Immunology of Infectious Disease Commons^™

Development Of A Split Deoxyribozyme-Based Assay For Detecting Hepatitis B Virus, Dalila Zovko

Honors Undergraduate Theses

Rapid, accessible nucleic acid-based detection methods are needed for hepatitis B virus (HBV). A split deoxyribozyme assay was developed for sequence-specific fluorescence detection. The assay was evaluated using synthetic target and plasmid-derived material. The assay showed target-dependent fluorescence and low-concentration linear range with a LOD of 1.9 nM. The assay supports detection and semi-quantification of HBV genetic material as shown using plasmid-derived transcript samples from HBV genotypes B, C, and D. The selected target corresponded to nt 363–406 of the HBV genome and was chosen based on sequence alignment showing conservation across most genotypes. Genotype-specific detection remains a future application …

Expanding Inducible Epithelial Resistance Against Pneumonia: Novel Virus, Novel Receptor, Michael Longmire

Dissertations and Theses (Open Access)

Pneumonia is the leading infectious cause of death worldwide and presents a continuing risk among immunocompromised patients. Our work has been focused for many years on the phenomenon of inducible epithelial resistance, where activation of the innate immune response in the airway epithelium is necessary and sufficient to produce a pathogen-killing but self-protective environment to prevent severe disease. Inducible resistance is pathogen-agnostic and has been demonstrated against an array of respiratory infections. We achieve this using a combination of pattern recognition receptor agonists – Pam2CSK4 and ODN M362 being the current formulation – which produce synergistic levels of pathogen reduction …

Interactions Of The Sars-Cov-2 Viral Genome 3’-Untranslated Region With Viral And Host Rnas, Caleb Frye, Mihaela Rita Mihailescu

Electronic Theses and Dissertations

This dissertation focuses on the characterization of RNA-RNA interactions within the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome and with host microRNAs. As the causative agent of coronavirus disease 2019 (COVID-19), SARS-CoV-2 has evolved rapidly since its appearance. This has warranted prompt characterization of the virus particularly of its single stranded RNA (ssRNA) genome. By using a combination of bioinformatics, biophysics, and/or biological assays, we analyzed the SARS-CoV-2 viral genomic RNA and uncovered interactions of genomic RNA with host RNAs, highlighting an underutilized method of targeting RNA viruses. We showed here that the conserved elements in the viral genomic …

Intestinal Microbiome, Fecal Fermentation Profile, And Health Indices In Hiv Infected Men Versus Non-Infected Controls, Mary Andreae, Mary C. Andreae Mrs

Electronic Theses and Dissertations

Many HIV-positive (HIV+) males on Highly Active Anti-Retroviral Therapy (HAART) experience metabolic abnormalities, including Non-Alcoholic Fatty Liver Disease (NAFLD) and lipodystrophy. The intestinal microbiota and short chain fatty acids (SCFA), participate in bidirectional communication with their host. Dysbiosis in HIV+ males on HAART demonstrate a Prevotella-rich enterotype shaped by multiple factors including, medications, adiposity, diet, intestinal permeability, and lifestyle; our objective was to investigate these factors. 19 HIV+ and 21 HIV- males were enrolled. BMI and hip-to-waist ratio (H:W) were obtained, and FibroScan for liver health. Intestinal permeability markers Claudin-21, flagellin, and intestinal fatty acid binding protein (IFABP) in …

Innate Immunity In The Pathobiology And Treatment Of Infectious And Neurodegenerative Diseases, Mai Mostafa

Theses & Dissertations

Mononuclear phagocytes (MPs; monocytes, macrophages, and dendritic cells) are the governors of innate immunity which is the body’s first line of defense against microbial pathogens. They act beneficial or detrimental. They are crucial for an effective non-specific immune response to invading pathogens by engulfing, destroying, then eliciting an adaptive specific immune response. Given their pivotal functions in the host immune defense, studying MP immune responses in disease is paramount important for understanding disease pathobiology and uncovering therapeutic strategies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the driver of acute respiratory distress syndrome (ARDS) in coronavirus disease 2019 (COVID-19) amongst …

