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Edward S Mocarski - One of the best experts on this subject based on the ideXlab platform.
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necroptosis based crispr knockout screen reveals neuropilin 1 as a critical host factor for early stages of Murine Cytomegalovirus infection
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Rebecca Lane, Edward S Mocarski, Jason W. Upton, Hongyan Guo, Jan E. Carette, Amanda Fisher, Jonathan Diep, Zhao Lai, Yidong Chen, William J. KaiserAbstract:Herpesviruses are ubiquitous human pathogens that cause a wide range of health complications. Currently, there is an incomplete understanding of cellular factors that contribute to herpesvirus infection. Here, we report an antiviral necroptosis-based genetic screen to identify novel host cell factors required for infection with the β-herpesvirus Murine Cytomegalovirus (MCMV). Our genome-wide CRISPR-based screen harnessed the capacity of herpesvirus mutants that trigger antiviral necroptotic cell death upon early viral gene expression. Vascular endothelial growth factor (VEGF) and semaphorin-binding receptor Neuropilin-1 (Nrp-1) emerge as crucial determinants of MCMV infection. We find that elimination of Nrp-1 impairs early viral gene expression and reduces infection rates in endothelial cells, fibroblasts, and macrophages. Furthermore, preincubation of virus with soluble Nrp-1 dramatically inhibits infection by reducing virus attachment. Thus, Nrp-1 is a key determinant of the initial phase of MCMV infection.
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DAI/ZBP1/DLM-1 Complexes with RIP3 to Mediate Virus-Induced Programmed Necrosis that Is Targeted by Murine Cytomegalovirus vIRA
Cell host & microbe, 2012Co-Authors: Jason W. Upton, William J. Kaiser, Edward S MocarskiAbstract:Programmed necrosis, like apoptosis, eliminates pathogen-infected cells as a component of host defense. Receptor-interacting protein kinase (RIP) 3 (also called RIPK3) mediates RIP homotypic interaction motif (RHIM)-dependent programmed necrosis induced by Murine Cytomegalovirus (MCMV) infection or death receptor activation and suppressed by the MCMV-encoded viral inhibitor of RIP activation (vIRA). We find that interferon-independent expression of DNA-dependent activator of interferon regulatory factors (DAI, also known as ZBP1 or DLM-1) sensitizes cells to virus-induced necrosis and that DAI knockdown or knockout cells are resistant to this death pathway. Importantly, as with RIP3(-/-) mice, vIRA mutant MCMV pathogenesis is restored in DAI(-/-) mice, consistent with a DAI-RIP3 complex being the natural target of vIRA. Thus, DAI interacts with RIP3 to mediate virus-induced necrosis analogous to the RIP1-RIP3 complex controlling death receptor-induced necroptosis. These studies unveil a role for DAI as the RIP3 partner mediating virus-induced necrosis.
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dai zbp1 dlm 1 complexes with rip3 to mediate virus induced programmed necrosis that is targeted by Murine Cytomegalovirus vira
Cell Host & Microbe, 2012Co-Authors: Jason W. Upton, William J. Kaiser, Edward S MocarskiAbstract:Summary Programmed necrosis, like apoptosis, eliminates pathogen-infected cells as a component of host defense. Receptor-interacting protein kinase (RIP) 3 (also called RIPK3) mediates RIP homotypic interaction motif (RHIM)-dependent programmed necrosis induced by Murine Cytomegalovirus (MCMV) infection or death receptor activation and suppressed by the MCMV-encoded viral inhibitor of RIP activation (vIRA). We find that interferon-independent expression of DNA-dependent activator of interferon regulatory factors (DAI, also known as ZBP1 or DLM-1) sensitizes cells to virus-induced necrosis and that DAI knockdown or knockout cells are resistant to this death pathway. Importantly, as with RIP3 −/− mice, vIRA mutant MCMV pathogenesis is restored in DAI −/− mice, consistent with a DAI-RIP3 complex being the natural target of vIRA. Thus, DAI interacts with RIP3 to mediate virus-induced necrosis analogous to the RIP1-RIP3 complex controlling death receptor-induced necroptosis. These studies unveil a role for DAI as the RIP3 partner mediating virus-induced necrosis.
