhea virus, a ruminant pestivirus of the family Flaviviridae, but has no appreciable effect on VSV, a rhabdovirus. We have also shown that TRIM56 forms a complex with the Toll-like receptor-3 (TLR3) adaptor, TRIF, via its C-terminal residues 621-750, and augments TLR3-mediated interferon (IFN) induction and establishment of an antiviral state. Yet, TRIM56’s antiviral spectrum and the precise underlying mechanisms by which TRIM56 executes …

Dietary Nitrate In Decreased Blood Pressure In Obstructive Sleep Apnoea Syndrome: A Series Of N-Of-1trials, Conor Kerley, Liam Cormican, Eamon Dolan

Articles

Obstructive sleep apnoea syndrome (OSAS) is a consequence of repetitive oropharyngeal airway narrowing/closure during sleep resulting in chronic intermittent hypoxaemia [1]. OSAS is regarded as an independent risk factor for hypertension (HTN) development [2] and is associated with decreased cerebral blood flow [3], leading to daytime neuropsychological sequelae [1]. Blood pressure (BP) follows a circadian rhythm termed dipping and the absence of nocturnal BP dipping is associated with target-organ damage, cerebrovascular disease, myocardial remodelling and increased cardiovascular events/mortality [4]. Abnormal BP in OSAS typically manifests as reduced nocturnal BP dipping [5]. Although continuous positive airway pressure therapy (CPAP) represents the …

The Homophilic Domain – An Immunological Archetype, Heinz Kohler, Jagadeesh Bayry, Srinivas V. Kaveri

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The homophilic potential emerges as an important biological principle to boost the potency of immunoglobulins. Since homophilic antibodies in human and mouse sera exist prior environmental exposure, they are part of the natural antibody repertoire. Nevertheless, hemophilic properties are also identified in induced antibody repertoire. The use of homophilicity of antibodies in the adaptive immunity signifies an archetypic antibody structure. The unique feature of homophilicity in the antibody repertoire also highlights an important mechanism to boost the antibody potency to protect against infection and atherosclerosis as well to treat cancer patients.

Effects Of A Mindfulness-Based Weight Loss Intervention In Adults With Obesity: A Randomized Clinical Trial., Jennifer Daubenmier, Patricia J Moran, Jean Kristeller, Michael Acree, Peter Bacchetti, Margaret E Kemeny, Douglas F. Nixon, +11 Additional Authors

Microbiology, Immunology, and Tropical Medicine Faculty Publications

OBJECTIVE: To determine whether adding mindfulness-based eating and stress management practices to a diet-exercise program improves weight loss and metabolic syndrome components.

METHODS: In this study 194 adults with obesity were randomized to a 5.5-month program with or without mindfulness training and identical diet-exercise guidelines. Intention-to-treat analyses with multiple imputation were used for missing data. The primary outcome was 18-month weight change.

RESULTS: Estimated effects comparing the mindfulness to control arm favored the mindfulness arm in (a) weight loss at 12 months, -1.9 kg (95% CI: -4.5, 0.8; P = 0.17), and 18 months, -1.7 kg (95% CI: -4.7, 1.2; …

Lipidomic Dataset Of Plasma From Patients Infected With Wild Type And Nef-Deficient Hiv-1 Strain., Peter Meikle, Hann Low, Melissa J Churchill, Michael Bukrinsky, Dmitri Sviridov

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Previous in vitro and in vivo studies demonstrated that HIV protein nef plays a key role in impairing cellular and systemic cholesterol metabolism in HIV disease, but clinical support for these findings is lacking. Here we present the data of comparative lipidomic analysis (330 lipid species) of plasma samples from HIV-negative subjects, patients infected with WT HIV-1 strain and patients infected with nef-deficient strain of HIV-1. We determine which effects of HIV on plasma lipidome are explained by the presence of nef. The data can be used to evaluate cardiovascular risk in HIV disease and to assess the role of …

Micro-Rna And Mrna Profiles Associated With Ectopic Germinal Center Formation In Thymus Samples Of Patients With Autoimmune Myas, Manjistha Sengupta, Bi-Dar Wang, Norman H. Lee, Gary Cutter, Linda Louise Kusner, Henry J. Kaminski