Antibiotic Permeation In Gram-Negative Bacteria And Contribution Of Inflammasome Activation And Pyroptosis In Pathogenesis Of Salmonella Systemic Infection, Ankit Pandeya

Theses and Dissertations--Chemistry

Antibiotic resistance is one of the major global issues in the field of public health and medicine. Good antibiotic candidates need to be selectively toxic, inhibit cellular target, and effectively penetrate and accumulate in bacterial cells. The last factor is a formidable barrier in the development of antimicrobials effective in Gram-negative bacteria, due to the presence of two layers of cell envelope. The first half of my thesis focuses on understanding the permeation of small molecules through this formidable cell envelope, distribution inside the cell of Gram-negative bacteria, and design of novel methods to make small molecules effectively cross the …

Mesenchymal Stem Cells And Their Extracellular Vesicles: A Potential Game Changer For The Covid-19 Crisis, Dina H. Kassem, Mohamed M. Kamal

Pharmacy

Corona virus disease 2019 (COVID-19) is a global public health crisis. The high infectivity of the disease even from non-symptomatic infected patients, together with the lack of a definitive cure or preventive measures are all responsible for disease outbreak. The severity of COVID-19 seems to be mostly dependent on the patients’ own immune response. The over-activation of the immune system in an attempt to kill the virus, can cause a “cytokine storm” which in turn can induce acute respiratory distress syndrome (ARDS), as well as multi-organ damage, and ultimately may lead to death. Thus, harnessing the immunomodulatory properties of mesenchymal …

Mutational Analysis And Domain Characterization Of The Apolipoprotein L-1 Ion Channel, Charles M. Schaub

Dissertations, Theses, and Capstone Projects

The human innate immunity factor Apolipoprotein L-1 (APOL1) protects against Trypanosoma brucei brucei infection. Recent studies have shown recombinant APOL1 (rAPOL1) inserts into planar lipid bilayers at an acidic pH 5.6 and forms a cation-selective channel, which opens upon subsequent neutralization, pH 7.2. This corresponds with the pH changes APOL1 would encounter during endosome recycling, suggesting that APOL1 forms a pH-gated ion channel in the plasma membrane of the parasite, leading to uncontrolled ion flux and osmotic imbalance. However, structural and domain characteristics of the APOL1 channel are poorly understood, despite potential similarities to diphtheria and colicin toxins. Utilizing E. …

The Wet Bridge Transfer System: An Novel In Vitro Tool For Assessing Exogenous Surfactant As A Pulmonary Drug Delivery Vehicle, Brandon J. Baer

Western Research Forum

Background:

Due to its complex branching structure, direct drug delivery to the remote areas of the lung is a major challenge. Consequently, most therapies, such as those treating pulmonary infection and inflammation, must utilize large systemic dosing, with the potential for adverse side effects. A novel alternative strategy is to use exogenous surfactant, a material capable of distributing throughout the lung, as a pulmonary drug delivery vehicle.

Objective:

Utilize an in vitro transferring system to assess exogenous surfactant (BLES) as a pulmonary delivery vehicle for different therapeutics.

Methods:

An in vitro technique was developed to simultaneously study surfactant delivery and …

Distribution Of Dengue And Zika Virus Igg Immunoglobulin, Madison Smith, Awadalkareem Adam, Anuja Mathew

Senior Honors Projects

Introduction. Dengue Virus (DENV) and Zika Virus (ZIKV) are viruses that belong to the Flavivirus family. They are transmitted by the Aedes aegypti species of mosquitoes. Infection with DENV can result in no symptoms, mild symptoms which include fever, rash, and headache (dengue fever) or more severe symptoms which include hemorrhage, dengue hemorrhagic fever (DHF) and shock, dengue shock syndrome (DSS). ZIKV, until recently caused mild disease but an outbreak in Brazil was associated with fetal complications such as microcephaly or Guillain-Barré syndrome in adults. Due to the similarity between ZIKV and DENV, antibodies (Abs) generated in humans to these …