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mitochondrial cell death suppressors carried by human and Murine Cytomegalovirus confer resistance to proteasome inhibitor induced apoptosis
Journal of Virology, 2005Co-Authors: Louise A Mccormick, Christopher D Meiering, Geoffrey B Smith, Edward S MocarskiAbstract:Human Cytomegalovirus carries a mitochondria-localized inhibitor of apoptosis (vMIA) that is conserved in primate Cytomegaloviruses. We find that inactivating mutations within UL37x1, which encodes vMIA, do not substantially affect replication in TownevarATCC (Towne-BAC), a virus that carries a functional copy of the betaherpesvirus-conserved viral inhibitor of caspase 8 activation, the UL36 gene product. In Towne-BAC infection, vMIA reduces susceptibility of infected cells to intrinsic death induced by proteasome inhibition. vMIA is sufficient to confer resistance to proteasome inhibition when expressed independent of viral infection. Murine Cytomegalovirus m38.5, whose position in the viral genome is analogous to UL37x1, exhibits mitochondrial association and functions in much the same manner as vMIA in inhibiting intrinsic cell death. This work suggests a common role for vMIA in rodent and primate Cytomegaloviruses, modulating the threshold of virus-infected cells to intrinsic cell death.
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common lymphoid progenitors rapidly engraft and protect against lethal Murine Cytomegalovirus infection after hematopoietic stem cell transplantation
Blood, 2003Co-Authors: Caroline Arber, Edward S Mocarski, Tim E Sparer, Andrew Bitmansour, John P Higgins, Irving L Weissman, Judith A Shizuru, Janice M BrownAbstract:Lymphoid deficiency after allogeneic hematopoietic cell transplantation (HCT) results in increased susceptibility to infection; however, transplantation of mature lymphocytes frequently results in a serious complication known as graft-versus-host disease (GVHD). Here we demonstrate in mice that both congenic as well as allogeneic transplantation of low numbers of highly purified common lymphoid progenitors (CLPs)-a rare population of lymphoid-lineage-committed bone marrow cells-accelerates immune reconstitution after lethal irradiation and rescue with hematopoietic stem cells (HSCs). After congenic transplantation, 3 x 10(3) CLPs protected against Murine Cytomegalovirus (MCMV) infection at a level roughly equivalent to 107 unfractionated lymph node cells. In the allogeneic model of matched unrelated donor HSC transplantation, cotransplantation of 3 x 10(3) CLPs protected thymus-bearing as well as thymectomized hosts from MCMV infection and attenuated disease severity. Immunohistochemistry in combination with antibody depletion of T and natural killer (NK) cells confirmed that CLP-derived as well as residual host lymphocytes contribute to antiviral protection. Importantly, transplantation of allogeneic CLPs provided a durable antiviral immunity without inducing GVHD. These data support the potential for composing grafts with committed progenitors to reduce susceptibility to viral infection following HCT.
Wayne M. Yokoyama - One of the best experts on this subject based on the ideXlab platform.
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zbtb32 restrains antibody responses to Murine Cytomegalovirus infections but not other repetitive challenges
Scientific Reports, 2019Co-Authors: Arijita Jash, You W Zhou, Diana K Gerardo, Tyler J Ripperger, Bijal A Parikh, Sytse J Piersma, Deepa R Jamwal, Pawel R Kiela, Adrianus C M Boon, Wayne M. YokoyamaAbstract:ZBTB32 is a transcription factor that is highly expressed by a subset of memory B cells and restrains the magnitude and duration of recall responses against hapten-protein conjugates. To define physiological contexts in which ZBTB32 acts, we assessed responses by Zbtb32-/- mice or bone marrow chimeras against a panel of chronic and acute challenges. Mixed bone marrow chimeras were established in which all B cells were derived from either Zbtb32-/- mice or control littermates. Chronic infection of Zbtb32-/- chimeras with Murine Cytomegalovirus led to nearly 20-fold higher antigen-specific IgG2b levels relative to controls by week 9 post-infection, despite similar viral loads. In contrast, IgA responses and specificities in the intestine, where memory B cells are repeatedly stimulated by commensal bacteria, were similar between Zbtb32-/- mice and control littermates. Finally, an infection and heterologous booster vaccination model revealed no role for ZBTB32 in restraining primary or recall antibody responses against influenza viruses. Thus, ZBTB32 does not limit recall responses to a number of physiological acute challenges, but does restrict antibody levels during chronic viral infections that periodically engage memory B cells. This restriction might selectively prevent recall responses against chronic infections from progressively overwhelming other antibody specificities.
