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https://www.readbyqxmd.com/read/29768211/long-term-persistence-of-exhausted-cd8-t-cells-in-chronic-infection-is-regulated-by-microrna-155
#1
Erietta Stelekati, Zeyu Chen, Sasikanth Manne, Makoto Kurachi, Mohammed-Alkhatim Ali, Keith Lewy, Zhangying Cai, Kito Nzingha, Laura M McLane, Jennifer L Hope, Adam J Fike, Peter D Katsikis, E John Wherry
Persistent viral infections and tumors drive development of exhausted T (TEX ) cells. In these settings, TEX cells establish an important host-pathogen or host-tumor stalemate. However, TEX cells erode over time, leading to loss of pathogen or cancer containment. We identified microRNA (miR)-155 as a key regulator of sustained TEX cell responses during chronic lymphocytic choriomeningitis virus (LCMV) infection. Genetic deficiency of miR-155 ablated CD8 T cell responses during chronic infection. Conversely, enhanced miR-155 expression promoted expansion and long-term persistence of TEX cells...
May 15, 2018: Cell Reports
https://www.readbyqxmd.com/read/29768177/expression-of-the-dna-binding-factor-tox-promotes-the-encephalitogenic-potential-of-microbe-induced-autoreactive-cd8-t-cells
#2
Nicolas Page, Bogna Klimek, Mathias De Roo, Karin Steinbach, Hadrien Soldati, Sylvain Lemeille, Ingrid Wagner, Mario Kreutzfeldt, Giovanni Di Liberto, Ilena Vincenti, Thomas Lingner, Gabriela Salinas, Wolfgang Brück, Mikael Simons, Rabih Murr, Jonathan Kaye, Dietmar Zehn, Daniel D Pinschewer, Doron Merkler
Infections are thought to trigger CD8+ cytotoxic T lymphocyte (CTL) responses during autoimmunity. However, the transcriptional programs governing the tissue-destructive potential of CTLs remain poorly defined. In a model of central nervous system (CNS) inflammation, we found that infection with lymphocytic choriomeningitis virus (LCMV), but not Listeria monocytogenes (Lm), drove autoimmunity. The DNA-binding factor TOX was induced in CTLs during LCMV infection and was essential for their encephalitogenic properties, and its expression was inhibited by interleukin-12 during Lm infection...
May 15, 2018: Immunity
https://www.readbyqxmd.com/read/29765612/crystal-structures-of-lymphocytic-choriomeningitis-virus-endonuclease-domain-complexed-with-diketo-acid-ligands
#3
Magali Saez-Ayala, Elsie Laban Yekwa, Mauro Carcelli, Bruno Canard, Karine Alvarez, François Ferron
The Arenaviridae family, together with the Bunyaviridae and Orthomyxoviridae families, is one of the three negative-stranded RNA viral families that encode an endonuclease in their genome. The endonuclease domain is at the N-terminus of the L protein, a multifunctional protein that includes the RNA-dependent RNA polymerase. The synthesis of mRNA in arenaviruses is a process that is primed by capped nucleotides that are 'stolen' from the cellular mRNA by the endonuclease domain in cooperation with other domains of the L protein...
March 1, 2018: IUCrJ
https://www.readbyqxmd.com/read/29762684/effective-treatment-of-experimental-lymphocytic-choriomeningitis-virus-infection-consideration-of-favipiravir-for-use-with-infected-organ-transplant-recipients
#4
Brady T Hickerson, Jonna B Westover, Kie-Hoon Jung, Takashi Komeno, Yousuke Furuta, Brian B Gowen
Lymphocytic choriomeningitis virus (LCMV) poses a substantial risk to immunocompromised individuals. The case fatality rate in recent clusters of LCMV infection in immunosuppressed organ transplantation recipients has exceeded 70%. In the present study, we demonstrate potent antiviral activity of favipiravir against acute, disseminated LCMV infection in NZB mice. Treatment resulted in complete protection against mortality and dramatic reductions in viral loads. In contrast, ribavirin, the current antiviral of choice, was mostly ineffective...
May 14, 2018: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/29743559/antigen-specific-primed-cytotoxic-t-cells-eliminate-tumour-cells-in-vivo-and-prevent-tumour-development-regardless-of-the-presence-of-anti-apoptotic-mutations-conferring-drug-resistance
#5
Paula Jaime-Sánchez, Elena Catalán, Iratxe Uranga-Murillo, Nacho Aguiló, Llipsy Santiago, Pilar M Lanuza, Diego de Miguel, Maykel A Arias, Julián Pardo
Cytotoxic CD8+ T (Tc) cells are the main executors of transformed and cancer cells during cancer immunotherapy. The latest clinical results evidence a high efficacy of novel immunotherapy agents that modulate Tc cell activity against bad prognosis cancers. However, it has not been determined yet whether the efficacy of these treatments can be affected by selection of tumoural cells with mutations in the cell death machinery, known to promote drug resistance and cancer recurrence. Here, using a model of prophylactic tumour vaccination based on the LCMV-gp33 antigen and the mouse EL4 T lymphoma, we analysed the molecular mechanism employed by Tc cells to eliminate cancer cells in vivo and the impact of mutations in the apoptotic machinery on tumour development...