Developing Novel Therapeutics For Bacterial Lung Infections, Brandon J. Baer, Ruud Veldhuizen, Cory Yamashita

Western Research Forum

Background: Bacterial lung infections are leading causes of death worldwide. Unfortunately, increasing resistance to antibiotics and the inflammation often accompanying these infections are leading to poor outcomes despite antibiotic intervention. Complicating treatment further, the tree-like branching structure of the lung makes drug delivery to distal sites of infection difficult. Our research aims to address these challenges by developing new therapeutics and new tools to improve and assess drug delivery, bacterial killing and inflammation. Our therapy combines host defense peptides, which have been shown to kill antibiotic-resistant bacteria and down regulate inflammation, with a pulmonary vehicle, exogenous surfactant, that can improve …

Type Ix Secretion System: Characterization Of An Effector Protein And An Insight Into The Role Of C-Terminal Domain Dimeration In Outer Membrane Translocation., Lahari Koneru

Electronic Theses and Dissertations

Porphyromonas gingivalis and Tannerella forsythia are two of the primary pathogens that are associated in the etiology and progression of chronic periodontitis. In T. forsythia, KLIKK proteases are the recently identified group of proteolytic enzymes that are secreted through Type IX secretion system (T9SS). Among, these KLIKK proteases a synergistic relationship was observed between karilysin and mirolysin in invading the host complement system for the survival of the bacteria. Since, karilysin has been already characterized, in this study we propose to study about mirolysin through structural, biochemical and biological characterization. The obtained results from the experiments has shown the …

Creation Of An Immunodeficient Hla-Transgenic Mouse (Humamice) And Functional Validation Of Human Immunity After Transfer Of Hla-Matched Human Cells, Yang Zeng, Bingrun Liu, Marie-Therese Rubio, Xinyue Wang, David M. Ojcius, Ruoping Tang, Antoine Durrbach, Zhitao Ru, Yusen Zhou, Yu-Chun Lone

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Research on human immunology has been hindered by the lack of optimal small animal models, given that the protective immune responses of human and non-human species show significant differences. However, due to ethical constraints[1] and the high cost of clinical trials, it is urgent to improve the current animal models that can mimic faithfully human physiology, particularly the human immune system (HIS). HIS mice had been generated recently by engrafting human hematopoietic stem cells (hHSCs) or human peripheral mononuclear cells (hPBMCs) into highly immuno-deficient mice such as NSG, NOG or NRG mice. However, a major experimental drawback for studies using …

Isolation, Culture And Characterization Of Hirsutella Sinensis Mycelium From Caterpillar Fungus Fruiting Body, Yun-Fei Komi, Jian-Ching Liau, Chien-Sheng Lee, Chen-Yaw Chiu, Jan Martel, Chuan-Sheng Lin, Shan-Fu Tseng, David M. Ojcius, Chia-Chen Lu, Hsin-Chih Lai, John Ding-E. Young

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The caterpillar fungus Ophiocordyceps sinensis (previously called Cordyceps sinensis) has been used for centuries in Asia as a tonic to improve health and longevity. Recent studies show that O. sinensis produces a wide range of biological effects on cells, laboratory animals and humans, including anti-fatigue, anti-infection, anti-inflammatory, antioxidant, and anti-tumor activities. In view of the rarity of O. sinensis fruiting bodies in nature, cultivation of its anamorph mycelium represents a useful alternative for large-scale production. However, O. sinensis fruiting bodies harvested in nature harbor several fungal contaminants, a phenomenon that led to the isolation and characterization of a large number …

Micrornas Modulate Pathogenesis Resulting From Chlamydial Infection In Mice, Laxmi Yeruva, S. Pouncey, Michael R. Eledge, Sudeepa Bhattacharya, Chunqiao Luo, Erin W. Weatherford, David M. Ojcius, Roger G. Rank

