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Uma Sriram, Beth L Hill, Jonathan M Cenna, Larisa Gofman, Nicole C Fernandes, Bijayesh Haldar, Raghava Potula
Methamphetamine (METH) is a widely used psychostimulant that severely impacts the host's innate and adaptive immune systems and has profound immunological implications. T cells play a critical role in orchestrating immune responses. We have shown recently how chronic exposure to METH affects T cell activation using a murine model of lymphocytic choriomeningitis virus (LCMV) infection. Using the TriCOM (trinary state combinations) feature of GemStone™ to study the polyfunctionality of T cells, we have analyzed how METH affected the cytokine production pattern over the course of chronic LCMV infection...
2016: PloS One
Achire N Mbanwi, Chao Wang, Kaoru Geddes, Dana J Philpott, Tania H Watts
Lymphocytic choriomeningitis virus clone 13 (LCMV13) infection of mice is a widely used model for investigating the mechanisms driving persistent viral infection in humans. LCMV13 disrupts splenic architecture early during infection, but this returns to normal within a few weeks. However, the long-term effects of LCMV13 infection on splenic structure have not been reported. Here we report that persistent infection with LCMV13 results in sustained splenic atrophy that persists for at least 500 days following infection, whereas infection with the acutely infecting LCMV Armstrong is associated with a return to pre-infection spleen weights...
October 11, 2016: European Journal of Immunology
Cristina Fevola, Kristian M Forbes, Satu Mäkelä, Niina Putkuri, Heidi C Hauffe, Hannimari Kallio-Kokko, Jukka Mustonen, Anne J Jääskeläinen, Antti Vaheri
BACKGROUND: The emergence and re-emergence of zoonotic and vector-borne diseases are increasing in Europe. Prominent rodent-borne zoonotic viruses include Puumala hantavirus (PUUV; the causative agent of nephropathia epidemica, NE), lymphocytic choriomeningitis virus (LCMV), and orthopoxviruses (OPV). In addition, Ljungan virus (LV) is considered a potentially zoonotic virus. OBJECTIVE: The aim of this study was to compare clinical picture between acute PUUV patients with and without additional rodent-borne viral infections, to investigate if concurrent infections influence disease severity...
October 4, 2016: Journal of Clinical Virology: the Official Publication of the Pan American Society for Clinical Virology
Sylvie Chabot, Fernando Alvarez, Abdelaziz Amrani, Idriss Djilali-Saiah
Identifying the type of diabetogenic CD8(+) T cells that initiate autoimmune diabetes (AID) is a critical step in designing appropriate strategies for the early detection of beta cell-directed autoimmunity and its progression to diabetes. We generated a novel double transgenic (Tg) mouse model on the naturally diabetes resistant C57Bl/6 background, co-expressing two transgenes including a specific TCR anti-lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP) carried by CD8(+) T cells and LCMV-NP (as neo-self antigen) expressed by pancreatic beta cells...
August 11, 2016: Autoimmunity
Hannah Klein, Glenda K Rabe, Bahri Karacay, Daniel J Bonthius
Lymphocytic choriomeningitis virus (LCMV) infection during pregnancy injures the human fetal brain. Neonatal rats inoculated with LCMV are an excellent model of congenital LCMV infection because they develop cerebellar injuries similar to those in humans. To evaluate the role of T-lymphocytes in LCMV-induced cerebellar pathology, congenitally athymic rats, deficient in T-lymphocytes were compared with euthymic rats. Peak viral titers and cellular targets of infection were similar, but viral clearance from astrocytes was impaired in the athymic rats...
September 25, 2016: Journal of Neuropathology and Experimental Neurology
Masaharu Iwasaki, Cherie T Ng, Beatrice Cubitt, Juan C de la Torre
: Several arenaviruses, chiefly Lassa virus (LASV), cause hemorrhagic fever disease in humans and pose serious public health concerns in their endemic regions. Moreover, mounting evidence indicates that the worldwide-distributed, prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV), is a neglected human pathogen of clinical significance. We have documented that a recombinant LCMV containing the glycoprotein gene (GPC) of LASV within the backbone of the immunosuppressive Clone 13 (Cl-13) variant of Armstrong strain of LCMV (rCl-13/LASV-GPC) exhibited Cl-13 like growth properties in cultured cells but in contrast to Cl-13, rCl-13/LASV-GPC was unable to establish persistence in immune competent adult mice, which prevented its use for some in vivo experiments...
August 31, 2016: Journal of Virology
Michael Bruns, Jara Wanger, Udo Schumacher, Wolfgang Deppert
Using the SV40 transgenic WAP-T/WAP-TNP mouse models for mammary carcinomas, we compared the response to immune checkpoint blockade therapy in tumor mice expressing either SV40 T-antigen containing the LCMV NP-epitope (T-AgNP in WAP-TNP mice), or the unmodified T-antigen (T-Ag in WAP-T mice). Specifically, we asked, whether the presence of the highly immunogenic NP-epitope in T-AgNP influences this response in comparison to the weakly immunogenic T-cell epitopes of T-Ag in WAP-T tumor mice. Treatment of WAP-TNP tumor mice with either anti-PD1 or anti-PD-L1 antibodies led to tumor regression, with anti-PD-L1 treatment being more effective...
