Medical Immunology Commons^™

Use Of Irf-3 And/Or Irf-7 Knockout Mice To Study Viral Pathogenesis: Lessons From A Murine Retrovirus-Induced Aids Model, Megan A. O'Connor, William R. Green

Dartmouth Scholarship

Interferon regulatory factor (IRF) regulation of the type I interferon response has not been extensively explored in murine retroviral infections. IRF-3(-/-) and select IRF-3/7(-/-) mice were resistant to LP-BM5-induced pathogenesis. However, further analyses strongly suggested that resistance could be attributed to strain 129-specific contamination of the known retrovirus resistance gene Fv1. Therefore, caution should be taken when interpreting phenotypes observed in these knockout mice, as strain 129-derived genetic polymorphisms may explain observed differences.

Toll-Like Receptors 2 And 9 Are Important For Innate Immune Cell Activation And Recruitment In Hypersensitivity Pneumonitis, Kelly J. Andrews

Theses and Dissertations (ETD)

Hypersensitivity pneumonitis (HP) is an interstitial lung disease caused by repeated inhalation of environmental antigens. The disease is characterized by alveolitis and granuloma formation; however, some patients develop chronic HP (CHP), a restrictive lung disease characterized by fibrosis. Previous studies revealed that neutrophils are recruited into the lung via a MyD88- dependent pathway and regulate disease severity through cytokine production. Toll-like receptors (TLRs) 2 and 9 recognize conserved molecular patterns present in bacteria, and signal through the adaptor molecule MyD88. The goal of my project is to investigate the role of TLRs 2 and 9 in the pathogenesis of HP …

A Novel Mechanism Of Enhanced Susceptibility To Bacterial Pneumonia In Influenza-Infected Hosts, Hazem Elsayed Ghoneim

Theses and Dissertations (ETD)

Viruses such as influenza suppress host immune function by a variety of methods. This may result in a significant morbidity through several pathways, including facilitation of secondary bacterial pneumonia from pathogens such as Streptococcus pneumoniae. Lungresident alveolar macrophages (AMs) act as the first line of innate cellular immunity against respiratory bacterial pathogens, including pneumococcus. Therefore, they represent an attractive target for study Before investigating the impact of influenza infection on resident AMs, we first characterized different subsets of lung-resident macrophages in naïve mice using a novel in vivo labeling approach in conjunction with multicolor flow cytometric analysis and confocal microscopic …

Nkg2d Ligands In Cancer, Neha Das Gupta

Theses and Dissertations (ETD)

NK cell transplantation has been increasingly used to treat cancers that are resistant to chemotherapy. However, not all cancers are susceptible to NK cell killing. The prevalence and mechanisms of NK cell resistance have not been well elucidated. Because NKG2D is a major activating receptor on NK cells, we sought to test the hypothesis that NKG2D is the primary pathway in tumor cell recognition. Herein, we comprehensively assessed 20 cancer cell lines representing a broad array of cancer types. In line with our primary hypothesis, no cancer cell lines that expressed low levels of NKG2D ligands were susceptible to NK …

Erg11-Mediated Azole Resistance In Candida Albicans, Stephanie Ann Flowers

Theses and Dissertations (ETD)

Although many medically important Candida species are commensal to the gut or colonizers of the skin, these organisms have the propensity to cause disease in the event of a waning immune system. Clinical manifestations of infections with Candida species can range from superficial mucosal infections to deep organ involvement usually resulting from haematogenous spread of infection. Despite significant progress made in the management of patients with fungal infections, the emergence of antifungal resistant clinical isolates creates significant problem in regards to antifungal prophylaxis and empirical treatment strategies. Antifungal resistance is associated with high mortality rates and hefty medical costs. The …

A Process Similar To Autophagy Is Associated With Cytocidal Chloroquine Resistance In Plasmodium Falciparum, David Gaviria, Michelle F. Paguio, Lindsey B. Turnbull, Asako Tan, Amila Siriwardana, Debasish Ghosh, Michael T. Ferdig, Anthony P. Sinai, Paul D. Roepe

