Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity

Virus infection of mammalian cells is sensed by pattern recognition receptors and leads to an innate immune response that restricts virus replication and induces adaptive immunity. In response, viruses have evolved many countermeasures that enable them to replicate and be transmitted to new hosts, despite the host innate immune response. Poxviruses, such as vaccinia virus (VACV), have large DNA genomes and encode many proteins that are dedicated to host immune evasion. Some of these proteins are secreted from the infected cell, where they bind and neutralize complement factors, interferons, cytokines and chemokines. Other VACV proteins function inside cells to inhibit apoptosis or signalling pathways that lead to the production of interferons and pro-inflammatory cytokines and chemokines. In this review, these VACV immunomodulatory proteins are described and the potential to create more immunogenic VACV strains by manipulation of the gene encoding these proteins is discussed

Viral cGAMP nuclease reveals the essential role of DNA sensing in protection against acute lethal virus infection

Cells contain numerous immune sensors to detect virus infection. The cyclic GMP-AMP (cGAMP) synthase (cGAS) recognizes cytosolic DNA and activates innate immune responses via stimulator of interferon genes (STING), but the impact of DNA sensing pathways on host protective responses has not been fully defined. We demonstrate that cGAS/STING activation is required to resist lethal poxvirus infection. We identified viral Schlafen (vSlfn) as the main STING inhibitor, and ectromelia virus was severely attenuated in the absence of vSlfn. Both vSlfn-mediated virulence and STING inhibitory activity were mapped to the recently discovered poxin cGAMP nuclease domain. Animals were protected from subcutaneous, respiratory, and intravenous infection in the absence of vSlfn, and interferon was the main antiviral protective mechanism controlled by the DNA sensing pathway. Our findings support the idea that manipulation of DNA sensing is an efficient therapeutic strategy in diseases triggered by viral infection or tissue damage-mediated release of self-DNA

Inhibition of apoptosis and NF-κB activation by vaccinia protein N1 occur via distinct binding surfaces and make different contributions to virulence.

Vaccinia virus (VACV) protein N1 is an intracellular virulence factor and belongs to a family of VACV B-cell lymphoma (Bcl)-2-like proteins whose members inhibit apoptosis or activation of pro-inflammatory transcription factors, such as interferon (IFN) regulatory factor-3 (IRF-3) and nuclear factor-κB (NF-κB). Unusually, N1 inhibits both apoptosis and NF-κB activation. To understand how N1 exerts these different functions, we have mutated residues in the Bcl-2-like surface groove and at the interface used to form N1 homodimers. Mutagenesis of the surface groove abolished only the N1 anti-apoptotic activity and protein crystallography showed these mutants differed from wild-type N1 only at the site of mutation. Conversely, mutagenesis of the dimer interface converted N1 to a monomer and affected only inhibition of NF-κB activation. Collectively, these data show that N1 inhibits pro-inflammatory and pro-apoptotic signalling using independent surfaces of the protein. To determine the relative contribution of each activity to virus virulence, mutant N1 alleles were introduced into a VACV strain lacking N1 and the virulence of these viruses was analysed after intradermal and intranasal inoculation in mice. In both models, VACV containing a mutant N1 unable to inhibit apoptosis had similar virulence to wild-type virus, whereas VACV containing a mutant N1 impaired for NF-κB inhibition induced an attenuated infection similar to that of the N1-deleted virus. This indicates that anti-apoptotic activity of N1 does not drive virulence in these in vivo models, and highlights the importance of pro-inflammatory signalling in the immune response against viral infections

Representing 3D Space in Working Memory: Spatial Images from Vision, Hearing, Touch, and Language

The chapter deals with a form of transient spatial representation referred to as a spatial image. Like a percept, it is externalized, scaled to the environment, and can appear in any direction about the observer. It transcends the concept of modality, as it can be based on inputs from the three spatial senses, from language, and from long-term memory. Evidence is presented that supports each of the claimed properties of the spatial image, showing that it is quite different from a visual image. Much of the evidence presented is based on spatial updating. A major concern is whether spatial images from different input modalities are functionally equivalent— that once instantiated in working memory, the spatial images from different modalities have the same functional characteristics with respect to subsequent processing, such as that involved in spatial updating. Going further, the research provides some evidence that spatial images are amodal (i.e., do not retain modality-specific features)

