scholarly journals Antiapoptotic Herpesvirus Bcl-2 Homologs Escape Caspase-Mediated Conversion to Proapoptotic Proteins

2000 ◽  
Vol 74 (11) ◽  
pp. 5024-5031 ◽  
Author(s):  
David S. Bellows ◽  
B. Nelson Chau ◽  
Percy Lee ◽  
Yuri Lazebnik ◽  
William H. Burns ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Apoptotic Cell ◽  
Caspase Cleavage ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Cell Extracts ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Herpesvirus 4 ◽  
Murine Gammaherpesvirus 68

ABSTRACT The antiapoptotic Bcl-2 and Bcl-xL proteins of mammals are converted into potent proapoptotic factors when they are cleaved by caspases, a family of apoptosis-inducing proteases (E. H.-Y. Cheng, D. G. Kirsch, R. J. Clem, R. Ravi, M. B. Kastan, A. Bedi, K. Ueno, and J. M. Hardwick, Science 278:1966–1968, 1997; R. J. Clem, E. H.-Y. Cheng, C. L. Karp, D. G. Kirsch, K. Ueno, A. Takahashi, M. B. Kastan, D. E. Griffin, W. C. Earnshaw, M. A. Veliuona, and J. M. Hardwick, Proc. Natl. Acad. Sci. USA 95:554–559, 1998). Gamma herpesviruses also encode homologs of the Bcl-2 family. All tested herpesvirus Bcl-2 homologs possess antiapoptotic activity, including the more distantly related homologs encoded by murine gammaherpesvirus 68 (γHV68) and bovine herpesvirus 4 (BHV4), as described here. To determine if viral Bcl-2 proteins can be converted into death factors, similar to their cellular counterparts, five herpesvirus Bcl-2 homologs from five different viruses were tested for their susceptibility to caspases. Only the viral Bcl-2 protein encoded by γHV68 was susceptible to caspase digestion. However, unlike the caspase cleavage products of cellular Bcl-2, Bcl-xL, and Bid, which are potent inducers of apoptosis, the cleavage product of γHV68 Bcl-2 lacked proapoptotic activity. KSBcl-2, encoded by the Kaposi's sarcoma-associated herpesvirus, was the only viral Bcl-2 homolog that was capable of killing cells when expressed as an N-terminal truncation. However, because KSBcl-2 was not cleavable by caspases, the latent proapoptotic activity of KSBcl-2 apparently cannot be released. The Bcl-2 homologs encoded by herpesvirus saimiri, Epstein-Barr virus, and BHV4 were not cleaved by apoptotic cell extracts and did not possess latent proapoptotic activities. Thus, herpesvirus Bcl-2 homologs escape negative regulation by retaining their antiapoptotic activities and/or failing to be converted into proapoptotic proteins by caspases during programmed cell death.

scholarly journals Kinetic and phenotypic changes in murine lymphocytes infected with murine gammaherpesvirus-68 in vitro

1999 ◽  
Vol 80 (10) ◽  
pp. 2729-2736 ◽  
Author(s):  
Bernadette M. Dutia ◽  
James P. Stewart ◽  
Robert A. E. Clayton ◽  
Heather Dyson ◽  
Anthony A. Nash
Keyword(s):  
Epstein Barr Virus ◽  
Herpesvirus Saimiri ◽  
Murine Splenocytes ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Growth Transformation ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

Primary infection with murine gammaherpesvirus-68 (MHV-68), as with other members of the gammaherpesvirus subfamily, is characterized by a lymphoproliferative phase. MHV-68 causes acute splenomegaly and an infectious mononucleosis-like syndrome in which there is expansion of the CD8+ T cell subset. In long-term infections, MHV-68 is associated with lymphoma development. In order to elucidate the mechanisms underlying the proliferative processes, the events following infection of murine splenocytes or purified murine B lymphocytes in vitro have been examined. MHV-68 infection prolonged the viability of murine splenocytes and stimulated cellular proliferation. Unlike Epstein–Barr virus and herpesvirus saimiri, MHV-68 did not cause growth transformation. Growth transformation did not occur even when cells with a predisposition to transformation were infected or when culture conditions were selected to enhance the viability of the cells. Following MHV-68 infection, the latency-associated viral tRNAs were transcribed. However, transcription of the other known latency- associated gene, M2, was not observed. In addition, there was no evidence of productive virus replication either by staining with antibodies specific for late virus antigens or by in situ hybridization for early and late mRNAs. In contrast to Epstein–Barr virus- and herpesvirus saimiri-infected lymphocytes, where episomal genomes are seen, Gardella gel analysis indicated that the primary lymphocytes infected by MHV-68 in vitro contained only linear virus DNA. This DNA was nuclease sensitive, indicating that, while MHV-68 was efficiently uncoated, its circularization in vitro was extremely inefficient. These results are discussed in terms of the host–virus interaction.