May 9, 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29734372/the-adaptor-molecule-cd2ap-in-cd4-t-cells-modulates-differentiation-of-follicular-helper-t-cells-during-chronic-lcmv-infection
#6
Saravanan Raju, Kohei Kometani, Tomohiro Kurosaki, Andrey S Shaw, Takeshi Egawa
CD4 T cell-mediated help to CD8 T cells and B cells is a critical arm of the adaptive immune system required for control of pathogen infection. CD4 T cells express cytokines and co-stimulatory molecules that support a sustained CD8 T cell response and also enhance generation of protective antibody by germinal center B cells. However, the molecular components that modulate CD4 T cell functions in response to viral infection or vaccine is incompletely understood. Here we demonstrate that inactivation of the signaling adaptor CD2-associated protein (CD2AP) promotes CD4 T cell differentiation towards the follicular helper lineage, leading to enhanced control of viral infection by augmented germinal center response in chronic lymphocytic choriomeningitis virus (LCMV) infection...
May 7, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29715623/weak-vaccinia-virus-induced-nk-cell-regulation-of-cd4-t-cells-is-associated-with-reduced-nk-cell-differentiation-and-cytolytic-activity
#7
Steven D Hatfield, Keith A Daniels, Carey L O'Donnell, Stephen N Waggoner, Raymond M Welsh
Natural killer (NK) cells control antiviral adaptive immune responses in mice during some virus infections, but the universality of this phenomenon remains unknown. Lymphocytic choriomeningitis virus (LCMV) infection of mice triggered potent cytotoxic activity of NK cells (NKLCMV ) against activated CD4 T cells, tumor cells, and allogeneic lymphocytes. In contrast, NK cells activated by vaccinia virus (VACV) infection (NKVACV ) exhibited weaker cytolytic activity against each of these target cells. Relative to NKLCMV cells, NKVACV cells exhibited a more immature (CD11b- CD27+ ) phenotype, and lower expression levels of the activation marker CD69, cytotoxic effector molecules (perforin, granzyme B), and the transcription factor IRF4...
April 28, 2018: Virology
https://www.readbyqxmd.com/read/29684247/tr1-cell-immunotherapy-promotes-transplant-tolerance-via-de-novo-tr1-cell-induction-in-mice-and-is-safe-and-effective-during-acute-viral-infection
#8
Tatiana Jofra, Roberta Di Fonte, Giuseppe Galvani, Mirela Kuka, Matteo Iannacone, Manuela Battaglia, Georgia Fousteri
Tr1 cell therapy is considered an emerging approach to improve transplant tolerance and enhance allogeneic graft survival. However, it remains unclear how Tr1 cells promote transplant tolerance and whether they will be safe and stable in the face of an acute viral infection. By employing a mouse model of pancreatic islet transplantation, we report that Tr1 cell therapy promoted transplant tolerance via de novo induction of Tr1 cells in the recipients. Acute viral infection with lymphocytic choriomeningitis virus (LCMV) had no impact on Tr1 cell number and function, neither on the Tr1 cells infused nor on the ones induced, and that was reflected in the robust maintenance of the graft...
April 23, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/29672594/type-i-interferon-signaling-attenuates-regulatory-t-cell-function-in-viral-infection-and-in-the-tumor-microenvironment
#9
Arunakumar Gangaplara, Craig Martens, Eric Dahlstrom, Amina Metidji, Ameya S Gokhale, Deborah D Glass, Maria Lopez-Ocasio, Rachel Baur, Kishore Kanakabandi, Stephen F Porcella, Ethan M Shevach
Regulatory T cells (Tregs) play a cardinal role in the immune system by suppressing detrimental autoimmune responses, but their role in acute, chronic infectious diseases and tumor microenvironment remains unclear. We recently demonstrated that IFN-α/β receptor (IFNAR) signaling promotes Treg function in autoimmunity. Here we dissected the functional role of IFNAR-signaling in Tregs using Treg-specific IFNAR deficient (IFNARfl/flxFoxp3YFP-Cre) mice in acute LCMV Armstrong, chronic Clone-13 viral infection, and in tumor models...
