mouse
not annotated - annotated - LINNAEUS only
20943971
Roles of vaccinia virus genes E3L and K3L and host genes PKR and RNase L during intratracheal infection of C57BL/6 mice.
The importance of the 2'-5' oligoadenylate synthetase (OAS)/RNase L and double-stranded RNA (dsRNA)-dependent protein kinase (PKR) pathways in host interferon induction resulting from virus infection in response to dsRNA has been well documented. In poxvirus infections, the interactions between the vaccinia virus (VV) genes E3L and K3L, which target RNase L and PKR, respectively, serve to prevent the induction of the dsRNA-dependent induced interferon response in cell culture. To determine the importance of these host genes in controlling VV infections, mouse single-gene knockouts of RNase L and PKR and double-knockout mice were studied following intratracheal infection with VV, VVDeltaK3L, or VVDeltaE3L. VV caused lethal disease in all mouse strains. The single-knockout animals were more susceptible than wild-type animals, while the RNase L(-/-) PKR(-/-) mice were the most susceptible. VVDeltaE3L infections of wild-type mice were asymptomatic, demonstrating that E3L plays a critical role in controlling the host immune response. RNase L(-/-) mice showed no disease, whereas 20% of the PKR(-/-) mice succumbed at a dose of 10(8) PFU. Lethal disease was routinely observed in RNase L(-/-) PKR(-/-) mice inoculated with 10(8) PFU of VVDeltaE3L, with a distinct pathology. VVDeltaK3L infections exhibited no differences in virulence among any of the mouse constructs, suggesting that PKR is not the exclusive target of K3L. Surprisingly, VVDeltaK3L did not disseminate to other tissues from the lung. Hence, the cause of death in this model is respiratory disease. These results also suggest that an unanticipated role of the K3L gene is to facilitate virus dissemination.
20951743
Development and validation of a lateral flow immunoassay using colloidal gold for the identification of serotype-specific foot-and-mouth disease virus O, A and Asia 1.
A lateral flow immunoassay (LFI) was developed to identify and diagnose foot-and-mouth disease virus (FMDV) serotypes Ofoot-and-mouth disease virus (FMDV) serotypesfoot-and-mouth disease virus (FMDV) serotypes O, A and Asia 1. Antibodies obtained from rabbits and guinea pigs immunized with cell-culture-adapted virus strains (O/CHA/99, A/GS/LX/66, Asia 1/CHN/05) and suckling-mouse adapted virus strains (O/AV99(L), A/AV88(L), Asia 1/YNBS/58) were used as capture antibodies. The diagnostic kit included three immunochromatographic strips of types O, A and Asia 1, and the type-specific results were confirmed by color on the test lines of the three strips. The LFI was evaluated using epithelial and vesicular samples (n=396) prepared from current and historical field samples (provide by the National Foot-and-Mouth Disease Reference Laboratory of China at Lanzhou Veterinary Research Institute). Negative samples (n=95) were collected from healthy animals. The diagnostic sensitivity of the LFI for FMDV serotypes OFMDV serotypesFMDV serotypes O, A and Asia 1 was 88.3% compared to 89.7% obtained by the reference method of indirect-sandwich ELISA. The sensitivity of the LFI for FMDV type Asia 1 was higher at 92.1% compared to 90.5% for the ELISA. The specificity of the LFI was 97.1% compared with 97.4%.
20962097
Variola and monkeypox viruses utilize conserved mechanisms of virion motility and release that depend on abl and SRC family tyrosine kinases.