Murine gammaherpesvirus-68 infection of mice: A new model for human cerebral Epstein-Barr virus infection

2005 ◽  
Vol 57 (4) ◽  
pp. 600-603 ◽  
Author(s):  
Martin Häusler ◽  
Bernd Sellhaus ◽  
Simone Scheithauer ◽  
Matthias Engler ◽  
Evelyn Alberg ◽  
...  
Keyword(s):  
Virus Infection ◽  
Epstein Barr Virus ◽  
Epstein Barr Virus Infection ◽  
New Model ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Barr Virus Infection ◽  
Murine Gammaherpesvirus 68

scholarly journals Endosomal Toll-Like Receptors 7 and 9 Cooperate in Detection of Murine Gammaherpesvirus 68 Infection

2018 ◽  
Vol 93 (3) ◽  
Author(s):  
Kendra A. Bussey ◽  
Sripriya Murthy ◽  
Elisa Reimer ◽  
Baca Chan ◽  
Bastian Hatesuer ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Toll Like Receptor ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68 ◽  
Deficient Mice

ABSTRACTMurine gammaherpesvirus 68 (MHV68) is a small-animal model suitable for study of the human pathogens Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus. Here, we have characterized the roles of the endosomal Toll-like receptor (TLR) escort protein UNC93B, endosomal TLR7, -9, and -13, and cell surface TLR2 in MHV68 detection. We found that the alpha interferon (IFN-α) response of plasmacytoid dendritic cells (pDC) to MHV68 was reduced inTlr9−/−cells compared to levels in wild type (WT) cells but not completely lost.Tlr7−/−pDC responded similarly to WT. However, we found that inUnc93b−/−pDC, as well as inTlr7−/−Tlr9−/−double-knockout pDC, the IFN-α response to MHV68 was completely abolished. Thus, the only pattern recognition receptors contributing to the IFN-α response to MHV68 in pDC are TLR7 and TLR9, but the contribution of TLR7 is masked by the presence of TLR9. To address the role of UNC93B and TLR for MHV68 infectionin vivo, we infected mice with MHV68. Lytic replication of MHV68 after intravenous infection was enhanced in the lungs, spleen, and liver of UNC93B-deficient mice, in the spleen of TLR9-deficient mice, and in the liver and spleen ofTlr7−/−Tlr9−/−mice. The absence of TLR2 or TLR13 did not affect lytic viral titers. We then compared reactivation of MHV68 from latently infected WT,Unc93b−/−,Tlr7−/−Tlr9−/−,Tlr7−/−, andTlr9−/−splenocytes. We observed enhanced reactivation and latent viral loads, particularly fromTlr7−/−Tlr9−/−splenocytes compared to levels in the WT. Our data show that UNC93B-dependent TLR7 and TLR9 cooperate in and contribute to detection and control of MHV68 infection.IMPORTANCEThe two human gammaherpesviruses, Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), can cause aggressive forms of cancer. These herpesviruses are strictly host specific, and therefore the homolog murine gammaherpesvirus 68 (MHV68) is a widely used model to obtainin vivoinsights into the interaction between these two gammaherpesviruses and their host. Like EBV and KSHV, MHV68 establishes lifelong latency in B cells. The innate immune system serves as one of the first lines of host defense, with pattern recognition receptors such as the Toll-like receptors playing a crucial role in mounting a potent antiviral immune response to various pathogens. Here, we shed light on a yet unanticipated role of Toll-like receptor 7 in the recognition of MHV68 in a subset of immune cells called plasmacytoid dendritic cells, as well as on the control of this virus in its host.

scholarly journals Selective Uptake of Small RNA Molecules in the Virion of Murine Gammaherpesvirus 68

2008 ◽  
Vol 83 (5) ◽  
pp. 2321-2326 ◽  
Author(s):  
Anna R. Cliffe ◽  
Anthony A. Nash ◽  
Bernadette M. Dutia
Keyword(s):  
Small Rna ◽  
Nuclear Staining ◽  
Rna Molecules ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Genes Encoding ◽  
Infected Cells ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT Noncoding RNAs are a feature of many herpesvirus genomes. They include microRNAs, whose function is the subject of intense investigation, in addition to longer RNA molecules such as the Epstein-Barr virus-encoded RNAs and herpesvirus saimiri U RNAs, which have been known for some time but whose function is still not well defined. Murine gammaherpesvirus 68 (MHV-68) encodes eight viral tRNA-like molecules (vtRNAs) of unknown function. Investigating the kinetics of expression of the vtRNAs, we observed that they were present directly after infection with the virus. This strongly suggested that vtRNAs were part of the virion structure, which was confirmed by their detection within various purified, RNase-treated preparations. Although both viral and cellular mRNAs were also detected within the MHV-68 virion, the major RNA species present were small RNAs of around 70 nucleotides in length. Interestingly, incorporation of viral mRNA was not related to the relative abundance in infected cells, as M11 mRNA, which is present at low abundance, was found in virions. MHV-76, which lacks the genes encoding the vtRNAs, also incorporated small RNA molecules within the virion, suggesting a requirement for these molecules for virion maturation. In productively infected cells the vtRNAs localized predominantly within the cytoplasm, although they also exhibited a globular pattern of nuclear staining. Their presence in the cytoplasm is consistent with interaction with virion components prior to maturation of virus particles. The significance of these findings for virion architecture and function is discussed.