April 19, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29659579/replication-incompetent-rabies-virus-vector-harboring-glycoprotein-gene-of-lymphocytic-choriomeningitis-virus-lcmv-protects-mice-from-lcmv-challenge
#10
Mutsuyo Takayama-Ito, Chang-Kweng Lim, Yukie Yamaguchi, Guillermo Posadas-Herrera, Hirofumi Kato, Itoe Iizuka, Md Taimur Islam, Kinjiro Morimoto, Masayuki Saijo
BACKGROUND: Lymphocytic choriomeningitis virus (LCMV) causes a variety of diseases, including asymptomatic infections, meningitis, and congenital infections in the fetus of infected mother. The development of a safe and effective vaccine against LCMV is imperative. This study aims to develop a new candidate vaccine against LCMV using a recombinant replication-incompetent rabies virus (RV) vector. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we have generated a recombinant deficient RV expressing the LCMV glycoprotein precursor (GPC) (RVΔP-LCMV/GPC) which is lacking the RV-P gene...
April 2018: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/29643234/visualization-of-arenavirus-rna-species-in-individual-cells-by-single-molecule-fluorescence-in-situ-hybridization-smfish-suggests-a-model-of-cyclical-infection-and-clearance-during-persistence
#11
Benjamin R King, Aubin Samacoits, Philip L Eisenhauer, Christopher M Ziegler, Emily A Bruce, Daniel Zenklusen, Christophe Zimmer, Florian Mueller, Jason Botten
Lymphocytic choriomeningitis mammarenvirus (LCMV) is an enveloped, negative-strand RNA virus that causes serious disease in humans but establishes an asymptomatic, lifelong infection in reservoir rodents. Different models have been proposed to describe how arenaviruses regulate the replication and transcription of their bisegmented, single-stranded RNA genomes, particularly during persistent infection. However, these models were largely based on viral RNA profiling data derived from entire populations of cells...
April 11, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29627230/analysis-of-adenovirus-induced-immunity-to-infection-with-listeria-monocytogenes-fading-protection-coincides-with-declining-cd8-t-cell-numbers-and-phenotypic-changes
#12
Marie Louise Jahn, Maria Abildgaard Steffensen, Jan Pravsgaard Christensen, Allan Randrup Thomsen
Defining correlates of T cell mediated protection is important in order to accelerate the development of efficient T cell based vaccines conferring long-term immunity. Extensive studies have provided important insight regarding the characteristics and functional properties of the effector and memory CD8 T cells induced by viral vector based vaccines. However, long-term protection has been difficult to achieve with T cell inducing vaccines, and the determinants underlying this loss in protection over time are still not fully defined...
April 4, 2018: Vaccine
https://www.readbyqxmd.com/read/29620933/dynamics-of-lymphocyte-reconstitution-after-hematopoietic-transplantation-during-chronic-lymphocytic-choriomeningitis-virus-infection
#13
Mitra Bhattacharyya, Pablo Penaloza-MacMaster
Bone marrow transplantation is a treatment for various cancers and genetic diseases, and the only case of a cured HIV infection involved the use of this clinical procedure, highlighting the potential use of this therapy for curing many chronic diseases. However, little is known about how chronic viral infection influences lymphocyte reconstitution after bone marrow transplantation. To address this, we infected mice with chronic lymphocytic choriomeningitis virus, and performed bone marrow transplantation to assess lymphocyte reconstitution...
May 2018: AIDS Research and Human Retroviruses
https://www.readbyqxmd.com/read/29602153/lymphocytic-choriomeningitis-virus-infection-of-dendritic-cells-interferes-with-tlr-induced-il-12-il-23-cytokine-production-in-an-il-10-independent-manner
#14
Nor Fazila Che Mat, Sarah Siddiqui, Divya Mehta, Kyle Seaver, Andra Banete, Torki Alothaimeen, Katrina Gee, Sameh Basta
Dendritic cells produce IL-12 and IL-23 in response to viral and bacterial infection and these cytokines are responsible for successful pathogen clearance. How sequential viral and bacterial infections affect the production of IL-12 and IL-23 is currently not known. Our study demonstrates that in dendritic cells infected with Lymphocytic choriomeningitis virus (LCMV), TLR activation with bacterial PAMPs resulted in reduced IL-12 and IL-23 expression compared to non-infected cells. Furthermore, expression of other proinflammatory cytokines, TNF-α and IL-6, were not inhibited under these conditions...
March 26, 2018: Cytokine
https://www.readbyqxmd.com/read/29593047/il-27r-signalling-mediates-early-viral-containment-and-impacts-innate-and-adaptive-immunity-after-chronic-lymphocytic-choriomeningitis-virus-infection
#15
James A Harker, Kurt A Wong, Simone Dallari, Phuc Bao, Aleksandr Dolgoter, Yeara Jo, Ellen J Wehrens, Monica Macal, Elina I Zuniga
Chronic viral infections represent a major challenge to host's immune response and a unique network of immunological elements, including cytokines, are required for their containment. By using a model persistent infection with the natural murine pathogen lymphocytic choriomeningitis virus clone 13 (LCMV Cl13) we investigated the role of one such cytokine, interleukin 27 (IL-27), in the control of chronic infection. We found that IL-27R signalling promoted control of LCMV Cl13 as early as day 1 and 5 after infection and that il27p28 transcripts were rapidly elevated in multiple subsets of dendritic cells (DCs) and myeloid cells...