Vaccinia virus (VacV) enters mammalian cells, replicates extranuclearly, and produces virions that move to the cell surface along microtubules, fuse with the plasma membrane, and move from infected cells toward apposing cells on actin-filled membranous protrusions or actin tails. To form actin tails, cell-associated enveloped virions (CEV) require Abl and Src family tyrosine kinases. Furthermore, release of CEV from the cell requires Abl but not Src family tyrosine kinases and is blocked by imatinib mesylate (STI-571; Gleevec), an Abl family kinase inhibitor used to treat chronic myelogenous leukemia in humans. Here we demonstrate that the Poxviridae family members monkeypox virus (MPX) and variola virus (VarV) use conserved mechanisms for actin motility and extracellular enveloped virion (EEV) release. Furthermore, we show that imatinib mesylate is effective in a mouse model of infection with VacV, whether delivered prophylactically or postinfection, and restricts spread of virions from the site of inoculation. While inhibitors of both Src and Abl family kinases, such as dasatinib (BMS-354825; Sprycel), are effective in limiting dissemination of VacV, VarV, and MPX in vitro, members of this class of drugs appear to have immunosuppressive effects in vivo that preclude their use as anti-infectives. Together, these data suggest a possible utility for imatinib mesylate in treating smallpox or MPX infections or complications associated with vaccination.
20971911
Glucose-dependent activation of Bacillus anthracis toxin gene expression and virulence requires the carbon catabolite protein CcpA.
Sensing environmental conditions is an essential aspect of bacterial physiology and virulence. In Bacillus anthracis, the causative agent of anthrax, transcription of the two major virulence factors, toxin and capsule, is triggered by bicarbonate, a major compound in the mammalian body. Here it is shown that glucose is an additional signaling molecule recognized by B. anthracis for toxin synthesis. The presence of glucose increased the expression of the protective antigen toxin component-encoding gene (pagA) by stimulating induction of transcription of the AtxA virulence transcription factor. Induction of atxA transcription by glucose required the carbon catabolite protein CcpA via an indirect mechanism. CcpA did not bind specifically to any region of the extended atxA promoter. The virulence of a B. anthracis strain from which the ccpA gene was deleted was significantly attenuated in a mouse model of infection. The data demonstrated that glucose is an important host environment-derived signaling molecule and that CcpA is a molecular link between environmental sensing and B. anthracis pathogenesis.
20980503
Adenovirus membrane penetration activates the NLRP3 inflammasome.
Adenovirus type 5 (Ad5) infection of macrophages results in rapid secretion of interleukin-1Beta (IL-1Beta) and is dependent on the inflammasome components NLRP3 and ASC and the catalytic activity of caspase-1. Using lentivirus-expressed short hairpin RNA (shRNA) and competitive inhibitors, we show that Ad-induced IL-1Beta release is dependent upon Toll-like receptor 9 (TLR9) sensing of the Ad5 double-stranded DNA (dsDNA) genome in human cell lines and primary monocyte-derived macrophages but not in mouse macrophages. Additionally, a temperature-sensitive mutant of Ad5 unable to penetrate endosomal membranes, ts1, is unable to induce IL-1Beta release in TLR2-primed THP-1 cells, suggesting that penetration of endosomal membranes is required for IL-1Beta release. Disruption of lysosomal membranes and the release of cathepsin B into the cytoplasm are required for Ad-induced NLRP3 activation. Ad5 cell entry also induces reactive oxygen species (ROS) production, and inhibitors of ROS prevent Ad-induced IL-1Beta release. Ad5 activation of NLRP3 also induces necrotic cell death, resulting in the release of the proinflammatory molecule HMGB1. This work further defines the mechanisms of virally induced inflammasome activation.
20980509
Reovirus infection or ectopic expression of outer capsid protein micro1 induces apoptosis independently of the cellular proapoptotic proteins Bax and Bak.
Mammalian orthoreoviruses induce apoptosis in vivo and in vitro; however, the specific mechanism by which apoptosis is induced is not fully understood. Recent studies have indicated that the reovirus outer capsid protein mu1 is the primary determinant of reovirus-induced apoptosis. Ectopically expressed mu1 induces apoptosis and localizes to intracellular membranes. Here we report that ectopic expression of mu1 activated both the extrinsic and intrinsic apoptotic pathways with activation of initiator caspases-8 and -9 and downstream effector caspase-3. Activation of both pathways was required for mu1-induced apoptosis, as specific inhibition of either caspase-8 or caspase-9 abolished downstream effector caspase-3 activation. Similar to reovirus infection, ectopic expression of mu1 caused release into the cytosol of cytochrome c and smac/DIABLO from the mitochondrial intermembrane space. Pancaspase inhibitors did not prevent cytochrome c release from cells expressing mu1, indicating that caspases were not required. Additionally, mu1- or reovirus-induced release of cytochrome c occurred efficiently in Bax(-/-)Bak(-/-) mouse embryonic fibroblasts (MEFs). Finally, we found that reovirus-induced apoptosis occurred in Bax(-/-)Bak(-/-) MEFs, indicating that reovirus-induced apoptosis occurs independently of the proapoptotic Bcl-2 family members Bax and Bak.
