Medical Immunology Commons^™

Advances And Future Challenges In Adenoviral Vector Pharmacology And Targeting, Reeti Khare, Christopher Y. Chen, Eric A. Weaver, Michael A. Barry

Virology Papers

Adenovirus is a robust vector for therapeutic applications, but its use is limited by our understanding of its complex in vivo pharmacology. In this review we describe the necessity of identifying its natural, widespread, and multi-faceted interactions with the host since this information will be crucial for efficiently redirecting virus into target cells. In the rational design of vectors, the notion of overcoming a sequence of viral “sinks” must be combined with re-targeting to target populations with capsid as well as shielding the vectors from pre-existing or toxic immune responses. It must also be noted that most known adenoviral pharmacology …

Species D Adenoviruses As Oncolytics Against B-Cell Cancers, Christopher Y. Chen, Julien S. Senac, Eric A. Weaver, Shannon M. May, Diane F. Jelinek, Philip Greipp, Thomas Witzig, Michael A. Barry

Virology Papers

Purpose: Oncolytic viruses are self-amplifying anticancer agents that make use of the natural ability of viruses to kill cells. Adenovirus serotype 5 (Ad5) has been extensively tested against solid cancers, but less so against B-cell cancers because these cells do not generally express the coxsackie and adenoviral receptor (CAR). To determine whether other adenoviruses might have better potency, we "mined" the adenovirus virome of 55 serotypes for viruses that could kill B-cell cancers.

Experimental Design: Fifteen adenoviruses selected to represent Ad species B, C, D, E, and F were tested in vitro against cell lines and primary patient B-cell cancers …

Role Of Pi3k-Akt Pathway In The Age Associated Decline In Tlr Mediated Activation Of Innate And Adaptive Immune Responses, Mosoka Papa Fallah

University of Kentucky Doctoral Dissertations

Immunosenescence results in reduced immune response to infections with Streptococcus pneumoniae as well as to pneumococcal polysaccharide vaccines. The antibody response to the capsular polysaccharide (CPS) provides protection against S. pneumoniae infection. CPS immunoresponse is T cell independent and needs the macrophage-derived cytokines such as IL-12, IL-6 and IL-1β to elicit an antibody response. We showed a cytokine dysregulation, i.e. a decrease in IL-12, IL-6 and TNF-α but an increase in IL-10, in the aged (18-24 months old comparable to >65 years in human) compared to young adult mouse (8-12 weeks less than 65 years old) splenic macrophages (SM) or …

Novel Mechanisms In Inflammatory Bowel Disease, Razvan I. Arsenescu

University of Kentucky Doctoral Dissertations

Inflammatory Bowel Diseases, Crohn's Disease and Ulcerative colitis, are idiopathic chronic conditions with multifactorial determinants. In general, terms, intestinal inflammation results from abnormal host-microbe interactions. Alterations in homeostasis involve host genetic factors, environmental cues and unique luminal microbial niches. We have examined the coordinated expressions of several molecular targets relevant to the mucosal immune system and identified signature biomarkers of IBD. Qualitative and quantitative changes in the composition of microbiota can be related to unique immuno-phenotypes. This in turn can have more systemic effects that involve energy metabolism. Adiponectin, an adipose tissue derived adipokine, can restore cellular ATP levels and …

A Retinoic Acid–Dependent Checkpoint In The Development Of Cd4+ T Cell–Mediated Immunity, Karina Pino-Lagos, Yanxia Guo, Chrysothemis Brown, Matthew P. Alexander, Raúl Elgueta, Kathryn A. Bennett, Victor De Vries, Elizabeth Nowak, Rune Blomhoff, Shanthini Sockanathan, Roshantha A. Chandraratna, Ethan Dmitrovsky, Randolph J. Noelle

Dartmouth Scholarship

It is known that vitamin A and its metabolite, retinoic acid (RA), are essential for host defense. However, the mechanisms for how RA controls inflammation are incompletely understood. The findings presented in this study show that RA signaling occurs concurrent with the development of inflammation. In models of vaccination and allogeneic graft rejection, whole body imaging reveals that RA signaling is temporally and spatially restricted to the site of inflammation. Conditional ablation of RA signaling in T cells significantly interferes with CD4⁺ T cell effector function, migration, and polarity. These findings provide a new perspective of the role of …

