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21.
Analysis of a foot-and-mouth disease virus type A24 isolate containing an SGD receptor recognition site in vitro and its pathogenesis in cattle 总被引:1,自引:0,他引:1 下载免费PDF全文
Foot-and-mouth disease virus (FMDV) initiates infection by binding to integrin receptors via an Arg-Gly-Asp (RGD) sequence found in the G-H loop of the structural protein VP1. Following serial passages of a type A(24) Cruzeiro virus (A(24)Cru) in bovine, via tongue inoculation, a virus was generated which contained an SGD sequence in the cell receptor-binding site and expressed a turbid plaque phenotype in BHK-21 cells. Propagation of this virus in these cells resulted in the rapid selection of viruses that grew to higher titers, produced clear plaques, and now contained an RGD sequence in place of the original SGD. To study the role of the SGD sequence in FMDV receptor recognition and bovine virulence, we assembled an infectious cDNA clone of an RGD-containing A(24)Cru and derived mutant clones containing either SGD with a single nucleotide substitution in the R(144) codon or double substitutions at this position to prevent mutation of the S to an R. The SGD viruses grew poorly in BHK-21 cells and stably maintained the sequence during propagation in BHK-21 cells expressing the bovine alpha(V)beta(6) integrin (BHK3-alpha(V)beta(6)), as well as in experimentally infected and contact steers. While all the SGD-containing viruses used only the bovine alpha(V)beta(6) integrin as a cellular receptor with relatively high efficiency, the revertant RGD viruses utilized either the alpha(V)beta(1) or alpha(V)beta(3) bovine integrins with higher efficiency than alpha(V)beta(6) and grew well in BHK-21 cells. Replacing the R at the -1 SGD position with either K or E showed that this residue did not contribute to integrin utilization in vitro. These results illustrate the rapid evolution of FMDV with alteration in receptor specificity and suggest that viruses with sequences other than RGD, but closely related to it, can still infect via integrin receptors and induce and transmit the disease to susceptible animals. 相似文献
22.
Vaccines prepared from chimeras of foot-and-mouth disease virus (FMDV) induce neutralizing antibodies and protective immunity to multiple serotypes of FMDV. 总被引:5,自引:4,他引:1 下载免费PDF全文
The G-H loop of VP1 (residues 132 to 159) of foot-and-mouth disease virus (FMDV) is a prominent feature on the virion surface and has an important role in vaccine efficacy, generation of antigenic variants, and cell binding. Using an infectious cDNA of FMDV, we have constructed serotype A viruses in which the G-H loop has been substituted with the homologous sequences from serotype O or C. These chimeric viruses replicated to high titer and displayed plaque morphologies similar to those of wild-type viruses, demonstrating that the functions provided by the loop can be readily exchanged between serotypes. Monoclonal antibody analyses showed that epitopes contained within the loop were transferred to the chimeras and that epitopes encoded by the type A backbone were maintained. Chemically inactivated vaccines prepared from chimeric viruses induced antibodies in guinea pigs that neutralized both type A and either type O or type C viruses. Swine inoculated with the A/C chimera vaccine also produced cross-reactive antibodies, were protected from challenge with the type A virus, and partially protected against challenge with type C. These studies emphasize the importance of epitopes outside of the G-H loop in protective immunity in swine, which is a natural host of FMDV. 相似文献
23.
Clara Correia‐Melo Francisco DM Marques Rhys Anderson Graeme Hewitt Rachael Hewitt John Cole Bernadette M Carroll Satomi Miwa Jodie Birch Alina Merz Michael D Rushton Michelle Charles Diana Jurk Stephen WG Tait Rafal Czapiewski Laura Greaves Glyn Nelson Mohammad Bohlooly‐Y Sergio Rodriguez‐Cuenca Antonio Vidal‐Puig Derek Mann Gabriele Saretzki Giovanni Quarato Douglas R Green Peter D Adams Thomas von Zglinicki Viktor I Korolchuk João F Passos 《The EMBO journal》2016,35(7):724-742
24.
25.
