The ribonucleotide reductase R1 subunits of herpes simplex virus types 1 and 2 protect cells against TNFα- and FasL-induced apoptosis by interacting with caspase-8

We previously reported that HSV-2 R1, the R1 subunit (ICP10; UL39) of herpes simplex virus type-2 ribonucleotide reductase, protects cells against apoptosis induced by the death receptor (DR) ligands tumor necrosis factor-alpha- (TNFα) and Fas ligand (FasL) by interrupting DR-mediated signaling at, or upstream of, caspase-8 activation. Further investigation of the molecular mechanism underlying HSV-2 R1 protection showed that extracellular-regulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase (PI3-K)/Akt, NF-κB and JNK survival pathways do not play a major role in this antiapoptotic function. Interaction studies revealed that HSV-2 R1 interacted constitutively with caspase-8. The HSV-2 R1 deletion mutant R1(1-834)-GFP and Epstein–Barr virus (EBV) R1, which did not protect against apoptosis induced by DR ligands, did not interact with caspase-8, indicating that interaction is required for protection. HSV-2 R1 impaired caspase-8 activation induced by caspase-8 over-expression, suggesting that interaction between the two proteins prevents caspase-8 dimerization/activation. HSV-2 R1 bound to caspase-8 directly through its prodomain but did not interact with either its caspase domain or Fas-associated death domain protein (FADD). Interaction between HSV-2 R1 and caspase-8 disrupted FADD-caspase-8 binding. We further demonstrated that individually expressed HSV-1 R1 (ICP6) shares, with HSV-2 R1, the ability to bind caspase-8 and to protect cells against DR-induced apoptosis. Finally, as the long-lived Fas protein remained stable during the early period of infection, experiments with the HSV-1 UL39 deletion mutant ICP6∆ showed that HSV-1 R1 could be essential for the protection of HSV-1-infected cells against FasL.     

Trophic theory of island biogeography

MacArthur and Wilson's Theory of Island Biogeography (TIB) is among the most well-known process-based explanations for the distribution of species richness. It helps understand the species-area relationship, a fundamental pattern in ecology and an essential tool for conservation. The classic TIB does not, however, account for the complex structure of ecological systems. We extend the TIB to take into account trophic interactions and derive a species-specific model for occurrence probability. We find that the properties of the regional food web influence the species-area relationship, and that, in return, immigration and extinction dynamics affect local food web properties. We compare the accuracy of the classic TIB to our trophic TIB to predict community composition of real food webs and find strong support for our trophic extension of the TIB. Our approach provides a parsimonious explanation to species distributions and open new perspectives to integrate the complexity of ecological interactions into simple species distribution models.     

CD8+ T cells and IFN-γ mediate the time-dependent accumulation of infected red blood cells in deep organs during experimental cerebral malaria

Background

Infection with Plasmodium berghei ANKA (PbA) in susceptible mice induces a syndrome called experimental cerebral malaria (ECM) with severe pathologies occurring in various mouse organs. Immune mediators such as T cells or cytokines have been implicated in the pathogenesis of ECM. Red blood cells infected with PbA parasites have been shown to accumulate in the brain and other tissues during infection. This accumulation is thought to be involved in PbA–induced pathologies, which mechanisms are poorly understood.

Methods and Findings

Using transgenic PbA parasites expressing the luciferase protein, we have assessed by real-time in vivo imaging the dynamic and temporal contribution of different immune factors in infected red blood cell (IRBC) accumulation and distribution in different organs during PbA infection. Using deficient mice or depleting antibodies, we observed that CD8⁺ T cells and IFN-γ drive the rapid increase in total parasite biomass and accumulation of IRBC in the brain and in different organs 6–12 days post-infection, at a time when mice develop ECM. Other cells types like CD4⁺ T cells, monocytes or neutrophils or cytokines such as IL-12 and TNF-α did not influence the early increase of total parasite biomass and IRBC accumulation in different organs.

Conclusions

CD8⁺ T cells and IFN-γ are the major immune mediators controlling the time-dependent accumulation of P. berghei-infected red blood cells in tissues.     

Herpes simplex virus glycoprotein B binds to cell surfaces independently of heparan sulfate and blocks virus entry

Virion glycoproteins gB, gD, and gH/gL play essential roles for herpes simplex virus (HSV) entry. The function of gD is to interact with a cognate receptor, and soluble forms of gD block HSV entry by tying up cell surface receptors. Both gB and the nonessential gC interact with cell surface heparan sulfate proteoglycan (HSPG), promoting viral attachment. However, cells deficient in proteoglycan synthesis can still be infected by HSV. This suggests another function for gB. We found that a soluble truncated form of gB bound saturably to the surface of Vero, A431, HeLa, and BSC-1 cells, L-cells, and a mouse melanoma cell line expressing the gD receptor nectin-1. The HSPG analog heparin completely blocked attachment of the gC ectodomain to Vero cells. In contrast, heparin only partially blocked attachment of soluble gB, leaving 20% of the input gB still bound even at high concentrations of inhibitor. Moreover, heparin treatment removed soluble gC but not gB from the cell surface. These data suggest that a portion of gB binds to cells independently of HSPG. In addition, gB bound to two HSPG-deficient cell lines derived from L-cells. Gro2C cells are deficient in HSPG, and Sog9 cells are deficient in HSPG, as well as chondroitin sulfate proteoglycan (CSPG). To identify particular gB epitopes responsible for HSPG-independent binding, we used a panel of monoclonal antibodies (MAbs) to gB to block gB binding. Only those gB MAbs that neutralized virus blocked binding of soluble gB to the cells. HSV entry into Gro2C and Sog9 cells was reduced but still detectable relative to the parental L-cells, as previously reported. Importantly, entry into Gro2C cells was blocked by purified forms of either the gD or gB ectodomain. On a molar basis, the extent of inhibition by gB was similar to that seen with gD. Together, these results suggest that soluble gB binds specifically to the surface of different cell types independently of HSPG and CSPG and that by doing so, the protein inhibits entry. The results provide evidence for the existence of a cellular entry receptor for gB.     