August 25, 2016: Oncotarget
Eoin F McKinney, Kenneth G C Smith
During acute viral infection CD8 T cells rapidly expand before contracting down to a persistent memory population that confers long-lasting immunity. However when the antigen persists, such as during chronic viral infection, a dysfunctional process termed 'exhaustion' limits the antiviral response, facilitating ongoing viraemia and poor clinical outcome. CD8 T cell exhaustion was originally identified in lymphocytic choriomeningitis virus (LCMV) infection of mice however new evidence has shown that exhaustion is associated with the control of a wide range of human chronic inflammatory states including chronic viral infection, autoimmunity and cancer...
August 31, 2016: Immunology and Cell Biology
Martin P Hosking, Claudia T Flynn, J Lindsay Whitton
CD8(+) memory T cells produce IFNγ within hours of secondary infection, but this is quickly terminated in vivo despite the presence of stimulatory viral antigen, suggesting that active suppression occurs. Herein, we investigated the in vivo effector function of CD8(+) memory T cells during successive encounters with viral antigen. CD8(+) T cells in immune mice receiving prior viral or peptide challenge failed to reproduce IFNγ during LCMV rechallenge. Surprisingly, this refractory state was induced even in memory cells that had not encountered their cognate antigen, indicating that the silencing of CD8(+) T cell responses is TCR-independent...
November 2016: Virology
Sibel Durlanik, Lucie Loyal, Regina Stark, Özen Sercan Alp, Anett Hartung, Andreas Radbruch, Matthias von Herrath, Nadine Matzmohr, Marco Frentsch, Andreas Thiel
CD40-CD40 Ligand (CD40L) signaling plays multiple indispensable roles in cellular and humoral immunity. Impaired memory T-cell responses in the absence of CD40L have been well documented, but the requirement of this interaction for efficient priming of CD8(+) T cells especially under inflammatory conditions has been under debate. In contrast to previous publications, we report here that virus-specific CD8(+) T-cell responses as well as viral clearance are affected not only in the memory but also in the effector phase in CD40L(-/-) mice infected with lymphocytic choriomeningitis virus (LCMV) Armstrong strain...
August 26, 2016: European Journal of Immunology
Cornelia Hilpert, Selina Sitte, Alexander Matthies, David Voehringer
Dendritic cells (DCs) are considered to be the major APCs with potent activity for priming of naive CD4 and CD8 T cells. However, T cell priming can also be achieved by other APCs including macrophages, B cells, or even nonhematopoietic cell types. Systemic low-dose infection of mice with lymphocytic choriomeningitis virus (LCMV) results in massive expansion of virus-specific CD4 and CD8 T cells. To determine the role of DCs as APCs and source of type I IFNs in this infection model, we used ΔDC mice in which DCs are constitutively ablated because of expression of the diphtheria toxin α subunit within developing DCs...
October 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Se Jin Im, Masao Hashimoto, Michael Y Gerner, Junghwa Lee, Haydn T Kissick, Matheus C Burger, Qiang Shan, J Scott Hale, Judong Lee, Tahseen H Nasti, Arlene H Sharpe, Gordon J Freeman, Ronald N Germain, Helder I Nakaya, Hai-Hui Xue, Rafi Ahmed
Chronic viral infections are characterized by a state of CD8(+) T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor. A better understanding of the mechanisms that regulate CD8(+) T-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8(+) T cells. Here we identify a population of virus-specific CD8(+) T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV)...
August 2, 2016: Nature
Ran He, Shiyue Hou, Cheng Liu, Anli Zhang, Qiang Bai, Miao Han, Yu Yang, Gang Wei, Ting Shen, Xinxin Yang, Lifan Xu, Xiangyu Chen, Yaxing Hao, Pengcheng Wang, Chuhong Zhu, Juanjuan Ou, Houjie Liang, Ting Ni, Xiaoyan Zhang, Xinyuan Zhou, Kai Deng, Yaokai Chen, Yadong Luo, Jianqing Xu, Hai Qi, Yuzhang Wu, Lilin Ye
During chronic viral infection, virus-specific CD8(+) T cells become exhausted, exhibit poor effector function and lose memory potential. However, exhausted CD8(+) T cells can still contain viral replication in chronic infections, although the mechanism of this containment is largely unknown. Here we show that a subset of exhausted CD8(+) T cells expressing the chemokine receptor CXCR5 has a critical role in the control of viral replication in mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV)...