Human Papillomavirus 16 Variants From Zambian Women With Normal Pap Smears, Yan Jun Lei, Kgomotso Makhaola, Daraporn Pittayakhajonwut, Charles Wood, Peter C. Angeletti

Virology Papers

Human papillomavirus (HPV) type 16 is the most prevalent high-risk viral genotype associated with cervical cancer. Six distinct phylogenetic clusters of HPVs have been identified and are distributed differently across five continents. HPV16 DNA was extracted from cervico-lavage samples from women with normal pap smears. The LCR regions were amplified in triplicate, cloned, sequenced, and analyzed from a total of 11 recovered HPV16 positive samples [Ng’andwe et al. (2007): BMC Infect Dis 7:77] were analyzed for sequence variation. The HPV16 LCR variants were assessed for promoter activity by use of a luciferase reporter gene. Six novel HPV16 variants with nucleotide …

Myelopoiesis Related To Perinatal Spleen, Rebecca Hinton, Sawang Petvises, Helen O'Neill

Helen O'Neill

Adult murine spleen is known to have a major role in the development of dendritic cell (DC) subsets, including conventional DC and plasmacytoid DC. In this lab, long-term cultures (LTCs) established from murine spleen support continuous production of novel dendritic-like cells, termed LTC-DC. An in vivo equivalent subset also exists in spleen, namely L-DC. As co-cultures using LTC-derived splenic stroma support the outgrowth of L-DC from spleen and bone marrow sources, it is likely that spleen represents an important niche for DC development. To investigate the appearance of L-DC during ontogeny, spleen was isolated from embryonic and neonatal mice of …

Enhancement Of Reactive Oxygen Species Production And Chlamydial Infection By The Mitochondrial Nod-Like Family Member Nlrx1, Ali A. Abdul-Sater, Najwene Saïd-Sadier, Verissa M. Lam, Bhavni Singh, Matthew A. Pettengill, Fraser Soares, Ivan Tattoli, Simone Lipinski, Stephen E. Girardin, Philip Rosenstiel, David M. Ojcius

All Dugoni School of Dentistry Faculty Articles

Chlamydia trachomatis infections cause severe and irreversible damage that can lead to infertility and blindness in both males and females. Following infection of epithelial cells, Chlamydia induces production of reactive oxygen species (ROS). Unconventionally, Chlamydiae use ROS to their advantage by activating caspase-1, which contributes to chlamydial growth. NLRX1, a member of the Nod-like receptor family that translocates to the mitochondria, can augment ROS production from the mitochondria following Shigella flexneri infections. However, in general, ROS can also be produced by membrane-bound NADPH oxidases. Given the importance of ROS-induced caspase-1 activation in growth of the chlamydial vacuole, we investigated the …

The Pseudomonas Aeruginosa Magnesium Transporter Mgte Inhibits Transcription Of The Type Iii Secretion System, Gregory G. Anderson, Timothy L. Yahr, Rustin R. Lovewell, George A. O'Toole

Dartmouth Scholarship

Pseudomonas aeruginosa is an opportunistic pathogen that causes life-long pneumonia in individuals with cystic fibrosis (CF). These long-term infections are maintained by bacterial biofilm formation in the CF lung. We have recently developed a model of P. aeruginosa biofilm formation on cultured CF airway epithelial cells. Using this model, we discovered that mutation of a putative magnesium transporter gene, called mgtE, led to increased cytotoxicity of P. aeruginosa toward epithelial cells. This altered toxicity appeared to be dependent upon expression of the type III secretion system (T3SS). In this study, we found that mutation of mgtE results in increased T3SS …

Interactions Of Francisella Tularensis With Components Of The Host Fibrinolytic System, Shawn Russell Clinton

Theses and Dissertations (ETD)

Francisella tularensis (FT) is a Gram-negative coccobacillus and causative agent of a life-threatening disease commonly referred to as tularemia. Due to the highly infectious nature of the organism, its previous development as a biowarfare agent and its potential use in acts of bioterrorism, this bacterium is listed as a Category A select agent by the Centers for Disease Control and Prevention (CDC). Efforts to understand the pathogenic mechanisms of FT within the host environment are vital for the development of safe and effective vaccines, as well as treatments, against tularemia. Though considered an intracellular pathogen, FT research of late has …