The evolution of primate short-term memory

Short-term memory is implicated in a range of cognitive abilities and is critical for understanding primate cognitive evolution. To investigate the effects of phylogeny, ecology and sociality on short-term memory, we tested the largest and most diverse primate sample to date (421 non-human primates across 41 species) in an experimental delayed-response task. Our results confirm previous findings that longer delays decrease memory performance across species and taxa. Our analyses demonstrate a considerable contribution of phylogeny over ecological and social factors on the distribution of short-term memory performance in primates; closely related species had more similar short-term memory abilities. Overall, individuals in the branch of Hominoidea performed better compared to Cercopithecoidea, who in turn performed above Platyrrhini and Strepsirrhini. Interdependencies between phylogeny and socioecology of a given species presented an obstacle to disentangling the effects of each of these factors on the evolution of shortterm memory capacity. However, this study offers an important step forward in understanding the interspecies and individual variation in short-term memory ability by providing the first phylogenetic reconstruction of this trait’s evolutionary history. The dataset constitutes a unique resource for studying the evolution of primate cognition and the role of short-term memory in other cognitive abilities

The Strategies of the Spanish cotton textile companies before the Civil War: the road to longevity

This study, based on family business theories, offers an innovative vision of the Spanish cotton industry. It proves that Spanish cotton companies, just like their European counterparts, implemented a strategy that was consistent with their nature as family businesses and went beyond the economic-institutional frames within which they developed. The article identifies this strategy as `conservative, because its main objectives were longevity and family control and because it was based on a high percentage of own resources, low levels of indebtedness and organic growth, thus sacrificing profitability for the sake of security.Universidad Pablo de OlavidePostprin

Detection and survival of prion agents in aquatic environments

Environmental contamination is considered a potential mechanism of transmission of prion diseases. Sheep scrapie and cervid chronic wasting diseases (CWD) epizootics are thought to be maintained by natural horizontal transmission through the environment. Here, we describe a method for the detection of prion proteins (PrPres) in aquatic environments. The procedure is based on a glycine buffer-mediated extraction, sonication, and an ultracentrifugation step. The detection limit of the method was estimated to be over 5-10 microg of infected tissue. In order to determine the inactivation of these agents, we spiked infected brain tissue in urban sewage, seawater and a buffered solution (final concentrations of 0.1-0.2% brain in matrix), and studied the decay of BSE- and scrapie-associated PrPres over time (up to 265 days). Densitometric data from Western blots were plotted in logarithmic scale against time. Reduction of PrPres titer in sewage was quantified in one logarithm after 13.5 days for BSE, 27.9 days for mouse-passaged scrapie and 32.6 days for sheep scrapie. In the buffered solution, a logarithm of BSE-associated PrPres also disappeared earlier than that of scrapie (113.9 and 214.3 days, respectively). By means of the covariance analysis, these differences in the inactivation patterns were shown to be statistically significant. According to the data, prions may be stable for extended periods of time in buffered solutions like PBS, but would show limited survival in aquatic environmental matrices

Detection and survival of prion agents in aquatic environments

Environmental contamination is considered a potential mechanism of transmission of prion diseases. Sheep scrapie and cervid chronic wasting diseases (CWD) epizootics are thought to be maintained by natural horizontal transmission through the environment. Here, we describe a method for the detection of prion proteins (PrPres) in aquatic environments. The procedure is based on a glycine buffer-mediated extraction, sonication, and an ultracentrifugation step. The detection limit of the method was estimated to be over 5-10 microg of infected tissue. In order to determine the inactivation of these agents, we spiked infected brain tissue in urban sewage, seawater and a buffered solution (final concentrations of 0.1-0.2% brain in matrix), and studied the decay of BSE- and scrapie-associated PrPres over time (up to 265 days). Densitometric data from Western blots were plotted in logarithmic scale against time. Reduction of PrPres titer in sewage was quantified in one logarithm after 13.5 days for BSE, 27.9 days for mouse-passaged scrapie and 32.6 days for sheep scrapie. In the buffered solution, a logarithm of BSE-associated PrPres also disappeared earlier than that of scrapie (113.9 and 214.3 days, respectively). By means of the covariance analysis, these differences in the inactivation patterns were shown to be statistically significant. According to the data, prions may be stable for extended periods of time in buffered solutions like PBS, but would show limited survival in aquatic environmental matrices