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major histocompatibility complex class i restricted protection against Murine Cytomegalovirus requires missing self recognition by the natural killer cell inhibitory ly49 receptors
bioRxiv, 2019Co-Authors: Bijal A Parikh, Sytse J Piersma, Liping Yang, Michael D Bern, Diana L Beckman, Jennifer Poursinelaurent, Beatrice Plougastel Douglas, Wayne M. YokoyamaAbstract:Viruses have evolved strategies that highlight critical, intertwined host immune mechanisms. As postulated by the missing-self hypothesis, natural killer (NK) cells and major histocompatibility complex class I (MHC-I)-restricted cytotoxic T lymphocytes (CTLs) have opposing requirements for ubiquitously expressed MHC-I molecules. Since NK cell MHC-I-specific Ly49 inhibitory receptors prevent killing of cells with normal MHC-I, viruses evading CTLs by down-regulating MHC-I should be vulnerable to NK cells. However, definitive integrated in vivo evidence for this interplay has been lacking, in part due to receptor polymorphism and a proposed second function of Ly49 receptors in licensing NK cells via self-MHC-I. Here we generated mice lacking specific Ly49 inhibitory receptors to show their essential role in licensing and controlling Murine Cytomegalovirus (MCMV) infection in vivo in an MHC-restricted manner. When MCMV cannot down-regulate MHC-I, NK cells cannot control infection that instead is mediated by CTLs, as predicted by the missing-self hypothesis.
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dual requirement of cytokine and activation receptor triggering for cytotoxic control of Murine Cytomegalovirus by nk cells
PLOS Pathogens, 2015Co-Authors: Bijal A Parikh, Sytse J Piersma, Melissa A Pakwittel, Liping Yang, Robert D Schreiber, Wayne M. YokoyamaAbstract:Natural killer (NK) cells play a critical role in controlling Murine Cytomegalovirus (MCMV) and can mediate both cytokine production and direct cytotoxicity. The NK cell activation receptor, Ly49H, is responsible for genetic resistance to MCMV in C57BL/6 mice. Recognition of the viral m157 protein by Ly49H is sufficient for effective control of MCMV infection. Additionally, during the host response to infection, distinct immune and non-immune cells elaborate a variety of pleiotropic cytokines which have the potential to impact viral pathogenesis, NK cells, and other immune functions, both directly and indirectly. While the effects of various immune deficiencies have been examined for general antiviral phenotypes, their direct effects on Ly49H-dependent MCMV control are poorly understood. To specifically interrogate Ly49H-dependent functions, herein we employed an in vivo viral competition approach to show Ly49H-dependent MCMV control is specifically mediated through cytotoxicity but not IFNγ production. Whereas m157 induced Ly49H-dependent degranulation, efficient cytotoxicity also required either IL-12 or type I interferon (IFN-I) which acted directly on NK cells to produce granzyme B. These studies demonstrate that both of these distinct NK cell-intrinsic mechanisms are integrated for optimal viral control by NK cells.
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stability of Murine Cytomegalovirus genome after in vitro and in vivo passage
Journal of Virology, 2010Co-Authors: Tammy P. Cheng, Jeanette T. Pingel, Wayne M. Yokoyama, Mark C Valentine, Jian GaoAbstract:While large DNA viruses are thought to have low mutation rates, only a small fraction of their genomes have been analyzed at the single-nucleotide level. Here, we defined the genetic stability of Murine Cytomegalovirus (MCMV) by whole-genome sequencing. Independently assembled sequences of three sister plaques showed only two single-base-pair substitutions after in vitro passage. In vivo-passaged MCMV likewise demonstrated low mutation rates, comparable to those after in vitro passage, indicating high genome stability of MCMV at the single-nucleotide level in the absence of obvious selection pressure.