Leigh A. Baxt Elena Rastew Rivka Bracha David Mirelman Upinder Singh 《Eukaryotic cell》2010,9(8):1283-1293
Entamoeba histolytica is a deep-branching eukaryotic pathogen. Rhomboid proteases are intramembrane serine proteases, which cleave transmembrane proteins in, or in close proximity to, their transmembrane domain. We have previously shown that E. histolytica contains a single functional rhomboid protease (EhROM1) and has unique substrate specificity. EhROM1 is present on the trophozoite surface and relocalizes to internal vesicles during erythrophagocytosis and to the base of the cap during surface receptor capping. In order to further examine the biological function of EhROM1 we downregulated EhROM1 expression by >95% by utilizing the epigenetic silencing mechanism of the G3 parasite strain. Despite the observation that EhROM1 relocalized to the cap during surface receptor capping, EhROM1 knockdown [ROM(KD)] parasites had no gross changes in cap formation or complement resistance. However, ROM(KD) parasites demonstrated decreased host cell adhesion, a result recapitulated by treatment of wild-type parasites with DCI, a serine protease inhibitor with activity against rhomboid proteases. The reduced adhesion phenotype of ROM(KD) parasites was noted exclusively with healthy cells, and not with apoptotic cells. Additionally, ROM(KD) parasites had decreased phagocytic ability with reduced ingestion of healthy cells, apoptotic cells, and rice starch. Decreased phagocytic ability is thus independent of the reduced adhesion phenotype, since phagocytosis of apoptotic cells was reduced despite normal adhesion levels. The defect in host cell adhesion was not explained by altered expression or localization of the heavy subunit of the Gal/GalNAc surface lectin. These results suggest no significant role of EhROM1 in complement resistance but unexpected roles in parasite adhesion and phagocytosis.Entamoeba histolytica is an extracellular protozoan parasite and is a leading parasitic cause of death worldwide (48). The factors, which determine the outcome of amebic infection, are currently unknown, although it is likely that a combination of host and parasite determinants influence clinical outcome. A number of parasite factors required for amebic pathogenesis have been identified, including the Gal/GalNAc surface lectin, pore-forming proteins, and cysteine proteases (36,–38, 41).Recently, we identified several members of a class of intramembrane rhomboid proteases in the E. histolytica genome (4). Rhomboid proteases are seven-pass transmembrane proteases first identified in Drosophila melanogaster whose active site lies within the lipid bilayer, allowing them to cleave transmembrane proteins (6, 32). Substrates of rhomboid proteases are largely single-pass transmembrane proteins whose transmembrane domain contains helix-breaking residues (52). Recent work has revealed that there are multiple classes of rhomboid proteases that recognize different types of sequences within the transmembrane domains of their substrates (3). Despite low sequence similarity between individual rhomboid proteases of each class, these enzymes share a remarkable ability to functionally replace one another (16, 28, 52).Rhomboid proteases have been studied in flies, bacteria, mammals, and parasites, and roles ranging from quorum sensing to host cell entry have been identified (3, 11, 25, 33, 35, 46, 47, 49, 54, 59). In apicomplexan parasites, such as Plasmodium falciparum and Toxoplasma gondii, it has been suggested that rhomboid proteases mediate cleavage of surface adhesin proteins to facilitate host cell entry (3, 11, 46, 47). The E. histolytica genome encodes four rhomboid-like genes, with only a single gene containing the necessary catalytic residues for proteolytic activity (4). This gene, EhROM1, is a functional protease with substrate specificity similar to the P. falciparum ROM4 (PfROM4) (3, 4). In trophozoites EhROM1 is localized to the parasite surface and relocalizes to internal vesicles during erythrophagocytosis and to the base of the cap during surface receptor capping. We have shown that the heavy subunit of the amebic surface Gal/GalNAc lectin (Hgl) is a substrate of EhROM1 in vitro. Mutational analyses using a COS cell cleavage assay demonstrated that the cleavage of Hgl requires the catalytic serine in EhROM1 as well as a helix-breaking glycine residue in the transmembrane domain of Hgl (4). These data indicate that EhROM1 is a functional rhomboid protease whose physiological substrate may be Hgl.In order to further elucidate the biological function of EhROM1 we have utilized the epigenetic silencing mechanism of the E. histolytica G3 strain (8, 9). The mechanism of gene silencing in G3 ameba is not well understood. However, it is known that the silencing mechanism is epigenetically maintained, and epigenetic changes in the chromatin state of the silenced genes have been noted (22). G3 parasites transfected with a plasmid containing an upstream region of the 5′ end of EhROM showed almost complete downregulation of expression; we have named these parasites ROM(KD) for ROM knockdown. Phenotypes examined in ROM(KD) parasites included cap formation, complement resistance, adhesion, phagocytosis, hemolysis, and motility. We observed defects in both adhesion and phagocytosis in the ROM(KD) parasites compared to the parent G3 strain but no changes in cap formation or complement resistance. Importantly, the reduced phagocytosis phenotype appears independent of the reduced adhesion phenotype, implying that EhROM1 has distinct roles in both pathways. 相似文献
26.