20980515
Reverse genetics generation of chimeric infectious Junin/Lassa virus is dependent on interaction of homologous glycoprotein stable signal peptide and G2 cytoplasmic domains.
The Arenaviridae are a diverse and globally distributed collection of viruses that are maintained primarily by rodent reservoirs. Junin virus (JUNV) and Lassa virus (LASV) can both cause significant outbreaks of severe and often fatal human disease throughout their respective areas of endemicity. In an effort to improve upon the existing live attenuated JUNV Candid1 vaccine, we generated a genetically homogenous stock of this virus from cDNA copies of the virus S and L segments by using a reverse genetics system. Further, these cDNAs were used in combination with LASV cDNAs to successfully generate two recombinant Candid1 JUNV/LASV chimeric viruses (via envelope glycoprotein [GPC] exchange). It was found that while the GPC extravirion domains were readily exchangeable, homologous stable signal peptide (SSP) and G2 transmembrane and cytoplasmic tail domains were essential for correct GPC maturation and production of infectious chimeric viruses. The switching of the JUNV and LASV G1/G2 ectodomains within the Candid1 vaccine background did not alter the attenuated phenotype of the vaccine strain in a lethal mouse model. These recombinant chimeric viruses shed light on the fundamental requirements of arenavirus GPC maturation and may serve as a strategy for the development of bivalent JUNV and LASV vaccine candidates.
20980520
Persistent Friend virus replication and disease in Apobec3-deficient mice expressing functional B-cell-activating factor receptor.
Rfv3 is an autosomal dominant gene that influences the recovery of resistant mice from Friend retrovirus (FV) infection by limiting viremia and promoting a more potent neutralizing antibody response. We previously reported that Rfv3 is encoded by Apobec3, an innate retrovirus restriction factor. However, it was recently suggested that the Rfv3 susceptible phenotype of high viremia at 28 days postinfection (dpi) was more dominantly controlled by the B-cell-activating factor receptor (BAFF-R), a gene that is linked to but located outside the genetically mapped region containing Rfv3. Although one prototypical Rfv3 susceptible mouse strain, A/WySn, indeed contains a dysfunctional BAFF-R, two other Rfv3 susceptible strains, BALB/c and A.BY, express functional BAFF-R genes, determined on the basis of genotyping and B-cell immunophenotyping. Furthermore, transcomplementation studies in (C57BL/6 [B6] x BALB/c)F(1) and (B6 x A.BY)F(1) mice revealed that the B6 Apobec3 gene significantly influences recovery from FV viremia, cellular infection, and disease at 28 dpi. Finally, the Rfv3 phenotypes of prototypic B6, A.BY, A/WySn, and BALB/c mouse strains correlate with reported Apobec3 mRNA expression levels. Overall, these findings argue against the generality of BAFF-R polymorphisms as a dominant mechanism to explain the Rfv3 recovery phenotype and further strengthen the evidence that Apobec3 encodes Rfv3.
20980523
T cell-mediated protection against lethal 2009 pandemic H1N1 influenza virus infection in a mouse model.