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Resistance to the cytostatic activity of the antimalarial drug chloroquine (CQ) is becoming well understood, however, resistance to cytocidal effects of CQ is largely unexplored. We find that PfCRT mutations that almost fully recapitulate P. falciparum cytostatic CQ resistance (CQR(CS)) as quantified by CQ IC50 shift, account for only 10-20% of cytocidal CQR (CQR(CC)) as quantified by CQ LD50 shift. Quantitative trait loci (QTL) analysis of the progeny of a chloroquine sensitive (CQS; strain HB3)×chloroquine resistant (CQR; strain Dd2) genetic cross identifies distinct genetic architectures for CQR(CS) vs CQR(CC) phenotypes, including identification of novel interacting chromosomal loci that influence CQ …

Evidence For Finely-Regulated Asynchronous Growth Of Toxoplasma Gondii Cysts Based On Data-Driven Model Selection, Adam M. Sullivan, Xiaopeng Zhao, Yasuhiro Suzuki, Eri Ochiai, Stephen Crutcher, Michael A. Gilchrist

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Toxoplasma gondii establishes a chronic infection by forming cysts preferentially in the brain. This chronic infection is one of the most common parasitic infections in humans and can be reactivated to develop life-threatening toxoplasmic encephalitis in immunocompromised patients. Host-pathogen interactions during the chronic infection include growth of the cysts and their removal by both natural rupture and elimination by the immune system. Analyzing these interactions is important for understanding the pathogenesis of this common infection. We developed a differential equation framework of cyst growth and employed Akaike Information Criteria (AIC) to determine the growth and removal functions that best describe …

Epigenetic Dominance Of Prion Conformers, Eri Saijo, Hae-Eun Kang, Jifeng Bian, Kristi G. Bowling, Shawn Browning, Sehun Kim, Nora Hunter, Glenn C. Telling

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Although they share certain biological properties with nucleic acid based infectious agents, prions, the causative agents of invariably fatal, transmissible neurodegenerative disorders such as bovine spongiform encephalopathy, sheep scrapie, and human Creutzfeldt Jakob disease, propagate by conformational templating of host encoded proteins. Once thought to be unique to these diseases, this mechanism is now recognized as a ubiquitous means of information transfer in biological systems, including other protein misfolding disorders such as those causing Alzheimer's and Parkinson's diseases. To address the poorly understood mechanism by which host prion protein (PrP) primary structures interact with distinct prion conformations to influence pathogenesis, …

Membrane Vesicles Nucleate Mineralo-Organic Nanoparticles And Induce Carbonate Apatite Precipitation In Human Body Fluids, Cheng-Yeu Wu, Jan Martel, Wei-Yun Cheng, Chao-Chih He, David M. Ojcius, John Ding-E. Young

All Dugoni School of Dentistry Faculty Articles

Recent studies indicate that membrane vesicles (MVs) secreted by various cells are associated with human diseases, including arthritis, atherosclerosis, cancer, and chronic kidney disease. The possibility that MVs may induce the formation of mineralo-organic nanoparticles (NPs) and ectopic calcification has not been investigated so far. Here, we isolated MVs ranging in size between 20 and 400 nm from human serum and FBS using ultracentrifugation and sucrose gradient centrifugation. The MV preparations consisted of phospholipid-bound vesicles containing the serum proteins albumin, fetuin-A, and apolipoprotein A1; the mineralization-associated enzyme alkaline phosphatase; and the exosome proteins TNFR1 and CD63. Notably, we observed that …

Identification Of Leptospira Interrogans Phospholipase C As A Novel Virulence Factor Responsible For Intracellular Free Calcium Ion Elevation During Macrophage Death, Jing-Fang Zhao, Hong-Hu Chen, David M. Ojcius, Xin Zhao, Dexter Sun, Yu-Mei Ge, Lin-Li Zheng, Xu'ai Lin, Lan-Juan Li, Jie Yan

All Dugoni School of Dentistry Faculty Articles

Background: Leptospira-induced macrophage death has been confirmed to play a crucial role in pathogenesis of leptospirosis, a worldwide zoonotic infectious disease. Intracellular free Ca²⁺ concentration ([Ca²⁺]i) elevation induced by infection can cause cell death, but [Ca²⁺]i changes and high [Ca²⁺]i-induced death of macrophages due to infection of Leptospira have not been previously reported.

