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a simple procedure for the derivation of electron density based surfaces of drug-receptor complexes from a combination of x-ray data and theoretical calculations.to contribute to an understanding of biological recognition and interaction, an easy-to-use procedure was developed to generate and display molecular surfaces and selected electron density based surface properties. to overcome the present limitations to derive electron densities of macromolecules, the considered systems were reduced to appropriate substructures around the active centers. the combination of experimental x-ray structural information and aspherical atomic electron density data from ...201020634077
sequential nearest-neighbor effects on computed 13calpha chemical shifts.to evaluate sequential nearest-neighbor effects on quantum-chemical calculations of (13)c(alpha) chemical shifts, we selected the structure of the nucleic acid binding (nab) protein from the sars coronavirus determined by nmr in solution (pdb id 2k87). nab is a 116-residue alpha/beta protein, which contains 9 prolines and has 50% of its residues located in loops and turns. overall, the results presented here show that sizeable nearest-neighbor effects are seen only for residues preceding proline ...201020644980
an interaction between the nucleocapsid protein and a component of the replicase-transcriptase complex is crucial for the infectivity of coronavirus genomic rna.the coronavirus nucleocapsid (n) protein plays an essential role in virion assembly via interactions with the large, positive-strand rna viral genome and the carboxy-terminal endodomain of the membrane protein (m). to learn about the functions of n protein domains in the coronavirus mouse hepatitis virus (mhv), we replaced the mhv n gene with its counterpart from the closely related bovine coronavirus (bcov). the resulting viral mutant was severely defective, even though individual domains of th ...201020660183
studies of severe acute respiratory syndrome coronavirus pathology in human cases and animal models.during the severe acute respiratory syndrome (sars) outbreak of 2003, approximately 10% of sars patients developed progressive respiratory failure and died. since then, several animal models have been established to study sars coronavirus, with the aim of developing new antiviral agents and vaccines. this short review describes the pathologic features of sars in relation to their clinical presentation in human cases. it also looks at animal susceptibility after experimental infection, animal mod ...201020664013
sars spike protein induces phenotypic conversion of human b cells to macrophage-like cells.massive aggregations of macrophages are frequently detected in afflicted lungs of patients with severe acute respiratory syndrome-associated coronavirus (sars-cov) infection. in vitro, ectopic expression of transcription factors, in particular ccaat/enhancer-binding protein alpha (c/ebpα) and c/ebpβ, can convert b cells into functional macrophages. however, little is known about the specific ligands responsible for such phenotype conversion. here, we investigated whether spike protein of sars-co ...201020667598
papain-like protease 1 from transmissible gastroenteritis virus: crystal structure and enzymatic activity toward viral and cellular substrates.coronaviruses encode two classes of cysteine proteases, which have narrow substrate specificities and either a chymotrypsin- or papain-like fold. these enzymes mediate the processing of the two precursor polyproteins of the viral replicase and are also thought to modulate host cell functions to facilitate infection. the papain-like protease 1 (pl1(pro)) domain is present in nonstructural protein 3 (nsp3) of alphacoronaviruses and subgroup 2a betacoronaviruses. it participates in the proteolytic ...201020668092
cooperative translocation enhances the unwinding of duplex dna by sars coronavirus helicase nsp13.sars coronavirus encodes non-structural protein 13 (nsp13), a nucleic acid helicase/ntpase belonging to superfamily 1 helicase, which efficiently unwinds both partial-duplex rna and dna. in this study, unwinding of dna substrates that had different duplex lengths and 5'-overhangs was examined under single-turnover reaction conditions in the presence of excess enzyme. the amount of dna unwound decreased significantly as the length of the duplex increased, indicating a poor in vitro processivity. ...201020671029
