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Peripheral viral transduction

Brenden Van Wyk, Marlene Snider, Erin Scruten, Sylvia van Drunen Littel-van den Hurk, Scott Napper
As a part of their pathogenic mechanism, many pathogens causing persistent infections, including bovine viral diarrhea virus (BVDV), immunosuppress their hosts, often by limiting the ability to either produce, or respond to, interferon. The objective of this study was to quantify the extent to which an acute infection of cattle with a non-cytopathic strain of BVDV induces interferon responses and to establish the functionality of these responses. Functionality of responses was investigated using a bovine specific peptide array to monitor kinase-mediated signal transduction activity within peripheral blood mononuclear cells (PBMCs) at time points corresponding to the interferon gamma (IFN-γ) and alpha (IFN-α) responsive phases of acute BVDV infection...
November 15, 2016: Veterinary Microbiology
Melissa R Andrews, Sara Soleman, Menghon Cheah, David A Tumbarello, Matthew R J Mason, Elizabeth Moloney, Joost Verhaagen, Jean-Charles Bensadoun, Bernard Schneider, Patrick Aebischer, James W Fawcett
The regenerative ability of CNS axons decreases with age, however, this ability remains largely intact in PNS axons throughout adulthood. These differences are likely to correspond with age-related silencing of proteins necessary for axon growth and elongation. In previous studies, it has been shown that reintroduction of the α9 integrin subunit (tenascin-C receptor, α9) that is downregulated in adult CNS can improve neurite outgrowth and sensory axon regeneration after a dorsal rhizotomy or a dorsal column crush spinal cord lesion...
July 2016: ENeuro
Md Aminul Islam, Christine Große-Brinkhaus, Maren Julia Pröll, Muhammad Jasim Uddin, Sharmin Aqter Rony, Dawit Tesfaye, Ernst Tholen, Michael Hölker, Karl Schellander, Christiane Neuhoff
BACKGROUND: Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically important viral diseases affecting swine industry worldwide. Despite routine farm vaccination, effective control strategies for PRRS remained elusive which underscores the need for in-depth studies to gain insight into the host immune response to vaccines. The current study aimed to investigate transcriptional responses to PRRS Virus (PRRSV) vaccine in the peripheral blood mononuclear cells (PBMCs) within 3 days following vaccination in German Landrace pigs...
2016: BMC Genomics
Andrew E Sloan, Hua Fung, Jane Reese, Lisa R Rogers, Christopher Murphay, Hillard Lazrus, Boro Dropulic, Stan L Gerson
INTRODUCTION: Glioblastoma (GBM) is the most common malignant brain tumor with a median survival of 15 months despite surgery and aggressive radiochemotherapy. The most important mechanism of temozolomide (TMZ) resistance is the O-methylguanine-DNA methyltransferase (MGMT) gene that repairs temozolomide-induced DNA methylation. The MGMT inhibitor O-benzylguanine (BG) has demonstrated efficacy in depleting MGMT and maximizing tumor response in early-phase clinical trials. However, because MGMT expression is also low in hematopoietic cells, this has resulted in unacceptable bone marrow toxicity, and this approach has been abandoned...
August 2016: Neurosurgery
Zachary L Watson, Monica K Ertel, Alfred S Lewin, Sonal S Tuli, Gregory S Schultz, Donna M Neumann, David C Bloom
UNLABELLED: Following infection of epithelial tissues, herpes simplex virus 1 (HSV-1) virions travel via axonal transport to sensory ganglia and establish a lifelong latent infection within neurons. Recent studies have revealed that, following intraganglionic or intrathecal injection, recombinant adeno-associated virus (rAAV) vectors can also infect sensory neurons and are capable of stable, long-term transgene expression. We sought to determine if application of rAAV to peripheral nerve termini at the epithelial surface would allow rAAV to traffic to sensory ganglia in a manner similar to that seen with HSV...
September 1, 2016: Journal of Virology
Saloni T Mehta, Xueting Luo, Kevin K Park, John L Bixby, Vance P Lemmon
Axonal regeneration after spinal cord injury (SCI) is intrinsically and extrinsically inhibited by multiple factors. One major factor contributing to intrinsic regeneration failure is the inability of mature neurons in the central nervous system (CNS) to activate regeneration-associated transcription factors (TFs) post-injury. A prior study identified TFs overexpressed in neurons of the peripheral nervous system (PNS) compared to the CNS; some of these could be involved in the ability of PNS neurons to regenerate...
June 2016: Experimental Neurology
Koen Vercauteren, Brad E Hoffman, Irene Zolotukhin, Geoffrey D Keeler, Jing W Xiao, Etiena Basner-Tschakarjan, Katherine A High, Hildegund Cj Ertl, Charles M Rice, Arun Srivastava, Ype P de Jong, Roland W Herzog
Adeno-associated viral (AAV) vectors are currently being tested in multiple clinical trials for liver-directed gene transfer to treat the bleeding disorders hemophilia A and B and metabolic disorders. The optimal viral capsid for transduction of human hepatocytes has been under active investigation, but results across various models are inconsistent. We tested in vivo transduction in "humanized" mice. Methods to quantitate percent AAV transduced human and murine hepatocytes in chimeric livers were optimized using flow cytometry and confocal microscopy with image analysis...