GW Research Days 2016 - 2020

Myasthenia gravis (MG) is an autoimmune neuromuscular disorder caused by antibodies directed against proteins present at the post-synaptic surface of neuromuscular junction (NMJ). A characteristic pathology of patients with early onset MG is thymic hyperplasia with ectopic germinal centers (GC). However, mechanisms that trigger and maintain thymic hyperplasia are poorly characterized. Micro-RNAs (miRNA) are small, non-coding RNAs that are increasingly appreciated to be involved in the pathology of several autoimmune diseases. In order to determine the central mechanisms involved in the pathology, thymus samples from MG patients were assessed by histology and grouped based on appearance of GC compared to …

Herpes Simplex Virus And Interferon Signaling Induce Novel Autophagic Clusters In Sensory Neurons, Sarah Katzenell, David A. Leib

Dartmouth Scholarship

Herpes simplex virus 1 (HSV-1) establishes lifelong infection in the neurons of trigeminal ganglia (TG), cycling between productive infection and latency. Neuronal antiviral responses are driven by type I interferon (IFN) and are crucial to controlling HSV-1 virulence. Autophagy also plays a role in this neuronal antiviral response, but the mechanism remains obscure. In this study, HSV-1 infection of murine TG neurons triggered unusual clusters of autophagosomes, predominantly in neurons lacking detectable HSV-1 antigen. Treatment of neurons with IFN-β induced a similar response, and cluster formation by infection or IFN treatment was dependent upon an intact IFN-signaling pathway. The autophagic …

Challenges Of Adoptive (T-)Cell Transfer Immunotherapy For Cancer, Aaron Volk

Biology: Student Scholarship & Creative Works

Background and significance: The rebirth of the theory of immunosurveillance in 2001 rejuvenated interest in anticancer immunotherapies. In particular, T-cell-based therapies have garnered substantial interest due to the robustness and tumor antigen-specific cytotoxicity of T-cell anticancer immune responses.

Hypothesis: The efficacy of adoptive cell transfer (ACT) T-cell immunotherapy could significantly improve and gain widespread approval if future innovations in ACT-based approaches account for the pro- and antitumoral properties of non-CD8⁺ lineages of effector T-cells, evasion of T-cell antitumor immunity, and tumor-induced suppression of antitumor immunity.

Problem Analysis: Despite numerous reports of highly successful ACT-based clinical trials, no such therapy …

The Significance Of A Common Idiotype (1f7) On Antibodies Against Human Immune Deficiency Virus Type 1 And Hepatitis C Virus, Sybille Muller, Matthew S. Parsons, Heinz Kohler, Michael Grant

Microbiology, Immunology, and Molecular Genetics Faculty Publications

In this review, we trace the concept and potential functional role of regulatory idiotypes in the immune response to human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus, and hepatitis C virus (HCV). A major idiotype involved in these viral infections is recognized and defined by a murine monoclonal antibody (1F7). Antibodies expressing the idiotype defined by 1F7 are dominant in HIV-1 infection and are also found on many broadly neutralizing antibodies against HIV-1. This regulatory idiotypic axis offers opportunities for exploitation in vaccine development for HIV-1, HCV, and other chronic viral infections.

Safety And Immunogenicity Of Sequential Rotavirus Vaccine Schedules., Romina Libster, Monica Mcneal, Emmanuel B. Walter, Andi L. Shane, Patricia Winokur, Gretchen Cress, Andrea A. Berry, Karen L. Kotloff, Kwabena Sarpong, Christine B. Turley, Christopher J. Harrison, Barbara A. Pahud, Jyothi Marbin, John Dunn, Jill El-Khorazaty, Jill Barrett, Kathryn M. Edwards, Vteu Rotavirus Vaccine Study Work Group

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND AND OBJECTIVES: Although both licensed rotavirus vaccines are safe and effective, it is often not possible to complete the schedule by using the same vaccine formulation. The goal of this study was to investigate the noninferiority of the immune responses to the 2 licensed rotavirus vaccines when administered as a mixed schedule compared with administering a single vaccine formulation alone.