severe acute respiratory syndrome and coronavirus.severe acute respiratory syndrome (sars) is a highly infectious disease with a significant morbidity and mortality. respiratory failure is the major complication, and patients may progress to acute respiratory distress syndrome. health care workers are particularly vulnerable to sars. sars has the potential of being converted from droplet to airborne transmission. there is currently no proven effective treatment of sars, so early recognition, isolation, and stringent infection control are the ke ...201020674795
genomic characterization of severe acute respiratory syndrome-related coronavirus in european bats and classification of coronaviruses based on partial rna-dependent rna polymerase gene sequences.bats may host emerging viruses, including coronaviruses (cov). we conducted an evaluation of cov in rhinolophid and vespertilionid bat species common in europe. rhinolophids carried severe acute respiratory syndrome (sars)-related cov at high frequencies and concentrations (26% of animals are positive; up to 2.4×10(8) copies per gram of feces), as well as two alphacoronavirus clades, one novel and one related to the hku2 clade. all three clades present in miniopterus bats in china (hku7, hku8, a ...201020686038
genomic characterization of severe acute respiratory syndrome-related coronavirus in european bats and classification of coronaviruses based on partial rna-dependent rna polymerase gene sequences.bats may host emerging viruses, including coronaviruses (cov). we conducted an evaluation of cov in rhinolophid and vespertilionid bat species common in europe. rhinolophids carried severe acute respiratory syndrome (sars)-related cov at high frequencies and concentrations (26% of animals are positive; up to 2.4×10(8) copies per gram of feces), as well as two alphacoronavirus clades, one novel and one related to the hku2 clade. all three clades present in miniopterus bats in china (hku7, hku8, a ...201020686038
molecular mapping of the rna cap 2'-o-methyltransferase activation interface between severe acute respiratory syndrome coronavirus nsp10 and nsp16.several protein-protein interactions within the sars-cov proteome have been identified, one of them being between non-structural proteins nsp10 and nsp16. in this work, we have mapped key residues on the nsp10 surface involved in this interaction. alanine-scanning mutagenesis, bioinformatics, and molecular modeling were used to identify several "hot spots," such as val(42), met(44), ala(71), lys(93), gly(94), and tyr(96), forming a continuous protein-protein surface of about 830 å(2), bearing ve ...201020699222
transcriptomic analysis reveals a mechanism for a prefibrotic phenotype in stat1 knockout mice during severe acute respiratory syndrome coronavirus infection.severe acute respiratory syndrome coronavirus (sars-cov) infection can cause the development of severe end-stage lung disease characterized by acute respiratory distress syndrome (ards) and pulmonary fibrosis. the mechanisms by which pulmonary lesions and fibrosis are generated during sars-cov infection are not known. using high-throughput mrna profiling, we examined the transcriptional response of wild-type (wt), type i interferon receptor knockout (ifnar1-/-), and stat1 knockout (stat1-/-) mic ...201020702617
differential downregulation of ace2 by the spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus nl63.the human coronaviruses (covs) severe acute respiratory syndrome (sars)-cov and nl63 employ angiotensin-converting enzyme 2 (ace2) for cell entry. it was shown that recombinant sars-cov spike protein (sars-s) downregulates ace2 expression and thereby promotes lung injury. whether nl63-s exerts a similar activity is yet unknown. we found that recombinant sars-s bound to ace2 and induced ace2 shedding with higher efficiency than nl63-s. shedding most likely accounted for the previously observed ac ...201019864379
the rna polymerase activity of sars-coronavirus nsp12 is primer dependent.an rna-dependent rna polymerase (rdrp) is the central catalytic subunit of the rna-synthesizing machinery of all positive-strand rna viruses. usually, rdrp domains are readily identifiable by comparative sequence analysis, but biochemical confirmation and characterization can be hampered by intrinsic protein properties and technical complications. it is presumed that replication and transcription of the approximately 30-kb severe acute respiratory syndrome (sars) coronavirus (sars-cov) rna genom ...201019875418