scholarly journals Identification of Novel Rodent Herpesviruses, Including the First Gammaherpesvirus of Mus musculus

2007 ◽  
Vol 81 (15) ◽  
pp. 8091-8100 ◽  
Author(s):  
Bernhard Ehlers ◽  
Judit Küchler ◽  
Nezlisah Yasmum ◽  
Güzin Dural ◽  
Sebastian Voigt ◽  
...  
Keyword(s):  
Mus Musculus ◽  
Human Herpesvirus ◽  
Murine Cytomegalovirus ◽  
Long Distance ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68 ◽  
Pcr Targeting

ABSTRACT Rodent herpesviruses such as murine cytomegalovirus (host, Mus musculus), rat cytomegalovirus (host, Rattus norvegicus), and murine gammaherpesvirus 68 (hosts, Apodemus species) are important tools for the experimental study of human herpesvirus diseases. However, alphaherpesviruses, roseoloviruses, and lymphocryptoviruses, as well as rhadinoviruses, that naturally infect Mus musculus (house mouse) and other Old World mice are unknown. To identify hitherto-unknown rodent-associated herpesviruses, we captured M. musculus, R. norvegicus, and 14 other rodent species in several locations in Germany, the United Kingdom, and Thailand. Samples of trigeminal ganglia, dorsal root ganglia, brains, spleens, and other organs, as well as blood, were analyzed with a degenerate panherpesvirus PCR targeting the DNA polymerase (DPOL) gene. Herpesvirus-positive samples were subjected to a second degenerate PCR targeting the glycoprotein B (gB) gene. The sequences located between the partial DPOL and gB sequences were amplified by long-distance PCR and sequenced, resulting in a contiguous sequence of approximately 3.5 kbp. By DPOL PCR, we detected 17 novel betaherpesviruses and 21 novel gammaherpesviruses but no alphaherpesvirus. Of these 38 novel herpesviruses, 14 were successfully analyzed by the complete bigenic approach. Most importantly, the first gammaherpesvirus of Mus musculus was discovered (Mus musculus rhadinovirus 1 [MmusRHV1]). This virus is a member of a novel group of rodent gammaherpesviruses, which is clearly distinct from murine herpesvirus 68-like rodent gammaherpesviruses. Multigenic phylogenetic analysis, using an 8-kbp locus, revealed that MmusRHV1 diverged from the other gammaherpesviruses soon after the evolutionary separation of Epstein-Barr virus-like lymphocryptoviruses from human herpesvirus 8-like rhadinoviruses and alcelaphine herpesvirus 1-like macaviruses.

scholarly journals Host Shutoff Is a Conserved Phenotype of Gammaherpesvirus Infection and Is Orchestrated Exclusively from the Cytoplasm

2009 ◽  
Vol 83 (18) ◽  
pp. 9554-9566 ◽  
Author(s):  
Sergio Covarrubias ◽  
Justin M. Richner ◽  
Karen Clyde ◽  
Yeon J. Lee ◽  
Britt A. Glaunsinger
Keyword(s):  
Murine Gammaherpesvirus ◽  
Functional Conservation ◽  
Barr Virus ◽  
Infected Cells ◽  
Host Shutoff ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68 ◽  
Cellular Transcriptome

ABSTRACT Lytic infection with the two human gammaherpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), leads to significant depletion of the cellular transcriptome. This host shutoff phenotype is driven by the conserved herpesviral alkaline exonuclease, termed SOX in KSHV and BGLF5 in EBV, which in gammaherpesviruses has evolved the genetically separable ability to target cellular mRNA. We now show that host shutoff is also a prominent consequence of murine gammaherpesvirus 68 (MHV68) infection, which is widely used as a model system to study pathogenesis of these viruses in vivo. The effector of MHV68-induced host shutoff is its SOX homolog, here termed muSOX. There is remarkable functional conservation of muSOX host shutoff activities with those of KSHV SOX, including the recently described ability of SOX to induce mRNA hyperadenylation in the nucleus as well as cause nuclear relocalization of the poly(A) binding protein. SOX and muSOX localize to both the nucleus and cytoplasm of infected cells. Using spatially restricted variants of these proteins, we go on to demonstrate that all known host shutoff-related activities of SOX and muSOX are orchestrated exclusively from the cytoplasm. These results have important mechanistic implications for how SOX and muSOX target nascent cellular transcripts in the nucleus. Furthermore, our findings establish MHV68 as a new, genetically tractable model to study host shutoff.

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