Methodology/Principal Findings: We first used a Ca²⁺-specific fluorescence probe to confirm that the infection of L. interrogans strain Lai triggered a significant increase of [Ca²⁺]i in mouse J774A.1 or human THP-1 macrophages. Laser confocal microscopic examination …

First Steps Phase Ii Initiative: Improving Developmental, Autism, And Lead Screening For Children, Kimberley S. Fox Mpa, Carolyn E. Gray Mph, Martha Elbaum Williamson Mpa

Population Health & Health Policy

First STEPS (Strengthening Together Early Preventive Services) is a learning initiative supported by Maine's CHIPRA quality demonstration grant to support measure-driven practice improvement in pediatric and family practices across the state on improving developmental, autism, and lead screening for children. This report, authored by research staff at the USM Muskie School, evaluates the impact of Phase II of Maine's First STEPS initiative, which was implemented from May to December 2012 and included 12 practices serving more than 20,000 children on MaineCare (Maine's Medicaid system). The authors assess changes in developmental, autism, and lead screening rates and evidence-based office processes in …

Fecal Transplantation Does Not Transfer Either Susceptibility Or Resistance To Food Borne Listeriosis In C57bl/6 And Balb/C/By Mice, Tanya Myers-Morales, Kate M. Bussell, Sarah E. F. D'Orazio

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The composition of the intestinal microbiota has wide reaching effects on the health of an individual, including the development of protective innate immune responses. In this report, a fecal transplantation approach was used to determine whether resistance to food borne listeriosis was dependent on the murine gut microbiota. Transplantation of BALB/c/By feces did not increase the susceptibility of C57BL/6 mice to Listeria monocytogenes infection. Likewise, transplantation of C57BL/6 fecal matter did not enhance the resistance of BALB/c/By mice. Thus, intestinal microbiota composition is not a key factor that confers either susceptibility or resistance to food borne listeriosis in mice.

Beginner's Guide To Colorectal Cancer Research, Kayla M. Walker

Summer Training Program in Cancer Immunotherapy

Introduction

For a while now obesity has been a health care concern for people all over the world. In the many years that obesity research has been conducted, various things have been taken into consideration including diet, exercise and medical history. In relatively recent years, researchers have expanded their definition of physical activity levels to include both the amounts of occupational physical activity and leisure time activity that a person partakes in.

The 2002 census occupation system assigned a 4 digit Metabolic equivalent (MET) to 509 separate occupations. These codes are particularly helpful for statistics agencies that need to collect …

The Conception Of Gcc- Specific Chimeric Antigen Receptors, Raven Smith-Parris

Summer Training Program in Cancer Immunotherapy

Colorectal Cancer is an aggressive disease that claims the lives of both men and women every year. It is the second leading cause of cancer-related death in the U.S. The overwhelming mortality rate it amasses begs for the discovery of alternative forms of treatment. The nature of cancer requires immunotherapeutic approach that is tumor specific in nature. Adoptive T-cell therapy is an alternative that satisfies these conditions. Guanylyl Cyclase C is a receptor found on the luminal side of the gut that is tissue-specific for the intestinal epithelium. Further, its expression is maintained throughout colorectal tumorigenesis making in an excellent …

Environmental Circadian Disruption Elevates The Il-6 Response To Lipopolysaccharide In Blood, Kandis L. Adams, Oscar Castanon-Cervantes, Jennifer A. Evans, Alec J. Davidson

Biomedical Sciences Faculty Research and Publications

The immune system is regulated by circadian clocks within the brain and immune cells. Environmental circadian disruption (ECD), consisting of a 6-h phase advance of the light:dark cycle once a week for 4 weeks, elevates the inflammatory response to lipopolysaccharide (LPS) both in vivo and in vitro. This indicates that circadian disruption adversely affects immune function; however, it remains unclear how the circadian system regulates this response under ECD conditions. Here, we develop an assay using ex vivo whole-blood LPS challenge to investigate the circadian regulation of immune responses in mice and to determine the effects of ECD on these …

The Involvement Of Beta-Catenin In The Inflammatory Response Leading To Autoimmune Diabetes Development., Arin Lee Zirnheld