discrete epidemic models.the mathematical theory of single outbreak epidemic models really began with the work of kermack and mackendrick about decades ago. this gave a simple answer to the long-standing question of why epidemics woould appear suddenly and then disappear just as suddenly without having infected an entire population. therefore it seemed natural to expect that theoreticians would immediately proceed to expand this mathematical framework both because the need to handle recurrent single infectious disease o ...201020104945
the n-terminal region of severe acute respiratory syndrome coronavirus protein 6 induces membrane rearrangement and enhances virus replication.the severe acute respiratory syndrome coronavirus (sars-cov) accessory protein 6 (p6) is a 63-amino-acid multifunctional golgi-endoplasmic reticulum (er) membrane-associated protein, with roles in enhancing virus replication and in evading the innate immune response to infection by inhibiting stat1 (signal transducer and activator of transcription factor 1) translocation to the nucleus. here, we demonstrate that p6 has an n-terminal region-cytoplasm-c-terminal region-cytoplasm configuration with ...201020106914
immunization with an attenuated severe acute respiratory syndrome coronavirus deleted in e protein protects against lethal respiratory disease.the severe acute respiratory syndrome coronavirus (sars-cov) caused substantial morbidity and mortality in 2002-2003. deletion of the envelope (e) protein modestly diminished virus growth in tissue culture but abrogated virulence in animals. here, we show that immunization with rsars-cov-deltae or sars-cov-delta[e,6-9b] (deleted in accessory proteins (6, 7a, 7b, 8a, 8b, 9b) in addition to e) nearly completely protected balb/c mice from fatal respiratory disease caused by mouse-adapted sars-cov a ...201020110095
identification of n-linked carbohydrates from severe acute respiratory syndrome (sars) spike glycoprotein.n-glycans were released from the sars coronavirus (sars-cov) spike glycoprotein produced in vero e6 cells and their structures were determined by a combination of matrix-assisted laser desorption/ionization (maldi) mass spectrometry, negative ion electrospray collision-induced dissociation time-of-flight mass spectrometry and normal-phase high-performance liquid chromatography with exoglycosidase digestion. major glycans were high-mannose (man(5-9)glcnac(2)), hybrid and bi-, tri- and tetra-anten ...201020129637
angiotensin-converting enzyme 2 (ace2) in disease pathogenesis.angiotensin-converting enzyme 2 (ace2), a first homolog of ace, regulates the renin-angiotensin system by counterbalancing ace activity. accumulating evidence in recent years has demonstrated a physiological and pathological role of ace2 in the cardiovascular, renal and respiratory systems. for instance, in the acute respiratory distress syndrome (ards), ace, angii, and at1r promote the disease pathogenesis, whereas ace2 and the at2r protect from ards. importantly, ace2 has been identified as a ...201020134095
annexin a2 on lung epithelial cell surface is recognized by severe acute respiratory syndrome-associated coronavirus spike domain 2 antibodies.severe acute respiratory syndrome-associated coronavirus (sars-cov) infection causes lung failure characterized by atypical pneumonia. we previously showed that antibodies against sars-cov spike domain 2 (s2) in the patient sera can cross-react with human lung epithelial cells; however, the autoantigen is not yet identified. in this study, we performed proteomic studies and identified several candidate autoantigens recognized by sars patient sera in human lung type ii epithelial cell a549. among ...201020015551
intraspecies diversity of sars-like coronaviruses in rhinolophus sinicus and its implications for the origin of sars coronaviruses in humans.the chinese rufous horseshoe bat (rhinolophus sinicus) has been suggested to carry the direct ancestor of severe acute respiratory syndrome (sars) coronavirus (scov), and the diversity of sars-like covs (slcov) within this rhinolophus species is therefore worth investigating. here, we demonstrate the remarkable diversity of slcovs in r. sinicus and identify a strain with the same pattern of phylogenetic incongruence (i.e. an indication of recombination) as reported previously in another slcov st ...201020016037
intraspecies diversity of sars-like coronaviruses in rhinolophus sinicus and its implications for the origin of sars coronaviruses in humans.the chinese rufous horseshoe bat (rhinolophus sinicus) has been suggested to carry the direct ancestor of severe acute respiratory syndrome (sars) coronavirus (scov), and the diversity of sars-like covs (slcov) within this rhinolophus species is therefore worth investigating. here, we demonstrate the remarkable diversity of slcovs in r. sinicus and identify a strain with the same pattern of phylogenetic incongruence (i.e. an indication of recombination) as reported previously in another slcov st ...201020016037
