46 research outputs found
Structural Insights into Viral Determinants of Nematode Mediated Grapevine fanleaf virus Transmission
Many animal and plant viruses rely on vectors for their transmission from host to
host. Grapevine fanleaf virus (GFLV), a picorna-like virus from
plants, is transmitted specifically by the ectoparasitic nematode
Xiphinema index. The icosahedral capsid of GFLV, which
consists of 60 identical coat protein subunits (CP), carries the determinants of
this specificity. Here, we provide novel insight into GFLV transmission by
nematodes through a comparative structural and functional analysis of two GFLV
variants. We isolated a mutant GFLV strain (GFLV-TD) poorly transmissible by
nematodes, and showed that the transmission defect is due to a glycine to
aspartate mutation at position 297 (Gly297Asp) in the CP. We next determined the
crystal structures of the wild-type GFLV strain F13 at 3.0 Å and of
GFLV-TD at 2.7 Å resolution. The Gly297Asp mutation mapped to an exposed
loop at the outer surface of the capsid and did not affect the conformation of
the assembled capsid, nor of individual CP molecules. The loop is part of a
positively charged pocket that includes a previously identified determinant of
transmission. We propose that this pocket is a ligand-binding site with
essential function in GFLV transmission by X. index. Our data
suggest that perturbation of the electrostatic landscape of this pocket affects
the interaction of the virion with specific receptors of the nematode's
feeding apparatus, and thereby severely diminishes its transmission efficiency.
These data provide a first structural insight into the interactions between a
plant virus and a nematode vector
Two Naturally Occurring Terpenes, Dehydrocostuslactone and Costunolide, Decrease Intracellular GSH Content and Inhibit STAT3 Activation
The main purpose of the present study is to envisage the molecular mechanism of
inhibitory action ofdehydrocostuslactone (DCE) andcostunolide (CS), two
naturally occurring sesquiterpene lactones, towards the activation of signal
transducer and activator of transcription 3 (STAT3). We report that, in human
THP-1 cell line, they inhibit IL-6-elicited tyrosine phosphorylation of STAT3
and its DNA binding activity with EC50 of 10 µM with
concomitantdown-regulation ofthe phosphorylation of the tyrosine Janus kinases
JAK1, JAK2 and Tyk2. Furthermore, these compounds that contain an
α-β-unsatured carbonyl moiety and function as potent Michael reaction
acceptor, induce a rapid drop in intracellular glutathione (GSH) concentration
by direct interaction with it, thereby triggering
S-glutathionylation of STAT3. Dehydrocostunolide (HCS), the
reduced form of CS lacking only the α-β-unsaturated carbonyl group,
fails to exert any inhibitory action. Finally, the glutathione ethylene ester
(GEE), the cell permeable GSH form, reverts the inhibitory action of DCE and CS
on STAT3 tyrosine phosphorylation. We conclude that these two sesquiterpene
lactones are able to induce redox-dependent post-translational modification of
cysteine residues of STAT3 protein in order to regulate its function
Role of Interleukin-6, Its Receptor and Soluble gp130 in Chronic Lung Disease of Prematurity
Background: Interleukin-6 (IL-6) signalling involves the interplay between IL-6, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130). IL-6 activity is modulated by the soluble receptors to produce both pro- and anti-inflammatory effects in human diseases and animal models. The expression and functional activity of these molecules in lungs of preterm ventilated infants is unknown. Objectives: We investigated this pathway in preterm infants who were at risk of developing chronic lung disease of prematurity (CLD). Methods: Cytokines and soluble receptors were measured in bronchoalveolar lavage fluid (BALF) from ventilated preterm infants ≤32 weeks of gestation who did or did not develop CLD. B9 cells, which specifically proliferate to IL-6, were used to assess BALF IL-6 functional activity. Results: Inflammatory cells, IL-8 and monocyte chemotactic protein-1 were increased in BALF from the CLD group when compared to the No CLD group (p < 0.05). BALF IL-6 and sIL-6R were similar in both groups. In contrast, BALF sgp130 and sgp130/sIL-6R were greater in the CLD group when compared to the No CLD group (p = 0.01 and p = 0.02, respectively). However, the increased BALF sgp130 did not appear to modulate the BALF IL-6 functional activity. Conclusion: Lung inflammation was observed in the CLD group. Increased BALF sgp130 was noted in the CLD group but it did not appear to modulate the pulmonary IL-6 bioactivity. Further research is needed to investigate the potential modulatory activity of sgp130 in the preterm lung