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Not all women infected with chlamydiae develop upper genital tract disease, but the reason(s) for this remains undefined. Host genetics and hormonal changes associated with the menstrual cycle are possible explanations for variable infection outcomes. It is also possible that disease severity depends on the virulence of the chlamydial inoculum. It is likely that the inoculum contains multiple genetic variants, differing in virulence. If the virulent variants dominate, then the individual is more likely to develop severe disease. Based on our previous studies, we hypothesized that the relative degree of virulence of a chlamydial population dictates the microRNA (miRNA) expression …

Characterization Of A Putative Hemolysin Expressed By Sneathia Amnii, A Preterm Birth-Associated Pathogen, Lizette Carrasco, Kimberly Jefferson

UROP Posters

The gram-negative bacteria Sneathia amnii is a poorly-characterized commensal of the female urogenital tract frequently associated with adverse clinical outcomes such as bacterial vaginosis (BV), amnionitis, and preterm labor. To investigate its potential role in virulence, we sought to identify and characterize virulence determinants produced by S. amnii in an effort to better understand the pathogenesis of infectious preterm birth. Through sequencing of the Sn35 genome (type strain of S. amnii), we identified two genes with amino acid sequence similarity and structural similarity to the filamentous hemagglutinin (FHA) protein of Bordetella pertussis and its Type Vb transporter. Because S. amnii …

Nucleoside-Diphosphate-Kinase Of P. Gingivalis Is Secreted From Epithelial Cells In The Absence Of A Leader Sequence Through A Pannexin-1 Interactome, Kalina Atanasova, Jungnam Lee, Joann Roberts, Kyulim Lee, David M. Ojcius, Özlem Yilmaz

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Nucleoside-diphosphate-kinases (NDKs) are leaderless, multifunctional enzymes. The mode(s) of NDK secretion is currently undefined, while extracellular translocation of bacterial NDKs is critical for avoidance of host pathogen clearance by opportunistic pathogens such as Porphyromonas gingivalis. P. gingivalis-NDK during infection inhibits extracellular-ATP (eATP)/P2X7-receptor mediated cell death in gingival epithelial cells (GECs) via eATP hydrolysis. Furthermore, depletion of pannexin-1-hemichannel (PNX1) coupled with P2X7-receptor blocks the infection-induced eATP release in GECs, and P. gingivalis-NDK impacts this pathway. Ultrastructural and confocal microscopy of P. gingivalis-co-cultured GECs or green-fluorescent-protein (GFP)-P. gingivalis-NDK transfected GECs revealed a perinuclear/cytoplasmic localization of NDK. eATP stimulation induced NDK recruitment to …

An Iron Detection System Determines Bacterial Swarming Initiation And Biofilm Formation, Chuan-Sheng Lin, Yu-Huan Tsai, Chih-Jung Chang, Shun-Fu Tseng, Tseng-Ru Wu, Chia-Chen Lu, Ting-Shu Wu, Jang-Jih Lu, Jim-Tong Horng, Jan Martel, David M. Ojcius, Hsin-Chih Lai, John Ding-E. Young

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Iron availability affects swarming and biofilm formation in various bacterial species. However, how bacteria sense iron and coordinate swarming and biofilm formation remains unclear. Using Serratia marcescens as a model organism, we identify here a stage-specific iron-regulatory machinery comprising a two-component system (TCS) and the TCS-regulated iron chelator 2-isocyano-6,7-dihydroxycoumarin (ICDH-Coumarin) that directly senses and modulates environmental ferric iron (Fe3+) availability to determine swarming initiation and biofilm formation. We demonstrate that the two-component system RssA-RssB (RssAB) directly senses environmental ferric iron (Fe³⁺) and transcriptionally modulates biosynthesis of flagella and the iron chelator ICDH-Coumarin whose production requires the pvc cluster. …