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Murine Cytomegalovirus displays selective infection of cells within hours after systemic administration
Journal of General Virology, 2009Co-Authors: Kimberly M Hsu, Jennifer R Pratt, Walter J Akers, Samuel Achilefu, Wayne M. YokoyamaAbstract:A distinctive feature of the Cytomegaloviruses is their wide tissue tropism, demonstrated by the infection of many organs and cell types in an active infection. However, in experimental models of systemic infection, the earliest stages of infection are not well characterized, and it is unclear whether only certain cells are initially infected. Using a recombinant Murine Cytomegalovirus (MCMV) expressing green fluorescent protein (GFP), we tracked viral infection after systemic administration via intraperitoneal injection and showed that specific cells are infected within the first hours. We provide evidence that MCMV traffics as free virus from the peritoneal cavity into the mediastinal lymphatics, providing access to the bloodstream. We demonstrate that MCMV productively infected CD169(+) subcapsular sinus macrophages in the mediastinal lymph nodes, ER-TR7(+) CD29(+) reticular fibroblasts in the spleen and hepatocytes. Infection in the spleen followed a distinctive pattern, beginning in the marginal zone at 6 h and spreading into the red pulp by 17 h. By 48 h after infection, there was widespread infection in the spleen and liver with degeneration of infected cells. In addition, infected dendritic cells appeared in the white pulp of the spleen at 48 h post-infection. On the other hand, cowpox virus showed a different pattern of infectivity in the spleen and liver. Thus, early MCMV infection produces a distinct pattern of infection of selective cells.
Jason W. Upton - One of the best experts on this subject based on the ideXlab platform.
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necroptosis based crispr knockout screen reveals neuropilin 1 as a critical host factor for early stages of Murine Cytomegalovirus infection
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Rebecca Lane, Edward S Mocarski, Jason W. Upton, Hongyan Guo, Jan E. Carette, Amanda Fisher, Jonathan Diep, Zhao Lai, Yidong Chen, William J. KaiserAbstract:Herpesviruses are ubiquitous human pathogens that cause a wide range of health complications. Currently, there is an incomplete understanding of cellular factors that contribute to herpesvirus infection. Here, we report an antiviral necroptosis-based genetic screen to identify novel host cell factors required for infection with the β-herpesvirus Murine Cytomegalovirus (MCMV). Our genome-wide CRISPR-based screen harnessed the capacity of herpesvirus mutants that trigger antiviral necroptotic cell death upon early viral gene expression. Vascular endothelial growth factor (VEGF) and semaphorin-binding receptor Neuropilin-1 (Nrp-1) emerge as crucial determinants of MCMV infection. We find that elimination of Nrp-1 impairs early viral gene expression and reduces infection rates in endothelial cells, fibroblasts, and macrophages. Furthermore, preincubation of virus with soluble Nrp-1 dramatically inhibits infection by reducing virus attachment. Thus, Nrp-1 is a key determinant of the initial phase of MCMV infection.
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Murine Cytomegalovirus ie3 dependent transcription is required for dai zbp1 mediated necroptosis
EMBO Reports, 2017Co-Authors: Haripriya Sridharan, Katherine B Ragan, Hongyan Guo, Ryan P. Gilley, Vanessa J Landsteiner, William J. Kaiser, Jason W. UptonAbstract:DNA-dependent activator of interferon regulatory factors/Z-DNA binding protein 1 (DAI/ZBP1) is a crucial sensor of necroptotic cell death induced by Murine Cytomegalovirus (MCMV) in its natural host. Here, we show that viral capsid transport to the nucleus and subsequent viral IE3-dependent early transcription are required for necroptosis. Necroptosis induction does not depend on input virion DNA or newly synthesized viral DNA A putative RNA-binding domain of DAI/ZBP1, Zα2, is required to sense virus and trigger necroptosis. Thus, MCMV IE3-dependent transcription from the viral genome plays a crucial role in activating DAI/ZBP1-dependent necroptosis. This implicates RNA transcripts generated by a large double-stranded DNA virus as a biologically relevant ligand for DAI/ZBP1 during natural viral infection.