June 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
Daniel O Griffin, Stephen P Goff
BACKGROUND: Gene therapy is currently being attempted using a number of delivery vehicles including lentiviral-based vectors. The delivery and insertion of a gene using lentiviral-based vectors involves multiple discrete steps, including reverse transcription of viral RNA into DNA, nuclear entry, integration of viral DNA into the host genome and expression of integrated genes. Transduction of murine stem cells by the murine leukemia viruses is inefficient because the expression of the integrated DNA is profoundly blocked...
2016: Retrovirology
Vikram Thakur, Mayra Gonzalez, Kristen Pennington, Munmun Chattopadhyay
Painful diabetic neuropathy is a common and difficult to treat complication of diabetes. A growing body of evidence implicates the role of inflammatory mediators in the damage to the peripheral axons and in the pathogenesis of neuropathic pain. Increased expression of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α in the peripheral nervous system suggests the possibility of change in pain perception in diabetes. In this study we investigated that continuous delivery of IL10 in the nerve fibers achieved by HSV vector mediated transduction of dorsal root ganglion (DRG) in animals with Type 1 diabetes, blocks the nociceptive and stress responses in the DRG neurons by reducing IL1β expression along with inhibition of phosphorylation of p38 MAPK (mitogen-activated protein kinase) and protein kinase C (PKC)...
April 2016: Molecular and Cellular Neurosciences
Florian Douam, Louis-Marie Bobay, Guillemette Maurin, Judith Fresquet, Noémie Calland, Carine Maisse, Tony Durand, François-Loïc Cosset, Cyrille Féray, Dimitri Lavillette
UNLABELLED: Hepatitis C virus (HCV) productively infects hepatocytes. Virion surface glycoproteins E1 and E2 play a major role in this restricted cell tropism by mediating virus entry into particular cell types. However, several pieces of evidence have suggested the ability of patient-derived HCV particles to infect peripheral blood mononuclear cells. The viral determinants and mechanisms mediating such events remain poorly understood. Here, we aimed at isolating viral determinants of HCV entry into B lymphocytes...
January 2016: Journal of Virology
Mitsuhiro Enomoto, Takashi Hirai, Hidetoshi Kaburagi, Takanori Yokota
RNA interference is a powerful tool used to induce loss-of-function phenotypes through post-transcriptional gene silencing. Small interfering RNA (siRNA) molecules have been used to target the central nervous system (CNS) and are expected to have clinical utility against refractory neurodegenerative diseases. However, siRNA is characterized by low transduction efficiency, insufficient inhibition of gene expression, and short duration of therapeutic effects, and is thus not ideal for treatment of neural tissues and diseases...
2016: Methods in Molecular Biology
Brett D Dufour, Jodi L McBride
Viral vector delivery of RNA silencing constructs, when administered into vasculature, typically results in poor central nervous system (CNS) transduction due to the inability of the vector to cross the blood-brain barrier (BBB). However, adeno-associated virus serotype 9 (AAV9) has the ability to cross the BBB and robustly transduce brain parenchyma and peripheral tissues at biologically meaningful levels when injected intravenously. Recent work by our lab has shown that this method can be used to deliver RNA silencing constructs, resulting in significant reductions in gene expression in multiple brain regions and in peripheral tissues...
2016: Methods in Molecular Biology
Sujata Halder, Kim Van Vliet, J Kennon Smith, Thao Thi Phuong Duong, Robert McKenna, James M Wilson, Mavis Agbandje-McKenna
Adeno-associated virus rhesus isolate 8 (AAVrh.8) is a leading vector for the treatment of neurological diseases due to its efficient transduction of neuronal cells and reduced peripheral tissue tropism. Toward identification of the capsid determinants for these properties, the structure of AAVrh.8 was determined by X-ray crystallography to 3.5 Å resolution and compared to those of other AAV isolates. The capsid viral protein (VP) structure consists of an αA helix and an eight-stranded anti-parallel β-barrel core conserved in parvoviruses, and large insertion loop regions between the β-strands form the capsid surface topology...
October 2015: Journal of Structural Biology
Andrew M Tan, Omar A Samad, Sulayman D Dib-Hajj, Stephen G Waxman
Diabetic neuropathic pain affects a substantial number of people and represents a major public health problem. Available clinical treatments for diabetic neuropathic pain remain only partially effective and many of these treatments carry the burden of side effects or the risk of dependence. The misexpression of sodium channels within nociceptive neurons contributes to abnormal electrical activity associated with neuropathic pain. Voltage-gated sodium channel Nav1.3 produces tetrodotoxin-sensitive sodium currents with rapid repriming kinetics and has been shown to contribute to neuronal hyperexcitability and ectopic firing in injured neurons...