Genetic mutation and reassortment of influenza virus gene segments, in particular those of hemagglutinin (HA) and neuraminidase (NA), that lead to antigenic drift and shift are the major strategies for influenza virus to escape preexisting immunity. The most recent example of such phenomena is the first pandemic of H1N1 influenza of the 21st century, which started in 2009. Cross-reactive antibodies raised against H1N1 viruses circulating before 1930 show protective activity against the 2009 pandemic virus. Cross-reactive T-cell responses can also contribute to protection, but in vivo support of this view is lacking. To explore the protection mechanisms in vivo, we primed mice with H1 and H3 influenza virus isolates and rechallenged them with a virus derived from the 2009 H1N1 A/CA/04/09 virus, named CA/E3/09. We found that priming with influenza viruses of both H1 and H3 homo- and heterosubtypes protected against lethal CA/E3/09 virus challenge. Convalescent-phase sera from these primed mice conferred no neutralization activity in vitro and no protection in vivo. However, T-cell depletion studies suggested that both CD4 and CD8 T cells contributed to the protection. Taken together, these results indicate that cross-reactive T cells established after initial priming with distally related viruses can be a vital component for prevention of disease and control of pandemic H1N1 influenza virus infection. Our results highlight the importance of establishing cross-reactive T-cell responses for protecting against existing or newly emerging pandemic influenza viruses.
21047954
Complement opsonization enhances friend virus infection of B cells and thereby amplifies the virus-specific CD8+ T cell response.
B cells are one of the targets of Friend virus (FV) infection, a well-established mouse model often used to study retroviral infections in vivo. Although B cells may be effective in stimulating cytotoxic T lymphocyte responses, studies involving their role in FV infection have mainly focused on neutralizing antibody production. Here we show that polyclonal activation of B cells promotes their infection with FV both in vitro and in vivo. Furthermore, we demonstrate that complement opsonization of Friend murine leukemia virus (F-MuLV) enhances infection of B cells, which correlates with increased potency of B cells to activate FV-specific CD8(+) T cells.
21349442
The sirtuin pathway in ageing and Alzheimer disease: mechanistic and therapeutic considerations.
BACKGROUND: Advances in gerontology have yielded crucial insights into the molecular and biochemical aspects of the ageing process. The sirtuin pathway, which is most notable for its association with the anti-ageing effects of calorie restriction, has received particular attention, and pharmacological or transgenic upregulation of the sirtuin pathway has shown promising results in laboratory models of ageing. Alzheimer's disease is a neurodegenerative disease that is imposing an increasing burden on society, and is the leading cause of senile dementia worldwide. The lack of therapies for Alzheimer's disease provides a strong incentive for the development of an effective treatment strategy and, interestingly, research has uncovered a mechanism of action of the sirtuin pathway that might have therapeutic potential for Alzheimer's disease. RECENT DEVELOPMENTS: SIRT1, one of the seven mammalian proteins of the sirtuin family of NAD(+)-dependent deacetylases, has recently been shown to attenuate amyloidogenic processing of amyloid-Beta protein precursor (APP) in cell culture studies in vitro and in transgenic mouse models of Alzheimer's disease. Mechanistically, SIRT1 increases alpha-secretase production and activity through activation of the alpha-secretase gene ADAM10. Because alpha-secretase is the enzyme responsible for the non-amyloidogenic cleavage of APP, upregulation of alpha-secretase shifts APP processing to reduce the pathological accumulation of the presumptive toxic ABeta species that results from Beta-secretase and gamma-secretase activity. Interestingly, the spatial patterns of ABeta deposition in the brain might correlate with increased aerobic glycolysis in those regions. Because aerobic glycolysis depletes cellular levels of NAD(+) (through a decreased NAD(+)/NADH ratio), it is possible that a corresponding downregulation of the NAD(+)-dependent sirtuin pathway contributes to the amyloidogenic processing of APP. WHERE NEXT?: The specific inhibition of ABeta generation by SIRT1 coupled with the potential link between aerobic glycolysis, NAD(+) depletion, and amyloidogenesis through the sirtuin pathway has translational implications. On the one hand, the possible underlying role of the sirtuin pathway in Alzheimer's disease onset and development might increase our understanding of this devastating condition. On the other hand, therapeutic upregulation of SIRT1 might provide opportunities for the amelioration of Alzheimer's-disease-type neuropathology through inhibition of amyloidogenesis. Ultimately, further analysis into both aspects is necessary if any progress is to be made.
21907298
Galleria mellonella as model host for the trans-kingdom pathogen Fusarium oxysporum.