Ms4a4b, A Cd20 Homologue In T Cells, Inhibits T Cell Propagation By Modulation Of Cell Cycle., Hui Xu, Yaping Yan, Mark S Williams, Gregory B Carey, Jingxian Yang, Hongmei Li, Guang-Xian Zhang, Abdolmohamad Rostami

Department of Neurology Faculty Papers

MS4a4B, a CD20 homologue in T cells, is a novel member of the MS4A gene family in mice. The MS4A family includes CD20, FcεRIβ, HTm4 and at least 26 novel members that are characterized by their structural features: with four membrane-spanning domains, two extracellular domains and two cytoplasmic regions. CD20, FcεRIβ and HTm4 have been found to function in B cells, mast cells and hematopoietic cells respectively. However, little is known about the function of MS4a4B in T cell regulation. We demonstrate here that MS4a4B negatively regulates mouse T cell proliferation. MS4a4B is highly expressed in primary T cells, natural …

The Addition Of Rituximab To Fludarabine And Cyclophosphamide Improves Progression-Free Survival In Patients With Previously Treated Chronic Lymphocytic Leukemia., Amit Mahipal, Mark Weiss

Department of Medical Oncology Faculty Papers

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the United States. There has been considerable progress in understanding the biology and treatment of CLL in last 20 years. The introduction of purine analogs (pentostatin, fludarabine, and cladribine) dramatically increased the response rates compared to alkylating agents. Combination chemoimmunotherapy has further improved the overall frequency of response to over 80% in treatment-naïve and over 60% in relapsed/ refractory disease, respectively.

Complement Factor H-Related Proteins Cfhr2 And Cfhr5 Represent Novel Ligands For The Infection-Associated Crasp Proteins Of Borrelia Burgdorferi, Corinna Siegel, Teresia Hallström, Christine Skerka, Hannes Eberhardt, Barbara Uzonyi, Tobias Beckhaus, Michael Karas, Reinhard Wallich, Brian Stevenson, Peter F. Zipfel, Peter Kraiczy

Microbiology, Immunology, and Molecular Genetics Faculty Publications

BACKGROUND: One virulence property of Borrelia burgdorferi is its resistance to innate immunity, in particular to complement-mediated killing. Serum-resistant B. burgdorferi express up to five distinct complement regulator-acquiring surface proteins (CRASP) which interact with complement regulator factor H (CFH) and factor H-like protein 1 (FHL1) or factor H-related protein 1 (CFHR1). In the present study we elucidate the role of the infection-associated CRASP-3 and CRASP-5 protein to serve as ligands for additional complement regulatory proteins as well as for complement resistance of B. burgdorferi.

METHODOLOGY/PRINCIPAL FINDINGS: To elucidate whether CRASP-5 and CRASP-3 interact with various human proteins, both borrelial proteins …

Composition And Methods For Treating Yersinia Pestis Infection, Susan C. Straley, Brian S. Murphy, Stanislav Forman, Christine R. Wulff, Robert D. Perry, Tanya Myers-Morales

Microbiology, Immunology and Molecular Genetics Faculty Patents

Compositions and methods for treating a Yersinia pestis (Y. pestis) infection are provided. Compositions and methods of for inducing an immune response in a subject are provided. Composition can include a YadC polypeptide.

Interferon Regulatory Factor 3-Dependent Pathways Are Critical For Control Of Herpes Simplex Virus Type 1 Central Nervous System Infection, Vineet D. Menachery, Tracy J. Pasieka, David A. Leib

Dartmouth Scholarship

The initiation of the immune response at the cellular level relies on specific recognition molecules to rapidly signal viral infection via interferon (IFN) regulatory factor 3 (IRF-3)-dependent pathways. The absence of IRF-3 would be expected to render such pathways inoperative and thereby significantly affect viral infection. Unexpectedly, a previous study found no significant change in herpes simplex virus (HSV) pathogenesis in IRF-3^−/− mice following intravenous HSV type 1 (HSV-1) challenge (K. Honda, H. Yanai, H. Negishi, M. Asagiri, M. Sato, T. Mizutani, N. Shimada, Y. Ohba, A. Takaoka, N. Yoshida, and T. Taniguchi, Nature 434:772-777, 2005). In contrast, the …

Factors Associated With The Acquisition And Severity Of Gestational Listeriosis, M. M. Suyemoto, P. A. Spears, T. S. Hamrick, J. A. Barnes, E. A. Havell, P. E. Orndorff

Osteopathic Medicine, Jerry M. Wallace School of

No abstract provided.