Pyk2 Activates The Nlrp3 Inflammasome By Directly Phosphorylating Asc And Contributes To Inflammasome-Dependent Peritonitis, I-Che Chung, Chun-Nan Ouyang, Sheng-Ning Yuan, Hsin-Pai P. Li, Jeng-Ting Chen, Hui-Ru Shieh, Yu-Jen Chen, David M. Ojcius, Ching-Liang Chu, Jau-Song Yu, Yu-Sun Chang, Lih-Chyang Chen

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The inflammasome adaptor protein, ASC, contributes to both innate immune responses and inflammatory diseases via self-oligomerization, which leads to the activation of the protease, caspase-1. Here, we report that the cytosolic tyrosine kinases, FAK and Pyk2, are differentially involved in NLRP3 and AIM2 inflammasome activation. The inhibition of FAK and Pyk2 with RNA interference or chemical inhibitors dramatically abolished ASC oligomerization, caspase-1 activation, and IL-1β secretion in response to NLRP3 or AIM2 stimulation. Pyk2 is phosphorylated by the kinase Syk and relocalizes to the ASC specks upon NLRP3 inflammasome activation. Pyk2, but not FAK, could directly phosphorylate ASC at Tyr146, …

Hepatitis C Virus Frameshift/Alternate Reading Frame Protein Suppresses Interferon Responses Mediated By Pattern Recognition Receptor Retinoic-Acid-Inducible Gene-I, Seung Bum Park, Scott Seronello, Wasima Mayer, David M. Ojcius

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Hepatitis C virus (HCV) actively evades host interferon (IFN) responses but the mechanisms of how it does so are not completely understood. In this study, we present evidence for an HCV factor that contributes to the suppression of retinoic-acid-inducible gene-I (RIG-I)-mediated IFN induction. Expression of frameshift/alternate reading frame protein (F/ARFP) from HCV -2/+1 frame in Huh7 hepatoma cells suppressed type I IFN responses stimulated by HCV RNA pathogen-associated molecular pattern (PAMP) and poly(IC). The suppression occurred independently of other HCV factors; and activation of interferon stimulated genes, TNFα, IFN-λ1, and IFN-λ2/3 was likewise suppressed by HCV F/ARFP. Point mutations in …

Hiv Vaccines: Progress, Limitations And A Crispr/Cas9 Vaccine, Omar A. Garcia Martinez

Biology: Student Scholarship & Creative Works

ABSTRACT: The HIV-1 pandemic continues to thrive due to ineffective HIV-1 vaccines. Historically, the world’s most infectious diseases, such as polio and smallpox, have been eradicated or have come close to eradication due to the advent of effective vaccines. Highly active antiretroviral therapy is able to delay the onset of AIDS but can neither rid the body of HIV-1 proviral DNA nor prevent further transmission. A prophylactic vaccine that prevents the various mechanisms HIV-1 has to evade and attack our immune system is needed to end the HIV-1 pandemic. Recent advances in engineered nuclease systems, like the CRISPR/Cas9 system, have …

Synthesis And Evaluation Of Biological Activity Of A Potential Immunomodulatory Zwitterionic Polysaccharide, Vikram Basava

Seton Hall University Dissertations and Theses (ETDs)

The gram-negative anaerobic bacterium Bacteroides fragilis is an integral component of the normal gastrointestinal flora. The bacterium colonizes the intestinal tract of human beings as it has no reservoir other than mammals. An unprecedented proportion of the genomic DNA of B. fragilus is involved in the production of capsular polysaccharides. These capsular polysaccharides are important virulence factors in most extracellular bacterial pathogens. Eight of these polysaccharides have been identified thus far, out of which two were found to be zwitterionic polymers, PSA1 and PSA2. PSA1 was found to stimulate T-cell lineage of the immune system because of the dual charge …