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Murine Cytomegalovirus deubiquitinase regulates viral chemokine levels to control inflammation and pathogenesis
Mbio, 2017Co-Authors: Adam T Hilterbrand, Daniel R Boutz, Edward M Marcotte, Jason W. UptonAbstract:Maintaining control over inflammatory processes represents a paradox for viral pathogens. Although many viruses induce host inflammatory responses to facilitate infection, control is necessary to avoid overactivation. One way is through the manipulation of proinflammatory chemokine levels, both host and viral. Murine Cytomegalovirus (MCMV), a model betaherpesvirus, encodes a viral C-C chemokine, MCK2, which promotes host inflammatory responses and incorporates into virions to facilitate viral dissemination. Here, we show that the activity of M48, the conserved MCMV deubiquitinating enzyme (DUB), regulates MCK2 levels during infection. Inactivation of M48 DUB activity results in viral attenuation and exacerbates virally induced, MCK2-dependent inflammatory responses. M48 DUB activity also influences MCK2 incorporation into virions. Importantly, attenuation of DUB-mutant virus acute replication in vitro and in vivo is largely ameliorated by targeted deletion of MCK2. Thus, uncontrolled MCK2 levels appear to mediate DUB-mutant virus attenuation in specific tissues or cell types. This demonstrates that MCMV M48 DUB activity plays a previously unappreciated role in controlling MCK2 levels, thereby managing MCK2-dependent processes. These findings reveal a novel intrinsic control mechanism of virally induced inflammation and support the identification of betaherpesvirus DUBs as possible new targets for antiviral therapies. IMPORTANCE Human Cytomegalovirus infections represent a tremendous burden not only to those afflicted but also to health care systems worldwide. As Cytomegalovirus infections are a leading cause of nongenetic sensory loss and neurodevelopmental delay, it is imperative that valuable model systems exist in order that we might understand what viral factors contribute to replication and pathogenesis. Currently, the only approved drug treatments against CMV infection are nucleoside analogues, to which some strains have become resistant. Understanding unique viral enzymatic contributions to infections will allow the development of novel pharmacological therapies. Here, we show that M48, the conserved MCMV deubiquitinase, is critical for MCMV replication in mice and demonstrate that attenuation is due to deregulated production of a viral proinflammatory chemokine. The deubiquitinases of both human and Murine CMV represent structurally unique DUBs and are therefore attractive targets for pharmacological intervention. Continued research into the substrates of these DUBs will lend additional insight into their potential as targets.
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DAI/ZBP1/DLM-1 Complexes with RIP3 to Mediate Virus-Induced Programmed Necrosis that Is Targeted by Murine Cytomegalovirus vIRA
Cell host & microbe, 2012Co-Authors: Jason W. Upton, William J. Kaiser, Edward S MocarskiAbstract:Programmed necrosis, like apoptosis, eliminates pathogen-infected cells as a component of host defense. Receptor-interacting protein kinase (RIP) 3 (also called RIPK3) mediates RIP homotypic interaction motif (RHIM)-dependent programmed necrosis induced by Murine Cytomegalovirus (MCMV) infection or death receptor activation and suppressed by the MCMV-encoded viral inhibitor of RIP activation (vIRA). We find that interferon-independent expression of DNA-dependent activator of interferon regulatory factors (DAI, also known as ZBP1 or DLM-1) sensitizes cells to virus-induced necrosis and that DAI knockdown or knockout cells are resistant to this death pathway. Importantly, as with RIP3(-/-) mice, vIRA mutant MCMV pathogenesis is restored in DAI(-/-) mice, consistent with a DAI-RIP3 complex being the natural target of vIRA. Thus, DAI interacts with RIP3 to mediate virus-induced necrosis analogous to the RIP1-RIP3 complex controlling death receptor-induced necroptosis. These studies unveil a role for DAI as the RIP3 partner mediating virus-induced necrosis.
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dai zbp1 dlm 1 complexes with rip3 to mediate virus induced programmed necrosis that is targeted by Murine Cytomegalovirus vira
Cell Host & Microbe, 2012Co-Authors: Jason W. Upton, William J. Kaiser, Edward S MocarskiAbstract:Summary Programmed necrosis, like apoptosis, eliminates pathogen-infected cells as a component of host defense. Receptor-interacting protein kinase (RIP) 3 (also called RIPK3) mediates RIP homotypic interaction motif (RHIM)-dependent programmed necrosis induced by Murine Cytomegalovirus (MCMV) infection or death receptor activation and suppressed by the MCMV-encoded viral inhibitor of RIP activation (vIRA). We find that interferon-independent expression of DNA-dependent activator of interferon regulatory factors (DAI, also known as ZBP1 or DLM-1) sensitizes cells to virus-induced necrosis and that DAI knockdown or knockout cells are resistant to this death pathway. Importantly, as with RIP3 −/− mice, vIRA mutant MCMV pathogenesis is restored in DAI −/− mice, consistent with a DAI-RIP3 complex being the natural target of vIRA. Thus, DAI interacts with RIP3 to mediate virus-induced necrosis analogous to the RIP1-RIP3 complex controlling death receptor-induced necroptosis. These studies unveil a role for DAI as the RIP3 partner mediating virus-induced necrosis.
