Histone deacetylase 6 regulates human immunodeficiency virus type 1 infection

Efficient human immunodeficiency virus (HIV)-1 infection depends on multiple interactions between the viral gp41/gp120 envelope (Env) proteins and cell surface receptors. However, cytoskeleton-associated proteins that modify membrane dynamics may also regulate the formation of the HIV-mediated fusion pore and hence viral infection. Because the effects of HDAC6-tubulin deacetylase on cortical alpha-tubulin regulate cell migration and immune synapse organization, we explored the possible role of HDAC6 in HIV-1-envelope-mediated cell fusion and infection. The binding of the gp120 protein to CD4+-permissive cells increased the level of acetylated alpha-tubulin in a CD4-dependent manner. Furthermore, overexpression of active HDAC6 inhibited the acetylation of alpha-tubulin, and remarkably, prevented HIV-1 envelope-dependent cell fusion and infection without affecting the expression and codistribution of HIV-1 receptors. In contrast, knockdown of HDAC6 expression or inhibition of its tubulin deacetylase activity strongly enhanced HIV-1 infection and syncytia formation. These results demonstrate that HDAC6 plays a significant role in regulating HIV-1 infection and Env-mediated syncytia formation.     

Wiskott-Aldrich syndrome protein is needed for vaccinia virus pathogenesis

Smallpox, caused by variola virus, was a devastating disease in humans, but how the virus evolved a strategy to spread to tissue remains unknown. Through the use of microarrays, we identified the gene encoding the Wiskott-Aldrich syndrome protein (WASP), one of the five known WASP family members, which has been induced in the course of infection of human cells with different strains of vaccinia virus (VV) (S. Guerra, L. A. Lopez-Fernandez, A. Pascual-Montano, M. Munoz, K. Harshman, and M. Esteban, J. Virol. 77:6493-6506, 2003; S. Guerra, L. A. Lopez-Fernandez, R. Conde, A. Pascual-Montano, K. Harshman, and M. Esteban, J. Virol. 78:5820-5834, 2004). In a mouse model, we evaluated the role of WASP in infection with VV, a close relative of variola virus. WASP(-/-) (KO) mice infected intranasally and intraperitoneally with VV showed reduced weight loss and mortality compared to wild-type (WT) mice. WASP expression correlated with VV replication in the ovaries but not in the liver or spleen. WT mouse macrophages express WASP but not N-WASP; after VV infection, WASP levels increase threefold. KO macrophages lack N-WASP expression and, when VV infected, are incapable of inducing actin tails and producing extracellular virus. These functions were rescued in KO macrophages after ectopic WASP expression. Overall, our findings demonstrate that WASP has a role in orthopoxvirus infections. Use of WASP proteins for virus spread via the actin tail provides a selective advantage for VV, and probably variola virus, dissemination to distant tissues.     

A fungal tRNA of Aspergillus niger induces IFN-beta synthesis in HEp-2 cells

In this work, we evaluated the capacity of a fungal transfer RNA (F-tRNA) from Aspergillus niger to protect HEp-2 cells against a viral infection, and as an inducer of IFN-beta synthesis. HEp-2 cells previously incubated with F-tRNA, polyI:polyC, or IFN-alpha, at different concentrations for 24 h were infected with 200 pfu of adenovirus type 6 (AdV-6); after 5 days, we determined cellular viability, cytopathic effect of the virus, optimal concentration necessary to inhibit the cytopathic effect, and IFN-beta expression by RT-PCR. Results showed that HEp-2 cells treated with F-tRNA were less susceptible to the cytopathic effect of AdV-6 infection than those incubated with polyI:polyC (p < 0.05). On the other hand, F-tRNA- treated HEp-2 cells expressed IFN-beta mRNA, whereas monolayers incubated with polyI:polyC or IFN-alpha did not. Our results suggest that F-tRNA protected HEp-2 cells against AdV-6 infection, due to its capacity to induce IFN-beta synthesis.     

A second outer-core region in Klebsiella pneumoniae lipopolysaccharide

Up to now only one major type of core oligosaccharide has been found in the lipopolysaccharide of all Klebsiella pneumoniae strains analyzed. Applying a different screening approach, we identified a novel Klebsiella pneumoniae core (type 2). Both Klebsiella core types share the same inner core and the outer-core-proximal disaccharide, GlcN-(1,4)-GalA, but they differ in the GlcN substituents. In core type 2, the GlcpN residue is substituted at the O-4 position by the disaccharide beta-Glcp(1-6)-alpha-Glcp(1, while in core type 1 the GlcpN residue is substituted at the O-6 position by either the disaccharide alpha-Hep(1-4)-alpha-Kdo(2 or a Kdo residue (Kdo is 3-deoxy-D-manno-octulosonic acid). This difference correlates with the presence of a three-gene region in the corresponding core biosynthetic clusters. Engineering of both core types by interchanging this specific region allowed studying the effect on virulence. The replacement of Klebsiella core type 1 in a highly type 2 virulent strain (52145) induces lower virulence than core type 2 in a murine infection model.     