2015: Molecular Medicine
Sergio Gonzalez, Ruani Fernando, Jade Berthelot, Claire Perrin-Tricaud, Emmanuelle Sarzi, Roman Chrast, Guy Lenaers, Nicolas Tricaud
The myelin sheath that covers a large amount of neurons is critical for their homeostasis, and myelinating glia mitochondria have recently been shown to be essential for neuron survival. However morphological and physiological properties of these organelles remain elusive. Here we report a method to analyze mitochondrial dynamics and morphology in myelinating Schwann cells of living mice using viral transduction and time-lapse multiphoton microscopy. We describe the distribution, shape, size and dynamics of mitochondria in live cells...
July 2015: Mitochondrion
Christine V Möser, Heike Stephan, Katharina Altenrath, Katharina L Kynast, Otto Q Russe, Katrin Olbrich, Gerd Geisslinger, Ellen Niederberger
BACKGROUND: TANK-binding kinase (TBK1) is a non-canonical IκB kinase (IKK) involved in the regulation of type I interferons and of NF-κB signal transduction. It is activated by viral infections and inflammatory mediators and has therefore been associated with viral diseases, obesity, and rheumatoid arthritis. Its role in pain has not been investigated so far. Due to the important roles of NF-κB, classical IκB Kinases and the IKK-related kinase, IKKε, in inflammatory nociception, we hypothesized that TBK1, which is suggested to form a complex with IKKε under certain conditions, might also alter the inflammatory nociceptive response...
2015: Journal of Neuroinflammation
Heather D Hickman, Glennys V Reynoso, Barbara F Ngudiankama, Stephanie S Cush, James Gibbs, Jack R Bennink, Jonathan W Yewdell
CD8(+) T cells play a critical role in limiting peripheral virus replication, yet how they locate virus-infected cells within tissues is unknown. Here, we have examined the environmental signals that CD8(+) T cells use to localize and eliminate virus-infected skin cells. Epicutaneous vaccinia virus (VV) infection, mimicking human smallpox vaccination, greatly increased expression of the CXCR3 chemokine receptor ligands CXCL9 and CXCL10 in VV-infected skin. Despite normal T cell numbers in the skin, Cxcr3(-/-) mice exhibited dramatically impaired CD8(+)-T-cell-dependent virus clearance...
March 17, 2015: Immunity
Rathindra M Mukherjee, Budhapriyavilas Bansode, Puja Gangwal, Aparna Jakkampudi, Panyala B Reddy, Padaki N Rao, Rajesh Gupta, D Nageshwar Reddy
BACKGROUND: The interferon regulatory factors (IRFs) are a family of transcription factors known to be involved in the modulation of cellular responses to interferons (IFNs) and viral infection. While IRF-1 acts as a positive regulator, IRF-2 is known to repress IFN-mediated gene expression. The increase in the IRF-1/IRF-2 ratio is considered as an important event in the transcriptional activation of IFN-α gene toward development of the cellular antiviral response. OBJECTIVE: This study was performed to assess the expression of IRF mRNAs along with the expression level of IFN-α, its receptor (IFNAR-1), and the signal transduction factor (STAT-1) in treatment naive hepatitis C virus (HCV)-infected subjects...
March 2012: Journal of Clinical and Experimental Hepatology
Erez Pery, Ann Sheehy, N Miranda Nebane, Andrew Jay Brazier, Vikas Misra, Kottampatty S Rajendran, Sara J Buhrlage, Marie K Mankowski, Lynn Rasmussen, E Lucile White, Roger G Ptak, Dana Gabuzda
APOBEC3G (A3G) is a cellular cytidine deaminase that restricts HIV-1 replication by inducing G-to-A hypermutation in viral DNA and by deamination-independent mechanisms. HIV-1 Vif binds to A3G, resulting in its degradation via the 26 S proteasome. Therefore, this interaction represents a potential therapeutic target. To identify compounds that inhibit interaction between A3G and HIV-1 Vif in a high throughput format, we developed a homogeneous time-resolved fluorescence resonance energy transfer assay. A 307,520 compound library from the NIH Molecular Libraries Small Molecule Repository was screened...
April 17, 2015: Journal of Biological Chemistry
Martha Lappas
OBJECTIVE: Maternal peripheral insulin resistance and increased inflammation are two features of pregnancies complicated by pre-existing maternal obesity and gestational diabetes mellitus (GDM). There is now increasing evidence that activation of Toll-like receptor (TLR) signalling pathways by viral products may play a role in the pathophysiology of diabetes. Thus, the aim of this study was to assess the effect of the TLR3 ligand and viral dsRNA analogue polyinosinic polycytidilic acid (poly(I:C)) on inflammation and the insulin signalling pathway in skeletal muscle from pregnant women...
May 2015: Metabolism: Clinical and Experimental
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