Fusarium oxysporum, the causal agent of vascular wilt disease, affects a wide range of plant species and can produce disseminated infections in humans. F. oxysporum f. sp. lycopersici isolate FGSC 9935 causes disease both on tomato plants and immunodepressed mice, making it an ideal model for the comparative analysis of fungal virulence on plant and animal hosts. Here we tested the ability of FGSC 9935 to cause disease in the greater wax moth Galleria mellonella, an invertebrate model host that is widely used for the study of microbial human pathogens. Injection of living but not of heat-killed microconidia into the hemocoel of G. mellonella larvae resulted in dose-dependent killing both at 30^0C and at 37^0C. Fluorescence microscopy of larvae inoculated with a F. oxysporum transformant expressing GFP revealed hyphal proliferation within the hemocoel, interaction with G. mellonella hemocytes, and colonization of the killed insects by the fungus. Fungal gene knockout mutants previously tested in the tomato and immunodepressed mouse systems displayed a good correlation in virulence between the Galleria and the mouse model. Thus, Galleria represents a useful non-vertebrate infection model for studying virulence mechanisms of F. oxysporum on animal hosts.
20796206
Linking disease and community ecology through behavioural indicators: immunochallenge of white-footed mice and its ecological impacts.
1. Pathogens and immune challenges can induce changes in host phenotype in ways that indirectly impact important community interactions, including those that affect host-pathogen interactions. 2. To explore host behavioural response to immune challenge, we exposed wild white-footed mice (Peromyscus leucopus) to an immunogen from an endemic, zoonotic pathogen, the spirochete Borrelia burgdorferi. White-footed mice are a major reservoir host of Lyme disease (LD) spirochetes in northeastern USA and an abundant member of forest communities. The activity patterns, foraging behaviour, and space use of white-footed mice have implications for population growth rates of community members upon which mice incidentally prey (i.e. gypsy moths and native thrushes), as well as potentially determining host-vector encounter rates and human risk of LD. 3. Immunochallenge led to specific humoral (antibody) and cellular (i.e. elevated neutrophils and eosinophils) immune responses, supporting use of the immunogen as a surrogate for pathogenic infection. 4. Immunochallenged mice had reduced wheel-running activity early in the night when measured in the lab. However, mouse activity, as measured by track plates in natural field experiments, did not differ between mice exposed to the immunogen and unexposed mice. 5. Foraging behaviour of wild mice in the field - assessed with giving-up densities of seed at artificial feeding stations - was affected by exposure to the immunogen. Whereas immunochallenge did not influence whether foraging mice gained information on patch quality while foraging, it led to reductions in predator avoidance during foraging, suggesting that the proportion of space used by foraging mice may be greater as a result of immunochallenge. This increased space use is predicted to increase encounter rates with patchily distributed LD vectors (ticks) and with incidental prey items. 6. Thus, immunochallenge in white-footed mice, and potentially pathogenic infection, have the potential to indirectly impact community interactions, including those important for pathogen transmission.
20962098
PB2 residue 158 is a pathogenic determinant of pandemic H1N1 and H5 influenza a viruses in mice.
Influenza A viruses are human and animal pathogens that cause morbidity and mortality, which range from mild to severe. The 2009 H1N1 pandemic was caused by the emergence of a reassortant H1N1 subtype (H1N1pdm) influenza A virus containing gene segments that originally circulated in human, avian, and swine virus reservoirs. The molecular determinants of replication and pathogenesis of H1N1pdm viruses in humans and other mammals are poorly understood. Therefore, we set out to elucidate viral determinants critical to the pathogenesis of this novel reassortant using a mouse model. We found that a glutamate-to-glycine substitution at residue 158 of the PB2 gene (PB2-E158G) increased the morbidity and mortality of the parental H1N1pdm virus. Results from mini-genome replication assays in human cells and virus titration in mouse tissues demonstrated that PB2-E158G is a pathogenic determinant, because it significantly increases viral replication rates. The virus load in PB2-E158G-infected mouse lungs was 1,300-fold higher than that of the wild-type virus. Our data also show that PB2-E158G had a much stronger influence on the RNA replication and pathogenesis of H1N1pdm viruses than PB2-E627K, which is a known pathogenic determinant. Remarkably, PB2-E158G substitutions also altered the pathotypes of two avian H5 viruses in mice, indicating that this residue impacts genetically divergent influenza A viruses and suggesting that this region of PB2 could be a new antiviral target. Collectively, the data presented in this study demonstrate that PB2-E158G is a novel pathogenic determinant of influenza A viruses in the mouse model. We speculate that PB2-E158G may be important in the adaptation of avian PB2 genes to other mammals, and BLAST sequence analysis identified a naturally occurring human H1N1pdm isolate that has this substitution. Therefore, future surveillance efforts should include scrutiny of this region of PB2 because of its potential impact on pathogenesis.