Impacts of anthropogenic stresses on the early development stages of seaweeds

Seaweeds are important primary producers, and as such contributesignificantly to nearshore ecosystems. Studies on the effects ofanthropogenic stresses on these organisms have largely been concernedwith the vegetative adult stages of the life cycle. Here we review thelimited information on the sensitivity of early stages in the life cycleof seaweeds to global change (UV increase; global warming;increased storm frequencies) and pollution (eutrophication, trace metalsand oil). Impacts on fertility, substrate attachment, development,photosynthesis, growth and mortality are highlighted. In their naturalhabitats, early stages are shade-adapted, as they live shel tered underadult canopies and in pores of the substrata. Although some acclimationunder increased moderate irradiance is seen, higher solar irradiance,and especially ultraviolet-B, inhibits early development. Global warmingmay decrease the fertility and shorten the fertile period of somespecies. With the increasing likelihood of storms associated with globalwarming, gamete release may be inhibited while scouring by suspendedsediments may detach newly settled stages. Succession and localdistribution patterns are likely to be affected. Eutrophication canresult in accelerated development of the early stages of some algalspecies but sewage discharges have a negative impact on sperm motility,fertilisation and can cause increased mortality in germlings. Impacts ofother, indirect effects of eutrophication, including increased sedimentcover of substrata, scouring caused by wind-induced resuspension ofsediments, and grazing, are also expected to be negative. Toxic tracemetals affect gamete viability, inhibit fertilisation and development,and reduce growth rates. Gametes are particularly susceptible to oilpollution and interactions between hydrocarbons and the adhesive mucussurrounding the embryonic stages seem to inhibit settlement.Recommendations for future studies are provided that are aimed atgaining greater insight into the effects of anthropogenic stress on theweakest links in the development cycle of seaweeds.     

Lizard thermal trait variation at multiple scales: a review

Thermal trait variation is of fundamental importance to forecasting the impacts of environmental change on lizard diversity. Here, we review the literature for patterns of variation in traits of upper and lower sub-lethal temperature limits, temperature preference and active body temperature in the field, in relation to space, time and phylogeny. Through time, we focus on the direction and magnitude of trait change within days, among seasons and as a consequence of acclimation. Across space, we examine altitudinal and latitudinal patterns, incorporating inter-specific analyses at regional and global scales. This synthesis highlights the consistency or lack thereof, of thermal trait responses, the relative magnitude of change among traits and several knowledge gaps identified in the relationships examined. We suggest that physiological information is becoming essential for forecasting environmental change sensitivity of lizards by providing estimates of plasticity and evolutionary scope.     

Role of the Apt1 Protein in Polysaccharide Secretion by Cryptococcus neoformans

Flippases are key regulators of membrane asymmetry and secretory mechanisms. Vesicular polysaccharide secretion is essential for the pathogenic mechanisms of Cryptococcus neoformans. On the basis of the observations that flippases are required for polysaccharide secretion in plants and the putative Apt1 flippase is required for cryptococcal virulence, we analyzed the role of this enzyme in polysaccharide release by C. neoformans, using a previously characterized apt1Δ mutant. Mutant and wild-type (WT) cells shared important phenotypic characteristics, including capsule morphology and dimensions, glucuronoxylomannan (GXM) composition, molecular size, and serological properties. The apt1Δ mutant, however, produced extracellular vesicles (EVs) with a lower GXM content and different size distribution in comparison with those of WT cells. Our data also suggested a defective intracellular GXM synthesis in mutant cells, in addition to changes in the architecture of the Golgi apparatus. These findings were correlated with diminished GXM production during in vitro growth, macrophage infection, and lung colonization. This phenotype was associated with decreased survival of the mutant in the lungs of infected mice, reduced induction of interleukin-6 (IL-6) cytokine levels, and inefficacy in colonization of the brain. Taken together, our results indicate that the lack of APT1 caused defects in both GXM synthesis and vesicular export to the extracellular milieu by C. neoformans via processes that are apparently related to the pathogenic mechanisms used by this fungus during animal infection.     

Soluble Co-Signaling Molecules Predict Long-Term Graft Outcome in Kidney-Transplanted Patients

Co-signaling molecules are responsible for full T-cell activation after solid organ transplantation. Their increased expression can lead to the release of a soluble form that can modulate the immune response post-transplantation. We analyzed the presence of co-signaling molecules (sCD30, sCD40, sCD137, sCTLA-4, sCD80, sCD28, sCD40L, sPD-1, and sPD-L1) in serum from kidney-transplanted patients (n = 59) obtained at different times (before transplantation, and 15 days, 3 months and 1 year post-transplantation) and their contribution to graft outcome was evaluated using principal component analysis. Before transplantation, high levels of soluble co-signaling molecules (mainly sCD30, sCD137 and sCD40) were detected in all patients. These molecules were modulated soon after receiving an allograft but never attained similar levels to those of healthy controls. A signature based on the determination of six soluble co-stimulatory (sCD30, sCD40, sCD137 and sCD40L) and co-inhibitory (sPD-1 and sPD-L1) molecules at 3 months post-transplantation allowed a group of patients to be identified (27.12%) with a worse long-term graft outcome. Patients with high levels of soluble molecules showed a progressive and gradual deterioration of kidney function (increased creatinine and proteinuria levels and decreased estimated glomerular filtration rate) over time and a higher risk of graft loss at 6 years post-transplantation than patients with low levels of these molecules (62.55% versus 5.14%, p<0.001). Thus, our data show an aberrant expression of soluble co-signaling molecules in kidney-transplanted patients whose quantification at 3 months post-transplantation might be a useful biomarker of immune status and help to predict long-term graft evolution.