D. P. Gladue V. O'Donnell R. Baker-Branstetter L. G. Holinka J. M. Pacheco I. Fernandez-Sainz Z. Lu E. Brocchi B. Baxt M. E. Piccone L. Rodriguez M. V. Borca 《Journal of virology》2012,86(22):12080-12090
Foot-and-mouth disease virus (FMDV), the causative agent of foot-and-mouth disease, is an Apthovirus within the Picornaviridae family. Replication of the virus occurs in association with replication complexes that are formed by host cell membrane rearrangements. The largest viral protein in the replication complex, 2C, is thought to have multiple roles during virus replication. However, studies examining the function of FMDV 2C have been rather limited. To better understand the role of 2C in the process of virus replication, we used a yeast two-hybrid approach to identify host proteins that interact with 2C. We report here that cellular Beclin1 is a specific host binding partner for 2C. Beclin1 is a regulator of the autophagy pathway, a metabolic pathway required for efficient FMDV replication. The 2C-Beclin1 interaction was further confirmed by coimmunoprecipitation and confocal microscopy to actually occur in FMDV-infected cells. Overexpression of either Beclin1 or Bcl-2, another important autophagy factor, strongly affects virus yield in cell culture. The fusion of lysosomes to autophagosomes containing viral proteins is not seen during FMDV infection, a process that is stimulated by Beclin1; however, in FMDV-infected cells overexpressing Beclin1 this fusion occurs, suggesting that 2C would bind to Beclin1 to prevent the fusion of lysosomes to autophagosomes, allowing for virus survival. Using reverse genetics, we demonstrate here that modifications to the amino acids in 2C that are critical for interaction with Beclin1 are also critical for virus growth. These results suggest that interaction between FMDV 2C and host protein Beclin1 could be essential for virus replication. 相似文献
27.
In a paper by Zimmermann and colleagues in this issue of Arthritis Research & Therapy, results of extended laboratory research with the drug combination of prednisolone and dipyridamole are reported. There seems
to be a boost and extension of the glucocorticoid effect by the combination, without a clear increase of adverse effects,
potentially allowing the application of lower dosages. However, laboratory models are not patients and the glucocorticoid
mechanisms leading to effects and adverse effects are manifold. The next required step will be to demonstrate the improved
therapeutic window in patients in adequate comparative clinical trials, assessing predefined beneficial effects and adverse
effects in a standardized way. 相似文献
28.
29.
Joel S Riley Giovanni Quarato Catherine Cloix Jonathan Lopez Jim O'Prey Matthew Pearson James Chapman Hiromi Sesaki Leo M Carlin João F Passos Ann P Wheeler Andrew Oberst Kevin M Ryan Stephen WG Tait 《The EMBO journal》2018,37(17)
During apoptosis, pro‐apoptotic BAX and BAK are activated, causing mitochondrial outer membrane permeabilisation (MOMP), caspase activation and cell death. However, even in the absence of caspase activity, cells usually die following MOMP. Such caspase‐independent cell death is accompanied by inflammation that requires mitochondrial DNA (mtDNA) activation of cGAS‐STING signalling. Because the mitochondrial inner membrane is thought to remain intact during apoptosis, we sought to address how matrix mtDNA could activate the cytosolic cGAS‐STING signalling pathway. Using super‐resolution imaging, we show that mtDNA is efficiently released from mitochondria following MOMP. In a temporal manner, we find that following MOMP, BAX/BAK‐mediated mitochondrial outer membrane pores gradually widen. This allows extrusion of the mitochondrial inner membrane into the cytosol whereupon it permeablises allowing mtDNA release. Our data demonstrate that mitochondrial inner membrane permeabilisation (MIMP) can occur during cell death following BAX/BAK‐dependent MOMP. Importantly, by enabling the cytosolic release of mtDNA, inner membrane permeabilisation underpins the immunogenic effects of caspase‐independent cell death. 相似文献
30.
Kumaresan Kavitha Subramanian Mathiyazhagan Vaithiyanathan Sendhilvel Sevagaperumal Nakkeeran GOPAL Chandrasekar WG Dilantha Fernando 《Archives Of Phytopathology And Plant Protection》2013,46(1):69-76
Antifungal antibiotic from Pseudomonas chlororaphis isolate PA23 was identified as Phenazine using TLC and HPLC. Phenazine recorded the highest inhibition zone of 21?mm with 35.55% percent inhibition of mycelial growth of Pythium aphanidermatum over control. It had a significant effect on the hyphal morphology of P. aphanidermatum and on spore germination of Botryodiplodia theobromae and Alternaria solani. Disorganization of hyphal morphology of P. aphanidermatum includes vacuolization, cell content degeneration and hyphal lysis. Similarly interaction of phenazine with Rhizoctonia solani resulted in abnormal swelling of hyphal tips was noticed in the hyphal tips. Similarly the germination of sclerotia of Macrophomina phaseolina, R. solani and Sclerotium rolfsii were completely inhibited by phenazine at a concentration 50?μl. Incubation of the eggs of the root knot nematode Meloidogyne incognita in 30?μl concentration of phenazine, completely suppressed the hatching of juveniles. 相似文献