21148734
Relating the physical properties of Pseudomonas aeruginosa lipopolysaccharides to virulence by atomic force microscopy.
Lipopolysaccharides (LPS) are an important class of macromolecules that are components of the outer membrane of Gram-negative bacteria such as Pseudomonas aeruginosa. P. aeruginosa contains two different sugar chains, the homopolymer common antigen (A band) and the heteropolymer O antigen (B band), which impart serospecificity. The characteristics of LPS are generally assessed after isolation rather than in the context of whole bacteria. Here we used atomic force microscopy (AFM) to probe the physical properties of the LPS of P. aeruginosa strain PA103 (serogroup O11) in situ. This strain contains a mixture of long and very long polymers of O antigen, regulated by two different genes. For this analysis, we studied the wild-type strain and four mutants, DeltaWzz1 (producing only very long LPS), DeltaWzz2 (producing only long LPS), DDeltaM (with both the wzz1 and wzz2 genes deleted), and Wzy::GM (producing an LPS core oligosaccharide plus one unit of O antigen). Forces of adhesion between the LPS on these strains and the silicon nitride AFM tip were measured, and the Alexander and de Gennes model of steric repulsion between a flat surface and a polymer brush was used to calculate the LPS layer thickness (which we refer to as length), compressibility, and spacing between the individual molecules. LPS chains were longest for the wild-type strain and DeltaWzz1, at 170.6 and 212.4 nm, respectively, and these values were not statistically significantly different from one another. Wzy::GM and DDeltaM have reduced LPS lengths, at 34.6 and 37.7 nm, respectively. Adhesion forces were not correlated with LPS length, but a relationship between adhesion force and bacterial pathogenicity was found in a mouse acute pneumonia model of infection. The adhesion forces with the AFM probe were lower for strains with LPS mutations, suggesting that the wild-type strain is optimized for maximal adhesion. Our research contributes to further understanding of the role of LPS in the adhesion and virulence of P. aeruginosa.
21401592
Negotiating a noisy, information-rich environment in search of cryptic prey: olfactory predators need patchiness in prey cues.
1. Olfactory predator search processes differ fundamentally to those based on vision, particularly when odour cues are deposited rather than airborne or emanating from a point source. When searching for visually cryptic prey that may have moved some distance from a deposited odour cue, cue context and spatial variability are the most likely sources of information about prey location available to an olfactory predator. 2. We tested whether the house mouse (Mus domesticus), a model olfactory predator, would use cue context and spatial variability when searching for buried food items; specifically, we tested the effect of varying cue patchiness, odour strength, and cue-prey association on mouse foraging success. 3. Within mouse- and predator-proof enclosures, we created grids of 100 sand-filled Petri dishes and buried peanut pieces in a set number of these patches to represent visually cryptic 'prey'. By adding peanut oil to selected dishes, we varied the spatial distribution of prey odour relative to the distribution of prey patches in each grid, to reflect different levels of cue patchiness (Experiment 1), odour strength (Experiment 2) and cue-prey association (Experiment 3). We measured the overnight foraging success of individual mice (percentage of searched patches containing prey), as well as their foraging activity (percentage of patches searched), and prey survival (percentage of unsearched prey patches). 4. Mouse foraging success was highest where odour cues were patchy rather than uniform (Experiment 1), and where cues were tightly associated with prey location, rather than randomly or uniformly distributed (Experiment 3). However, when cues at prey patches were ten times stronger than a uniformly distributed weak background odour, mice did not improve their foraging success over that experienced when cues were of uniform strength and distribution (Experiment 2). 5. These results suggest that spatial variability and cue context are important means by which olfactory predators can use deposited odour cues to locate visually cryptic prey. They also indicate that chemical crypsis can disrupt these search processes as effectively as background matching in visually based predator-prey systems.