Electronic Theses and Dissertations

We identified and characterized a novel defect in β-catenin expression in bone marrow derived dendritic cells (BMDC) from NOD mice, a model for human Type I diabetes. This protein is expressed at high levels throughout the lifespan of the mouse and correlates with increased pro-inflammatory cytokine production by the BMDC and IFNγ induction by T cells cocultured with the BMDC. These defects, including a similar pattern of pro-inflammatory cytokine production, are also observed in human monocytederived DC from diabetic patients. After exploring several potential mechanisms involved in the accumulation of β-catenin in NOD BMDC, we found that β-catenin is phosphorylated …

T-Cell Treatments For Solid And Hematological Tumors, Drew C. Deniger

Dissertations and Theses (Open Access)

Cell-based therapies have demonstrated potency and efficacy as cancer treatment modalities. T cells can be dichotomized by their T cell receptor (TCR) complexes where alpha/beta T cells (95% of T cells) and gamma/delta T cells (+T cells proliferated to clinically significant numbers and ROR1⁺ tumor cells were effectively targeted and killed by both ROR1-specific CAR⁺ T cell populations, although ROR1RCD137 were superior to ROR1RCD28 in clearance of leukemia xenografts in vivo. The second specific aim focused on generating bi-specific CD19-specific CAR⁺ gamma/delta T cells with polyclonal TCRgamma/delta repertoire on CD19⁺ artificial antigen presenting cells (aAPC). …

Severe Combined Immune Deficiency Syndrome, Ali Faisal Saleem, Ranish Deedar Ali Khawaja, Abdul Sattar Shaikh, Syed Asad Ali, Anita Kaniz Mehdi Zaidi

Department of Paediatrics and Child Health

Objective: To determine the clinico-demographic features and laboratory parameters of children with severe combined immunodeficiency (SCID).

Study Design: Case series.

Place and Duration of Study: Department of Paediatrics and Child Health, the Aga Khan University, Karachi, from July 2006 to July 2011.

Methodology: Thirteen infants who were discharged with a diagnosis of SCID were inducted in the study. Their clinicodemographic features and laboratory parameters were determined. Descriptive statistics has been used for computing frequency and percentage.

Results: The median age at diagnosis was five months; 5 infants presented within 3 months of life. Three-fourth (77%) were males. Most of the …

Studies On Tracheorelaxant And Anti-Inflammatory Activities Of Rhizomes Of Polygonatum Verticillatum, Haroon Khan, Muhammad Saeed, Hassan Mehmood, Najeeb-Ur Rehman, Naveed Muhammad, Ikram-Ul Haq, Nadeem Ashraf, Kamal Eldin H El-Tahir, Anwar Gilani

Department of Biological & Biomedical Sciences

Background: The present study describes the tracheorelaxant and anti-inflammatory effects of Polygonatum verticillatum which may support its medicinal use in hyperactive airway complaints and inflammatory disorders.
Methods: The tracheorelaxant activity of crude extract of the rhizomes of P. verticillatum (PR) was assessed in isolated guinea-pig tracheal tissues immersed in tissue organ bath filled with Tyrode's solution and a continuous supply of carbogen gas (95% O2 and 5% CO2). The contractile and relaxant responses of the tissue were measured using isometric transducers coupled with Power-Lab data acquisition system. The anti-inflammatory effect was evaluated in carrageenan-induced rat paw edema model, while the …

P2x4 Assembles With P2x7 And Pannexin-1 In Gingival Epithelial Cells And Modulates Reactive Oxygen Species Production And Inflammasome Activation, Shu-Chen Hung, Chul Hee Choi, Najwane Said-Sadier, Larry Johnson, Kalina Rosenova Atanasova, Hanen Sellami, Özlem Yilmaz, David M. Ojcius

All Dugoni School of Dentistry Faculty Articles

We have previously reported that Porphyromonas gingivalis infection of gingival epithelial cells (GEC) requires an exogenous danger signal such as ATP to activate an inflammasome and caspase-1, thereby inducing secretion of interleukin (IL)-1β. Stimulation with extracellular ATP also stimulates production of reactive oxygen species (ROS) in GEC. However, the mechanism by which ROS is generated in response to ATP, and the role that different purinergic receptors may play in inflammasome activation, is still unclear. In this study, we revealed that the purinergic receptor P2X₄ is assembled with the receptor P2X₇ and its associated pore, pannexin-1. ATP induces ROS …