Hepatitis C Virus Core-Derived Peptides Inhibit Genotype 1b Viral Genome Replication Via Interaction With Ddx3x, Chaomin Sun, Cara T. Pager, Guangxiang Luo, Peter Sarnow, Jamie H. D. Cate

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The protein DDX3X is a DEAD-box RNA helicase that is essential for the hepatitis C virus (HCV) life cycle. The HCV core protein has been shown to bind to DDX3X both in vitro and in vivo. However, the specific interactions between these two proteins and the functional importance of these interactions for the HCV viral life cycle remain unclear. We show that amino acids 16-36 near the N-terminus of the HCV core protein interact specifically with DDX3X both in vitro and in vivo. Replication of HCV replicon NNeo/C-5B RNA (genotype 1b) is significantly suppressed in HuH-7-derived cells expressing green fluorescent …

Sialic Acid Transport And Catabolism Are Cooperatively Regulated By Siar And Crp In Nontypeable Haemophilus Influenzae, Jason W. Johnston, Haider Shamsulddin, Anne-Frances Miller, Michael A. Apicella

Microbiology, Immunology, and Molecular Genetics Faculty Publications

BACKGROUND: The transport and catabolism of sialic acid, a critical virulence factor for nontypeable Haemophilus influenzae, is regulated by two transcription factors, SiaR and CRP.

RESULTS: Using a mutagenesis approach, glucosamine-6-phosphate (GlcN-6P) was identified as a co-activator for SiaR. Evidence for the cooperative regulation of both the sialic acid catabolic and transport operons suggested that cooperativity between SiaR and CRP is required for regulation. cAMP was unable to influence the expression of the catabolic operon in the absence of SiaR but was able to induce catabolic operon expression when both SiaR and GlcN-6P were present. Alteration of helical phasing supported …

Bpab, A Novel Protein Encoded By The Lyme Disease Spirochete's Cp32 Prophages, Binds To Erp Operator 2 Dna, Logan H. Burns, Claire A. Adams, Sean P. Riley, Brandon L. Jutras, Amy Bowman, Alicia M. Chenail, Anne E. Cooley, Laura A. Haselhorst, Alisha M. Moore, Kelly Babb, Michael G. Fried, Brian Stevenson

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Borrelia burgdorferi produces Erp outer surface proteins throughout mammalian infection, but represses their synthesis during colonization of vector ticks. A DNA region 5′ of the start of erp transcription, Operator 2, was previously shown to be essential for regulation of expression. We now report identification and characterization of a novel erp Operator 2-binding protein, which we named BpaB. erp operons are located on episomal cp32 prophages, and a single bacterium may contain as many as 10 different cp32s. Each cp32 family member encodes a unique BpaB protein, yet the three tested cp32-encoded BpaB alleles all bound to the same DNA …

Association Between Chronic Liver And Colon Inflammation During The Development Of Murine Syngeneic Graft-Versus-Host Disease, Jason Anthony Brandon, Jacqueline Perez-Rodriguez, C. Darrell Jennings, Donald A. Cohen, Vishal J. Sindhava, Subbarao Bondada, Alan M. Kaplan, J. Scott Bryson

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The murine model of cyclosporine A (CsA)-induced syngeneic graft-versus-host disease (SGVHD) is a bone marrow (BM) transplantation model that develops chronic colon inflammation identical to other murine models of CD4⁺ T cell-mediated colitis. Interestingly, SGVHD animals develop chronic liver lesions that are similar to the early peribiliary inflammatory stages of clinical chronic liver disease, which is frequently associated with inflammatory bowel disease (IBD). Therefore, studies were initiated to investigate the chronic liver inflammation that develops in the SGVHD model. To induce SGVHD, mice were lethally irradiated, reconstituted with syngeneic BM, and treated with CsA. All of the SGVHD animals …