Nanoparticle Conversion To Biofilms: In Vitro Demonstration Using Serum-Derived Mineralo-Organic Nanoparticles, Tsui-Yin Wong, Hsin-Hsin Peng, Cheng-Yeu Wu, Jan Martel, David M. Ojcius, Fu-Yung Hsu, John Ding-E. Young

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Aims: Mineralo-organic nanoparticles (NPs) detected in biological fluids have been described as precursors of physiological and pathological calcifications in the body. Our main objective was to examine the early stages of mineral NP formation in body fluids. Materials & methods: A nanomaterial approach based on atomic force microscopy, dynamic light scattering, electron microscopy and spectroscopy was used. Results: The mineral particles, which contain the serum proteins albumin and fetuin-A, initially precipitate in the form of round amorphous NPs that gradually grow in size, aggregate and coalesce to form crystalline mineral films similar to the structures observed in calcified human arteries. …

Eosinophils From Murine Lamina Propria Induce Differentiation Of Naïve T Cells Into Regulatory T Cells Via Tgf-Β1 And Retinoic Acid, Hong-Hu Chen, Ai-Hua Sun, David M. Ojcius, Wei-Lin Hu, Yu-Mei Ge, Xu'ai Lin, Lan-Juan Li, Jian-Ping Pan, Jie Yan

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Treg cells play a crucial role in immune tolerance, but mechanisms that induce Treg cells are poorly understood. We here have described eosinophils in lamina propria (LP) that displayed high aldehyde dehydrogenase (ALDH) activity, a rate-limiting step during all-trans retinoic acid (ATRA) synthesis, and expressed TGF-β1 mRNA and high levels of ATRA. Co-incubation assay confirmed that LP eosinophils induced the differentiation of naïve T cells into Treg cells. Differentiation promoted by LP eosinophils were inhibited by blocked either TGF-β1 or ATRA. Peripheral blood (PB) eosinophils did not produce ATRA and could not induce Treg differentiation. These data identifies LP eosinophils …

Detection And Characterization Of Mineralo-Organic Nanoparticles In Human Kidneys, Tsui-Yin Wong, Cheng-Yeu Wu, Jan Martel, Cheng-Wei Lin, Fu-Yung Hsu, David M. Ojcius, Paul Y. Lin, John Ding-E. Young

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Ectopic calcification is associated with various human diseases, including atherosclerosis, cancer, chronic kidney disease, and diabetes mellitus. Although mineral nanoparticles have been detected in calcified blood vessels, the nature and role of these particles in the human body remain unclear. Here we show for the first time that human kidney tissues obtained from end-stage chronic kidney disease or renal cancer patients contain round, multilamellar mineral particles of 50 to 1,500 nm, whereas no particles are observed in healthy controls. The mineral particles are found mainly in the extracellular matrix surrounding the convoluted tubules, collecting ducts and loops of Henle as …

Hirsutella Sinensis Mycelium Attenuates Bleomycin-Induced Pulmonary Inflammation And Fibrosis In Vivo, Tsung-Teng Huang, Hsin-Chih Lai, Yun-Fei Ko, David M. Ojcius, Ying-Wei Lan, Jan Martel, John Ding-E. Young, Kowit-Yu Chong

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Hirsutella sinensis mycelium (HSM), the anamorph of Cordyceps sinensis, is a traditional Chinese medicine that has been shown to possess various pharmacological properties. We previously reported that this fungus suppresses interleukin-1β and IL-18 secretion by inhibiting both canonical and non-canonical inflammasomes in human macrophages. However, whether HSM may be used to prevent lung fibrosis and the mechanism underlying this activity remain unclear. Our results show that pretreatment with HSM inhibits TGF-β1–induced expression of fibronectin and α-SMA in lung fibroblasts. HSM also restores superoxide dismutase expression in TGF-β1–treated lung fibroblasts and inhibits reactive oxygen species production in lung epithelial cells. Furthermore, …