Joëlle Goüy De Bellocq - One of the best experts on this subject based on the ideXlab platform.
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host subspecific viral strains in european house mice Murine Cytomegalovirus in the eastern mus musculus musculus and western house mouse mus musculus domesticus
Virology, 2018Co-Authors: Dagmar Cižkova, Stuart J.e. Baird, Jaroslav Piálek, Jana Těsikova, Sebastian Voigt, ďureje ľudovit, Joëlle Goüy De BellocqAbstract:Murine Cytomegalovirus (MCMV) has been reported from house mice (Mus musculus) worldwide, but only recently from Eastern house mice (M. m. musculus), of particular interest because they form a semi-permeable species barrier in Europe with Western house mice, M. m. domesticus. Here we report genome sequences of EastMCMV (from Eastern mice), and set these in the context of MCMV genomes from genus Mus hosts. We show EastMCMV and WestMCMV are genetically distinct. Phylogeny splitting analyses show a genome wide (94%) pattern consistent with no West-East introgression, the major exception (3.8%) being a genome-terminal region of duplicated genes involved in host immune system evasion. As expected from its function, this is a region of maintenance of ancestral polymorphism: The lack of clear splitting signal cannot be interpreted as evidence of introgression. The EastMCMV genome sequences reported here can therefore serve as a well-described resource for exploration of murid MCMV diversity.
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Murine Cytomegalovirus Is Not Restricted to the House Mouse Mus musculus domesticus: Prevalence and Genetic Diversity in the European House Mouse Hybrid Zone
Journal of virology, 2014Co-Authors: Joëlle Goüy De Bellocq, Stuart J.e. Baird, Jana Albrechtová, Karolna Sobekova, Jaroslav PiálekAbstract:Murine Cytomegalovirus (MCMV) is a betaherpesvirus of the house mouse, Mus musculus domesticus. It is a common infectious agent of wild mice and a highly studied pathogen of the laboratory mouse. Betaherpesviruses are specific to their hosts, and it is not known if other Mus taxa carry MCMV or if it is restricted to M. m. domesticus. We sampled mice over a 145-km transect of Bavaria-Bohemia crossing a hybrid zone between M. m. domesticus and Mus musculus musculus in order to investigate the occurrence of MCMV in two Mussubspecies and to test the limits of the specificity of the virus for its host. We hypothesized that if the two subspecies carry MCMV and if the virus is highly specific to its host, divergent MCMV lineages would have codiverged with their hosts and would have a geographical distribution constrained by the host genetic background. A total of 520 mice were tested by enzyme-linked immunosorbent assay (ELISA) and/or nested PCR targeting the M94 gene. Seropositive and PCRpositive individuals were found in both Mussubspecies. Seroprevalence was high, at 79.4%, but viral DNA was detected in only 41.7% of mice. Sequencing revealed 20 haplotypes clustering in 3 clades that match the host genetic structure in the hybrid zone, showing 1 and 2 MCMV lineages in M. m. domesticus and M. m. musculus, respectively. The estimated time to the most recent common ancestor (1.1 million years ago [Mya]) of the MCMVs matches that of their hosts. In conclusion, MCMV has coevolved with these hosts, suggesting that its diversity in nature may be underappreciated, since other members of the subgenus Mus likely carry different MCMVs. IMPORTANCE Murine Cytomegalovirus (MCMV) is a betaherpesvirus of the house mouse, Mus musculus domesticus, an important lab model for human Cytomegalovirus (HCMV) infection. The majority of lab studies are based on only two strains of MCMVs isolated from M. m. domesticus, Smith and K181, the latter derived from repeated passage of Smith in mouse submaxillary glands. The presence of MCMV in other members of the Mussubgenus had not even been investigated. By screening mouse samples collected in the European house mouse hybrid zone between M. m. domesticus and M. m. musculus, we show that MCMV is not restricted to the M. m. domesticus subspecies and that MCMVs likely codiverged with their Mus hosts. Thus, the diversity of MCMV in nature may be seriously underappreciated, since other members of the subgenus Muslikely carry their own MCMV lineages.