ecoepidemiology and complete genome comparison of different strains of severe acute respiratory syndrome-related rhinolophus bat coronavirus in china reveal bats as a reservoir for acute, self-limiting infection that allows recombination events.despite the identification of severe acute respiratory syndrome-related coronavirus (sarsr-cov) in rhinolophus chinese horseshoe bats (sarsr-rh-batcov) in china, the evolutionary and possible recombination origin of sarsr-cov remains undetermined. we carried out the first study to investigate the migration pattern and sarsr-rh-batcov genome epidemiology in chinese horseshoe bats during a 4-year period. of 1,401 chinese horseshoe bats from hong kong and guangdong, china, that were sampled, sarsr- ...201020071579
ecoepidemiology and complete genome comparison of different strains of severe acute respiratory syndrome-related rhinolophus bat coronavirus in china reveal bats as a reservoir for acute, self-limiting infection that allows recombination events.despite the identification of severe acute respiratory syndrome-related coronavirus (sarsr-cov) in rhinolophus chinese horseshoe bats (sarsr-rh-batcov) in china, the evolutionary and possible recombination origin of sarsr-cov remains undetermined. we carried out the first study to investigate the migration pattern and sarsr-rh-batcov genome epidemiology in chinese horseshoe bats during a 4-year period. of 1,401 chinese horseshoe bats from hong kong and guangdong, china, that were sampled, sarsr- ...201020071579
construction of an implicit membrane environment for the lattice monte carlo simulation of transmembrane protein.due to the complexity of biological membrane, computer simulation of transmembrane protein's folding is challenging. in this paper, an implicit biological membrane environment has been constructed in lattice space, in which the lipid chains and water molecules were represented by the unoccupied lattice sites. the biological membrane was characterized with three features: stronger hydrogen bonding interaction, membrane lateral pressure, and lipophobicity index for the amino acid residues. in addi ...201020079964
epidemic viral pneumonia.two recent viral epidemics producing pneumonitis (severe acute respiratory syndrome and pandemic influenza a h1n1) have highlighted the potential for viral infections to cause respiratory failure with a significant risk of mortality. this review describes these epidemics and other causes of epidemic viral pneumonia.201020087179
dynamic innate immune responses of human bronchial epithelial cells to severe acute respiratory syndrome-associated coronavirus infection.human lung epithelial cells are likely among the first targets to encounter invading severe acute respiratory syndrome-associated coronavirus (sars-cov). not only can these cells support the growth of sars-cov infection, but they are also capable of secreting inflammatory cytokines to initiate and, eventually, aggravate host innate inflammatory responses, causing detrimental immune-mediated pathology within the lungs. thus, a comprehensive evaluation of the complex epithelial signaling to sars-c ...201020090954
the open reading frame 3a protein of severe acute respiratory syndrome-associated coronavirus promotes membrane rearrangement and cell death.the genome of the severe acute respiratory syndrome-associated coronavirus (sars-cov) contains eight open reading frames (orfs) that encode novel proteins. these accessory proteins are dispensable for in vitro and in vivo replication and thus may be important for other aspects of virus-host interactions. we investigated the functions of the largest of the accessory proteins, the orf 3a protein, using a 3a-deficient strain of sars-cov. cell death of vero cells after infection with sars-cov was re ...201019889773
integrity of the early secretory pathway promotes, but is not required for, severe acute respiratory syndrome coronavirus rna synthesis and virus-induced remodeling of endoplasmic reticulum membranes.to accommodate its rna synthesis in the infected cell, severe acute respiratory syndrome coronavirus (sars-cov) induces a cytoplasmic reticulovesicular network (rvn) that is derived from endoplasmic reticulum (er) membranes. we set out to investigate how the early secretory pathway interacts with the rvn and the viral replication/transcription complex (rtc) that is anchored to it. when the secretory pathway was disrupted by brefeldin a (bfa) treatment at the start of infection, rvn formation and ...201019889777