Ganoderma Lucidum Reduces Obesity In Mice By Modulating The Composition Of The Gut Microbiota, Chih-Jung Chang, Chuan-Sheng Lin, Chia-Chen Lu, Jan Martel, Yun-Fei Ko, David M. Ojcius, Shun-Fu Tseng, Tsung-Ru Wu, Yi-Yuan Margaret Chen, John Ding-E. Young, Hsin-Chih Lai

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Obesity is associated with low-grade chronic inflammation and intestinal dysbiosis. Ganoderma lucidum is a medicinal mushroom used in traditional Chinese medicine with putative anti-diabetic effects. Here, we show that a water extract of Ganoderma lucidum mycelium (WEGL) reduces body weight, inflammation and insulin resistance in mice fed a high-fat diet (HFD). Our data indicate that WEGL not only reverses HFD-induced gut dysbiosis—as indicated by the decreased Firmicutes-to-Bacteroidetes ratios and endotoxin-bearing Proteobacteria levels—but also maintains intestinal barrier integrity and reduces metabolic endotoxemia. The anti-obesity and microbiota-modulating effects are transmissible via horizontal faeces transfer from WEGL-treated mice to HFD-fed mice. We further …

Selection Methods For Genetically-Modified T Cells: In Support Of Translational Therapy, David Rushworth

Dissertations and Theses (Open Access)

T cells are blood cells which organize the immune system of the host. These cells are necessary for the host to respond appropriately to threats from foreign organisms and cancerous growth. However, in the case of certain infections and cancer, T cells are unable to respond appropriately to a threat and establish immunity. This leads to disease when the infection or cancer is not sufficiently eliminated. On the other hand, T cells can lack tolerance for healthy tissue and perceive healthy tissue as infected. The ensuing over-reactive immune response also leads to disease. A delicate balance must exist between immunity …

Aggregatibacter Actinomycetemcomitans Cytolethal Distending Toxin Activates The Nlrp3 Inflammasome In Human Macrophages Leading To The Release Of Pro-Inflammatory Cytokines, Bruce J. Shenker, David M. Ojcius, Lisa P. Walker, Ali Zekavat, Monika Damek Scuron, Kathleen Boesze-Battaglia

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The cytolethal distending toxin (Cdt) is produced from a number of bacteria capable of causing infection and inflammatory disease. Our previous studies with Actinobacillus actinomycetemcomitans Cdt demonstrate not only that the active toxin subunit functions as a phosphatidylinositol-3,4,5-triphosphate (PIP3) phosphatase but also that macrophages exposed to the toxin were stimulated to produce proinflammatory cytokines. We now demonstrate that the Cdt-induced proinflammatory response involves the activation of the NLRP3 inflammasome. Specific inhibitors and short hairpin RNA (shRNA) were employed to demonstrate requirements for NLRP3 and ASC as well as caspase-1. Furthermore, Cdt-mediated inflammasome activation is dependent upon upstream signals, including reactive …

The Pathological Effects Of Ccr2+ Inflammatory Monocytes Are Amplified By An Ifnar1-Triggered Chemokine Feedback Loop In Highly Pathogenic Influenza Infection, Sue-Jane Lin, Ming Lo, Rei-Lin Kuo, Shin-Ru Shih, David M. Ojcius, Jean Lu, Chien-Kuo Lee, Hui-Chen Chen, Meei Yun Lin, Chuen-Miin Leu, Chia-Ni Lin, Ching-Hwa Tsai

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Background: Highly pathogenic influenza viruses cause high levels of morbidity, including excessive infiltration of leukocytes into the lungs, high viral loads and a cytokine storm. However, the details of how these pathological features unfold in severe influenza infections remain unclear. Accumulation of Gr1 + CD11b + myeloid cells has been observed in highly pathogenic influenza infections but it is not clear how and why they accumulate in the severely inflamed lung. In this study, we selected this cell population as a target to investigate the extreme inflammatory response during severe influenza infection.

Results: We established H1N1 IAV-infected mouse models using …