20962081
Varicella-zoster virus glycoprotein E is a critical determinant of virulence in the SCID mouse-human model of neuropathogenesis.
Varicella-zoster virus (VZV) is a neurotropic alphaherpesvirus. VZV infection of human dorsal root ganglion (DRG) xenografts in immunodeficient mice models the infection of sensory ganglia. We examined DRG infection with recombinant VZV (recombinant Oka [rOka]) and the following gE mutants: gEDelta27-90, gEDeltaCys, gE-AYRV, and gE-SSTT. gEDelta27-90, which lacks the gE domain that interacts with a putative receptor insulin-degrading enzyme (IDE), replicated as extensively as rOka, producing infectious virions and significant cytopathic effects within 14 days of inoculation. Since neural cells express IDE, the gE/IDE interaction was dispensable for VZV neurotropism. In contrast, gEDeltaCys, which lacks gE/gI heterodimer formation, was significantly impaired at early times postinfection; viral genome copy numbers increased slowly, and infectious virus production was not detected until day 28. Delayed replication was associated with impaired cell-cell spread in ganglia, similar to the phenotype of a gI deletion mutant (rOkaDeltagI). However, at later time points, infection of satellite cells and other supportive nonneuronal cells resulted in extensive DRG tissue damage and cell loss such that cytopathic changes observed at day 70 were more severe than those for rOka-infected DRG. The replication of gE-AYRV, which is impaired for trans-Golgi network (TGN) localization, and the replication of gE-SSTT, which contains mutations in an acidic cluster, were equivalent to that of rOka, causing significant cytopathic effects and infectious virus production by day 14; genome copy numbers were equivalent to those of rOka. These experiments suggest that the gE interaction with cellular IDE, gE targeting to TGN sites of virion envelopment, and phosphorylation at SSTT are dispensable for VZV DRG infection, whereas the gE/gI interaction is critical for VZV neurovirulence.
20980506
A new model of Epstein-Barr virus infection reveals an important role for earlylytic viral protein expression in the development of lymphomas.
Epstein-Barr virus (EBV) infects cells in latent or lytic forms, but the roleof lytic infection in EBV-induced lymphomas is unclear. Here, we have used anew humanized mouse model, in which both human fetal CD34(+) hematopoietic stemcells and thymus/liver tissue are transplanted, to compare EBV pathogenesis andlymphoma formation following infection with a lytic replication-defectiveBZLF1-deleted (Z-KO) virus or a lytically active BZLF1(+) control. Both thecontrol and Z-KO viruses established long-term viral latency in all infectedanimals. The infection appeared well controlled in some animals, but otherseventually developed CD20(+) diffuse large B cell lymphomas (DLBCL). Animalsinfected with the control virus developed tumors more frequently than Z-KOvirus-infected animals. Specific immune responses against EBV-infected B cellswere generated in mice infected with either the control virus or the Z-KOvirus. In both cases, forms of viral latency (type I and type IIB) wereobserved that are less immunogenic than the highly transforming form (type III)commonly found in tumors of immunocompromised hosts, suggesting that immunepressure contributed to the outcome of the infection. These results point to animportant role for lytic EBV infection in the development of B cell lymphomasin the context of an active host immune response.
21349440
Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease.
Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) are characterised by the appearance of reactive microglial and astroglial cells, a process referred to as neuroinflammation. In transgenic mouse models of mutant SOD1-associated familial ALS, reactive microglial cells and astrocytes actively contribute to the death of motor neurons. The biological processes that drive this glial reaction are complex and have both beneficial and deleterious effects on motor neurons. Therapeutic interventions targeting these cells are being explored. An improved understanding of the biological processes that cause neuroinflammation will help to define its medical importance and to identify the therapeutic potential of interfering with this reaction.