tace antagonists blocking ace2 shedding caused by the spike protein of sars-cov are candidate antiviral compounds.because outbreaks of severe acute respiratory syndrome coronavirus (sars-cov) might reemerge, identifying antiviral compounds is of key importance. previously, we showed that the cellular factor tnf-alpha converting enzyme (tace), activated by the spike protein of sars-cov (sars-s protein), was positively involved in viral entry, implying that tace is a possible target for developing antiviral compounds. to demonstrate this possibility, we here tested the effects of tace inhibitors on viral entr ...201019995578
a single tyrosine in the severe acute respiratory syndrome coronavirus membrane protein cytoplasmic tail is important for efficient interaction with spike protein.severe acute respiratory syndrome coronavirus (sars-cov) encodes 3 major envelope proteins: spike (s), membrane (m), and envelope (e). previous work identified a dibasic endoplasmic reticulum retrieval signal in the cytoplasmic tail of sars-cov s that promotes efficient interaction with sars-cov m. the dibasic signal was shown to be important for concentrating s near the virus assembly site rather than for direct interaction with m. here, we investigated the sequence requirements of the sars-cov ...201020007283
cellular immune responses to severe acute respiratory syndrome coronavirus (sars-cov) infection in senescent balb/c mice: cd4+ t cells are important in control of sars-cov infection.we characterized the cellular immune response to severe acute respiratory syndrome coronavirus (sars-cov) infection in 12- to 14-month-old balb/c mice, a model that mimics features of the human disease. following intranasal administration, the virus replicated in the lungs, with peak titers on day 2 postinfection. enhanced production of cytokines (tumor necrosis factor alpha [tnf-alpha] and interleukin-6 [il-6]) and chemokines (cxcl10, ccl2, ccl3, and ccl5) correlated with migration of nk cells, ...201019906920
recombination, reservoirs, and the modular spike: mechanisms of coronavirus cross-species transmission.over the past 30 years, several cross-species transmission events, as well as changes in virus tropism, have mediated significant animal and human diseases. most notable is severe acute respiratory syndrome (sars), a lower respiratory tract disease of humans that was first reported in late 2002 in guangdong province, china. the disease, which quickly spread worldwide over a period of 4 months spanning late 2002 and early 2003, infected over 8,000 individuals and killed nearly 800 before it was s ...201019906932
binding of sars coronavirus to its receptor damages islets and causes acute diabetes.multiple organ damage in severe acute respiratory syndrome (sars) patients is common; however, the pathogenesis remains controversial. this study was to determine whether the damage was correlated with expression of the sars coronavirus receptor, angiotensin converting enzyme 2 (ace2), in different organs, especially in the endocrine tissues of the pancreas, and to elucidate the pathogenesis of glucose intolerance in sars patients. the effect of clinical variables on survival was estimated in 13 ...201019333547
candidate genes associated with susceptibility for sars-coronavirus.assuming that no human had any previously acquired immunoprotection against severe acute respiratory syndrome coronavirus (sars-cov) during the 2003 sars outbreak, the biological bases for possible difference in individual susceptibility are intriguing. however, this issue has never been fully elucidated. based on the premise that sars patients belonging to a given genotype group having a significantly higher sars infection rate than others would imply that genotype group being more susceptible, ...201019590927
orf8a of sars-cov forms an ion channel: experiments and molecular dynamics simulations.orf8a protein is 39 residues long and contains a single transmembrane domain. the protein is synthesized using solid phase peptide synthesis and reconstituted into artificial lipid bilayers that forms cation-selective ion channels with a main conductance level of 8.9±0.8ps at elevated temperature (38.5°c). computational modeling studies including multi nanosecond molecular dynamics simulations in a hydrated popc lipid bilayer are done with a 22 amino acid transmembrane helix to predict a putativ ...201120708597