METHODS: Randomized, multicenter, open-label study. Healthy infants (6-14 weeks of age) were randomized to receive rotavirus vaccines in 1 of 5 different schedules (2 using a single vaccine for all doses, and 3 using mixed schedules). The group receiving …

The Gras Sensor In Staphylococcus Aureus Mediates Resistance To Host Defense Peptides Differing In Mechanisms Of Action, Siyang Chaili, Ambrose L. L. Cheung, Arnold S. Bayer, Yan Q. Xiong, Alan Waring, Guido Memmi, Niles Donegan

Dartmouth Scholarship

Staphylococcus aureus uses the two-component regulatory system GraRS to sense and respond to host defense peptides (HDPs). However, the mechanistic impact of GraS or its extracellular sensing loop (EL) on HDP resistance is essentially unexplored. Strains with null mutations in the GraS holoprotein (ΔgraS) or its EL (ΔEL) were compared for mechanisms of resistance to HDPs of relevant immune sources: neutrophil α-defensin (human neutrophil peptide 1 [hNP-1]), cutaneous β-defensin (human β-defensin 2 [hBD-2]), or the platelet kinocidin congener RP-1. Actions studied by flow cytometry included energetics (ENR); membrane permeabilization (PRM); annexin V binding (ANX), and cell death protease activation (CDP). …

Cd147 And Downstream Adamtss Promote The Tumorigenicity Of Kaposi's Sarcoma-Associated Herpesvirus Infected Endothelial Cells, Lu Dai, Jimena Trillo-Tinoco, Yihan Chen, Karlie Bonstaff, Luis Del Valle, Chris Parsons, Augusto C. Ochoa, Jovanny Zabaleta, Bryan P. Toole, Zhiqiang Qin

School of Medicine Faculty Publications

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi's sarcoma (KS), which preferentially arise in immunocompromised patients and lack effective therapeutic options. We have previously shown that KSHV or viral protein LANA up-regulates the glycoprotein CD147, thereby inducing primary endothelial cell invasiveness. In the current study, we identify the global network controlled by CD147 in KSHV-infected endothelial cells using Illumina microarray analysis. Among downstream genes, two specific metalloproteases, ADAMTS1 and 9, are strongly expressed in AIDS-KS tissues and contribute to KSHV-infected endothelial cell invasiveness through up-regulation of IL-6 and VEGF. By using a KS-like nude …

Gene Deletion By Fluorescence-Reported Allelic Exchange Mutagenesis In Chlamydia Trachomatis, Konrad E. Mueller, Katerina Wolf, Kenneth A. Fields

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Although progress in Chlamydia genetics has been rapid, genomic modification has previously been limited to point mutations and group II intron insertions which truncate protein products. The bacterium has thus far been intractable to gene deletion or more-complex genomic integrations such as allelic exchange. Herein, we present a novel suicide vector dependent on inducible expression of a chlamydial gene that renders Chlamydia trachomatis fully genetically tractable and permits rapid reverse genetics by fluorescence-reported allelic exchange mutagenesis (FRAEM). We describe the first available system of targeting chlamydial genes for deletion or allelic exchange as well as curing plasmids from C. trachomatis …

Vaccines And The Looming Threat Of Syphilis, Charles T. Ambrose

Microbiology, Immunology, and Molecular Genetics Faculty Publications

During the past several decades, syphilis has increased in the US and explosively so in China and Russia.While most current cases can be cured by penicillin or second line antibiotics, strains of the syphilis spirochete (Treponema pallidum) resistant to the latter have emerged.And the potential of strains to acquire resistance to penicillin via plasmids has recently been recognized.The 36 million-plus undertreated cases of syphilis in the world represent metaphorically a vast global 37°C incubator allowing exchange of antibiotic resistant genes among the human-borne bacteria and theoretically permitting the emergence of penicillin resistant strains.None has yet been identified but …

Characterization Of Rna Helicase Csha And Its Role In Protecting Mrnas And Small Rnas Of Staphylococcus Aureus Strain Newman, Samin Kim, Anna-Rita Corvaglia, Stefano Léo, Ambrose Cheung, Patrice Francois

Dartmouth Scholarship

The toxin MazF_sa in Staphylococcus aureus is a sequence-specific endoribonuclease that cleaves the majority of the mRNAs in vivo but spares many essential mRNAs (e.g., secY mRNA) and, surprisingly, an mRNA encoding a regulatory protein (i.e., sarA mRNA). We hypothesize that some mRNAs may be protected by RNA-binding protein(s) from degradation by MazF_sa. Using heparin-Sepharose-enriched fractions that hybridized to sarA mRNA on Northwestern blots, we identified among multiple proteins the DEAD box RNA helicase CshA (NWMN_1985 or SA1885) by mass spectroscopy. Purified CshA exhibits typical RNA helicase activities, as exemplified by RNA-dependent ATPase activity and unwinding of …