August 2, 2016: Nature
Bertram Bengsch, Andy L Johnson, Makoto Kurachi, Pamela M Odorizzi, Kristen E Pauken, John Attanasio, Erietta Stelekati, Laura M McLane, Michael A Paley, Greg M Delgoffe, E John Wherry
Dynamic reprogramming of metabolism is essential for T cell effector function and memory formation. However, the regulation of metabolism in exhausted CD8(+) T (Tex) cells is poorly understood. We found that during the first week of chronic lymphocytic choriomeningitis virus (LCMV) infection, before severe dysfunction develops, virus-specific CD8(+) T cells were already unable to match the bioenergetics of effector T cells generated during acute infection. Suppression of T cell bioenergetics involved restricted glucose uptake and use, despite persisting mechanistic target of rapamycin (mTOR) signaling and upregulation of many anabolic pathways...
August 16, 2016: Immunity
Benjamin Wittevrongel, Marc M Van Hulle
In brain-computer interfaces (BCIs) based on steady-state visual evoked potentials (SSVEPs) the number of selectable targets is rather limited when each target has its own stimulation frequency. One way to remedy this is by combining frequency- with phase encoding. We introduce a new multivariate spatiotemporal filter, based on Linearly Constrained Minimum Variance (LCMV) beamforming, for discriminating between frequency-phase encoded targets more accurately, even when using short signal lengths than with (extended) Canonical Correlation Analysis (CCA), which is traditionally posited for this stimulation paradigm...
2016: PloS One
Eunseon Ahn, Ben Youngblood, Junghwa Lee, Judong Lee, Surojit Sarkar, Rafi Ahmed
UNLABELLED: PD-1 is an inhibitory receptor that has a major role in T cell dysfunction during chronic infections and cancer. While demethylation of the PD-1 promoter DNA is observed in exhausted T cells isolated from chronically infected individuals, little is known about when this stable demethylation of PD-1 promoter DNA is programmed during the course of a chronic infection. To assess if PD-1 promoter DNA demethylation is impacted by prolonged stimulation during effector phase of chronic infection, we adoptively transferred virus-specific day 8 effector CD8 T cells from mice infected with lymphocytic choriomeningitis virus (LCMV) clone 13 into recipient mice that had cleared an acute infection...
October 1, 2016: Journal of Virology
Daniel T Utzschneider, Francesca Alfei, Patrick Roelli, David Barras, Vijaykumar Chennupati, Stephanie Darbre, Mauro Delorenzi, Daniel D Pinschewer, Dietmar Zehn
Chronic infections induce T cells showing impaired cytokine secretion and up-regulated expression of inhibitory receptors such as PD-1. What determines the acquisition of this chronic phenotype and how it impacts T cell function remain vaguely understood. Using newly generated recombinant antigen variant-expressing chronic lymphocytic choriomeningitis virus (LCMV) strains, we uncovered that T cell differentiation and acquisition of a chronic or exhausted phenotype depend critically on the frequency of T cell receptor (TCR) engagement and less significantly on the strength of TCR stimulation...
August 22, 2016: Journal of Experimental Medicine
Christopher M Ziegler, Philip Eisenhauer, Emily A Bruce, Vedran Beganovic, Benjamin R King, Marion E Weir, Bryan A Ballif, Jason Botten
We report that the lymphocytic choriomeningitis virus (LCMV) matrix protein, which drives viral budding, is phosphorylated at serine 41 (S41). A recombinant (r)LCMV bearing a phosphomimetic mutation (S41D) was impaired in infectious and defective interfering (DI) particle release, while a non-phosphorylatable mutant (S41A) was not. The S41D mutant was disproportionately impaired in its ability to release DI particles relative to infectious particles. Thus, DI particle production by LCMV may be dynamically regulated via phosphorylation of S41...
September 2016: Journal of General Virology
Hyo Jin Park, Ji Hoon Oh, Sang-Jun Ha
Regulatory T (Treg) cells, which express Foxp3 as a transcription factor, are subsets of CD4(+) T cells. Treg cells play crucial roles in immune tolerance and homeostasis maintenance by regulating the immune response. The primary role of Treg cells is to suppress the proliferation of effector T (Teff) cells and the production of cytokines such as IFN-γ, TNF-α, and IL-2. It has been demonstrated that Treg cells' ability to inhibit the function of Teff cells is enhanced during persistent pathogen infection and cancer development...
2016: Journal of Visualized Experiments: JoVE
M Sabeti, S D Katebi, K Rastgar, Z Azimifar
BACKGROUND AND OBJECTIVE: P300 is probably the most well-known component of event-related brain potentials (ERPs). Using an oddball paradigm, a P300 component can be identified, that is, elicited by the target stimuli recognition. Since P300 is associated with attention and memory operations of the brain, investigation of this component can improve our understanding of these mechanisms. The present study is aimed at identifying the P300 generators in 30 healthy subjects aged 18-30 years using time-reduction region-suppression linearly constrained minimum variance (TR-LCMV) beamformer...
September 2016: Computer Methods and Programs in Biomedicine
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