Ectoparasitic "jacks-of-all-trades": relationship between abundance and host specificity in fleas (Siphonaptera) parasitic on small mammals

Animal species with larger local populations tend to be widespread across many localities, whereas species with smaller local populations occur in fewer localities. This pattern is well documented for free-living species and can be explained by the resource breadth hypothesis: the attributes that enable a species to exploit a diversity of resources allow it to attain a broad distribution and high local density. In contrast, for parasitic organisms, the trade-off hypothesis predicts that parasites exploiting many host species will achieve lower mean abundance on those hosts than more host-specific parasites because of the costs of adaptations against multiple defense systems. We test these alternative hypotheses with data on host specificity and abundance of fleas parasitic on small mammals from 20 different regions. Our analyses controlled for phylogenetic influences, differences in host body surface area, and sampling effort. In most regions, we found significant positive relationships between flea abundance and either the number of host species they exploited or the average taxonomic distance among those host species. This was true whether we used mean flea abundance or the maximum abundance they achieved on their optimal host. Although fleas tended to exploit more host species in regions with either larger number of available hosts or more taxonomically diverse host faunas, differences in host faunas between regions had no clear effect on the abundance-host specificity relationship. Overall, the results support the resource breadth hypothesis: fleas exploiting many host species or taxonomically unrelated hosts achieve higher abundance than specialist fleas. We conclude that generalist parasites achieve higher abundance because of a combination of resource availability and stability.     

The relationship between specialization and local abundance: the case of helminth parasites of birds

Positive relationships are commonly observed between the abundance of a species in a locality and the frequency of its occurrence among localities on a larger scale. This pattern may not hold for parasitic organisms when the average abundance of a parasite among its hosts is related to the number of host species in which it occurs, because of the additive investment in specific adaptations to counter host immune responses required for each host species in a parasites repertoire. For a rigorous test of the hypothesis that there is a trade-off between the number of host species that can be successfully exploited and the average abundance of parasites in those hosts, one needs to take into account the phylogenetic (or taxonomic) distances among the host species used by a parasite. Differences in immune responses are likely to increase with increasing phylogenetic distances. The trade-off hypothesis was tested in a comparative analysis of 393 species of trematodes, cestodes and nematodes parasitic in birds surveyed from the same geographical area, using an index of host specificity that measures the average taxonomic distances between a parasites known host species. After correcting for the influences of parasite phylogeny and other potential confounding variables, mean abundance was negatively correlated with the average taxonomic distance among host species for nematodes, and with the variance in taxonomic distances among hosts for cestodes. In the case of trematodes, these variables covaried positively. The trade-off between average infection success and how taxonomically distant a parasites host species are from each other was only found in two of the three groups of helminths investigated, possibly because of compensating features in trematodes, such as their ability to multiply asexually in intermediate hosts. These results provide empirical evidence consistent with the hypothesis that specialization allows greater local adaptation and therefore greater local population abundance, supporting key predictions regarding the evolution of ecological specialization.Electronic Supplementary Material Supplementary material is available for this article at     

The marine viromes of four oceanic regions

Viruses are the most common biological entities in the marine environment. There has not been a global survey of these viruses, and consequently, it is not known what types of viruses are in Earth's oceans or how they are distributed. Metagenomic analyses of 184 viral assemblages collected over a decade and representing 68 sites in four major oceanic regions showed that most of the viral sequences were not similar to those in the current databases. There was a distinct “marine-ness” quality to the viral assemblages. Global diversity was very high, presumably several hundred thousand of species, and regional richness varied on a North-South latitudinal gradient. The marine regions had different assemblages of viruses. Cyanophages and a newly discovered clade of single-stranded DNA phages dominated the Sargasso Sea sample, whereas prophage-like sequences were most common in the Arctic. However most viral species were found to be widespread. With a majority of shared species between oceanic regions, most of the differences between viral assemblages seemed to be explained by variation in the occurrence of the most common viral species and not by exclusion of different viral genomes. These results support the idea that viruses are widely dispersed and that local environmental conditions enrich for certain viral types through selective pressure.     

Direct conversion of xylan into alkyl pentosides

Xylan has been used as a raw material in the synthesis of butyl, octyl and decyl glycosides. Mixtures of d-xylose-, l-arabinose- and d-glucose-based surfactants were obtained under smooth conditions with high yields in a one-pot process. The surface activities of octyl and decyl glycosides thus obtained have been studied and compared with that of pure alkyl d-xylosides. The results have confirmed that the new synthetic approach described in this paper is a potentially economical and efficient method for the preparation of environmentally friendly surfactants.     

KiSS-1: a likely candidate for the photoperiodic control of reproduction in seasonal breeders

In seasonal species, photoperiod exerts tight regulation of reproduction to ensure that birth occurs at the most favorable time of yr. A distinct photoneuroendocrine circuit composed of the retina, suprachiasmatic nucleus (SCN) of the hypothalamus, and pineal gland transduces daylength into a rhythmic secretion of melatonin. The duration of the night-time rise of this hormone conveys daylength information to the organism. Melatonin is known to mediate the control of seasonal reproduction, but how it modulates sexual activity is far from understood. Recent data indicate that the product of the KiSS-1 gene is a potent stimulator of the hypothalamic-pituitary-gonadal axis and may play, together with its receptor GPR54, a central role in the neuroendocrine regulation of gonadotropin secretion. This article briefly reviews these findings and presents arguments that KiSS-1 could take part in the seasonal control of reproduction.