Jaroslav Piálek - One of the best experts on this subject based on the ideXlab platform.
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host subspecific viral strains in european house mice Murine Cytomegalovirus in the eastern mus musculus musculus and western house mouse mus musculus domesticus
Virology, 2018Co-Authors: Dagmar Cižkova, Stuart J.e. Baird, Jaroslav Piálek, Jana Těsikova, Sebastian Voigt, ďureje ľudovit, Joëlle Goüy De BellocqAbstract:Murine Cytomegalovirus (MCMV) has been reported from house mice (Mus musculus) worldwide, but only recently from Eastern house mice (M. m. musculus), of particular interest because they form a semi-permeable species barrier in Europe with Western house mice, M. m. domesticus. Here we report genome sequences of EastMCMV (from Eastern mice), and set these in the context of MCMV genomes from genus Mus hosts. We show EastMCMV and WestMCMV are genetically distinct. Phylogeny splitting analyses show a genome wide (94%) pattern consistent with no West-East introgression, the major exception (3.8%) being a genome-terminal region of duplicated genes involved in host immune system evasion. As expected from its function, this is a region of maintenance of ancestral polymorphism: The lack of clear splitting signal cannot be interpreted as evidence of introgression. The EastMCMV genome sequences reported here can therefore serve as a well-described resource for exploration of murid MCMV diversity.
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Murine Cytomegalovirus Is Not Restricted to the House Mouse Mus musculus domesticus: Prevalence and Genetic Diversity in the European House Mouse Hybrid Zone
Journal of virology, 2014Co-Authors: Joëlle Goüy De Bellocq, Stuart J.e. Baird, Jana Albrechtová, Karolna Sobekova, Jaroslav PiálekAbstract:Murine Cytomegalovirus (MCMV) is a betaherpesvirus of the house mouse, Mus musculus domesticus. It is a common infectious agent of wild mice and a highly studied pathogen of the laboratory mouse. Betaherpesviruses are specific to their hosts, and it is not known if other Mus taxa carry MCMV or if it is restricted to M. m. domesticus. We sampled mice over a 145-km transect of Bavaria-Bohemia crossing a hybrid zone between M. m. domesticus and Mus musculus musculus in order to investigate the occurrence of MCMV in two Mussubspecies and to test the limits of the specificity of the virus for its host. We hypothesized that if the two subspecies carry MCMV and if the virus is highly specific to its host, divergent MCMV lineages would have codiverged with their hosts and would have a geographical distribution constrained by the host genetic background. A total of 520 mice were tested by enzyme-linked immunosorbent assay (ELISA) and/or nested PCR targeting the M94 gene. Seropositive and PCRpositive individuals were found in both Mussubspecies. Seroprevalence was high, at 79.4%, but viral DNA was detected in only 41.7% of mice. Sequencing revealed 20 haplotypes clustering in 3 clades that match the host genetic structure in the hybrid zone, showing 1 and 2 MCMV lineages in M. m. domesticus and M. m. musculus, respectively. The estimated time to the most recent common ancestor (1.1 million years ago [Mya]) of the MCMVs matches that of their hosts. In conclusion, MCMV has coevolved with these hosts, suggesting that its diversity in nature may be underappreciated, since other members of the subgenus Mus likely carry different MCMVs. IMPORTANCE Murine Cytomegalovirus (MCMV) is a betaherpesvirus of the house mouse, Mus musculus domesticus, an important lab model for human Cytomegalovirus (HCMV) infection. The majority of lab studies are based on only two strains of MCMVs isolated from M. m. domesticus, Smith and K181, the latter derived from repeated passage of Smith in mouse submaxillary glands. The presence of MCMV in other members of the Mussubgenus had not even been investigated. By screening mouse samples collected in the European house mouse hybrid zone between M. m. domesticus and M. m. musculus, we show that MCMV is not restricted to the M. m. domesticus subspecies and that MCMVs likely codiverged with their Mus hosts. Thus, the diversity of MCMV in nature may be seriously underappreciated, since other members of the subgenus Muslikely carry their own MCMV lineages.