March 28, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29593035/a-highly-conserved-leucine-in-mammarenavirus-matrix-z-protein-is-required-for-z-interaction-with-the-virus-l-polymerase-and-z-stability-in-cells-harboring-an-active-viral-ribonucleoprotein
#16
Masaharu Iwasaki, Juan C de la Torre
Mammarenaviruses cause chronic infections in their natural rodent hosts. Infected rodents shed infectious virus into excreta. Humans are infected through mucosal exposure to aerosols or direct contact of abraded skin with fomites, resulting in a wide-range of manifestations from asymptomatic or mild febrile illness to severe life-threatening hemorrhagic fever. The mammarenavirus matrix Z protein has been shown to be a main driving force of virus budding and to act as a negative regulator of viral RNA synthesis...
March 28, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29514912/adenovirus-vector-vaccination-impacts-nk-cell-rheostat-function-following-lymphocytic-choriomeningitis-virus-infection
#17
Eryn Blass, Malika Aid, Amanda J Martinot, Rafael A Larocca, Zi Han Kang, Alexander Badamchi-Zadeh, Pablo Penaloza-MacMaster, R Keith Reeves, Dan H Barouch
Natural killer (NK) cells respond rapidly as a first line of defense against infectious pathogens. In addition, NK cells may provide a "rheostat" function and have been shown to reduce the magnitude of antigen-specific T cell responses following infection to avoid immunopathology. However, it remains unknown whether NK cells similarly modulate vaccine-elicited T cell responses following virus challenge. We used the lymphocytic choriomeningitis virus (LCMV) clone 13 infection model to address whether NK cells regulate T cell responses in adenovirus vector-vaccinated mice following challenge...
June 1, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29463725/tim-3-co-stimulation-promotes-short-lived-effector-t-cells-restricts-memory-precursors-and-is-dispensable-for-t-cell-exhaustion
#18
Lyndsay Avery, Jessica Filderman, Andrea L Szymczak-Workman, Lawrence P Kane
Tim-3 is highly expressed on a subset of T cells during T cell exhaustion in settings of chronic viral infection and tumors. Using lymphocytic choriomeningitis virus (LCMV) Clone 13, a model for chronic infection, we found that Tim-3 was neither necessary nor sufficient for the development of T cell exhaustion. Nonetheless, expression of Tim-3 was sufficient to drive resistance to PD-L1 blockade therapy during chronic infection. Strikingly, expression of Tim-3 promoted the development of short-lived effector T cells, at the expense of memory precursor development, after acute LCMV infection...
March 6, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29462184/interactome-analysis-of-the-lymphocytic-choriomeningitis-virus-nucleoprotein-in-infected-cells-reveals-atpase-na-k-transporting-subunit-alpha-1-and-prohibitin-as-host-cell-factors-involved-in-the-life-cycle-of-mammarenaviruses
#19
Masaharu Iwasaki, Petra Minder, Yíngyún Caì, Jens H Kuhn, John R Yates, Bruce E Torbett, Juan C de la Torre
Several mammalian arenaviruses (mammarenaviruses) cause hemorrhagic fevers in humans and pose serious public health concerns in their endemic regions. Additionally, mounting evidence indicates that the worldwide-distributed, prototypic mammarenavirus, lymphocytic choriomeningitis virus (LCMV), is a neglected human pathogen of clinical significance. Concerns about human-pathogenic mammarenaviruses are exacerbated by of the lack of licensed vaccines, and current anti-mammarenavirus therapy is limited to off-label use of ribavirin that is only partially effective...
February 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29456247/b-cells-are-the-predominant-mediators-of-early-systemic-viral-dissemination-during-rectal-lcmv-infection
#20
Martin Trapecar, Shahzada Khan, Benjamin L Cohn, Frank Wu, Shomyseh Sanjabi
Determining the magnitude of local immune response during mucosal exposure to viral pathogens is critical to understanding the mechanism of viral pathogenesis. We previously showed that vaginal inoculation of lymphocytic choriomeningitis virus (LCMV) fails to induce a robust innate immune response in the lower female reproductive tract (FRT), allowing high titer viral replication and a delay in T-cell-mediated viral control. Despite this immunological delay, LCMV replication remained confined mainly to the FRT and the draining iliac lymph node...
February 19, 2018: Mucosal Immunology
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