detection of a virus related to betacoronaviruses in italian greater horseshoe bats.the association between coronaviruses and bats is a worldwide phenomenon and bats belonging to genus rhinolophus are the reservoir host for several coronaviruses, including a large number of viruses closely related genetically to severe acute respiratory syndrome-coronavirus (sars-cov). we carried out a survey in colonies of italian bats (rhinolophus ferrumequinum) for the presence of coronaviruses. two of 52 r. ferrumequinum captured from different italian areas tested positive by reverse trans ...201120478089
detection of a virus related to betacoronaviruses in italian greater horseshoe bats.the association between coronaviruses and bats is a worldwide phenomenon and bats belonging to genus rhinolophus are the reservoir host for several coronaviruses, including a large number of viruses closely related genetically to severe acute respiratory syndrome-coronavirus (sars-cov). we carried out a survey in colonies of italian bats (rhinolophus ferrumequinum) for the presence of coronaviruses. two of 52 r. ferrumequinum captured from different italian areas tested positive by reverse trans ...201120478089
gaps remain in china's ability to detect emerging infectious diseases despite advances since the onset of sars and avian flu.early detection of emerging infections in china is critical to the health of the 1.3 billion chinese people and to the world. china's surveillance system for endemic infectious diseases has improved greatly since 2003, but the country's ability to conduct surveillance for laboratory-confirmed infections remains underdeveloped. this is dangerous for china, the world's most populous country, which has been the focus of global attention since outbreaks of severe acute respiratory syndrome (sars) an ...201121209448
development of a molecular-beacon-based multi-allelic real-time rt-pcr assay for the detection of human coronavirus causing severe acute respiratory syndrome (sars-cov): a general methodology for detecting rapidly mutating viruses.emerging infectious diseases have caused a global effort for development of fast and accurate detection techniques. the rapidly mutating nature of viruses presents a major difficulty, highlighting the need for specific detection of genetically diverse strains. one such infectious agent is sars-associated coronavirus (sars-cov), which emerged in 2003. this study aimed to develop a real-time rt-pcr detection assay specific for sars-cov, taking into account its intrinsic polymorphic nature due to g ...201121221674
reverse transcription polymerase chain reaction and electrospray ionization mass spectrometry for identifying acute viral upper respiratory tract infections.diagnosis of respiratory viruses traditionally relies on culture or antigen detection. we aimed to demonstrate capacity of the reverse transcription polymerase chain reaction/electrospray ionization mass spectrometry (rt-pcr/esi-ms) platform to identify clinical relevant respiratory viruses in nasopharyngeal aspirate (npa) samples and compare the diagnostic performance characteristics relative to conventional culture- and antigen-based methods. an rt-pcr/esi-ms respiratory virus surveillance kit ...201121251562
distinct patterns of ifitm-mediated restriction of filoviruses, sars coronavirus, and influenza a virus.interferon-inducible transmembrane proteins 1, 2, and 3 (ifitm1, 2, and 3) are recently identified viral restriction factors that inhibit infection mediated by the influenza a virus (iav) hemagglutinin (ha) protein. here we show that ifitm proteins restricted infection mediated by the entry glycoproteins (gp(1,2)) of marburg and ebola filoviruses (marv, ebov). consistent with these observations, interferon-β specifically restricted filovirus and iav entry processes. ifitm proteins also inhibited ...201121253575
inactivation of surrogate coronaviruses on hard surfaces by health care germicides.in the 2003 severe acute respiratory syndrome outbreak, finding viral nucleic acids on hospital surfaces suggested surfaces could play a role in spread in health care environments. surface disinfection may interrupt transmission, but few data exist on the effectiveness of health care germicides against coronaviruses on surfaces.201121256627
a new method for monitoring and forecasting the case-fatality rate in ongoing epidemics and its evaluation using published data of sars in 2003, h1n1 pandemic in 2009/2010, hand-foot-mouth disease in china in 2009/2010, and cholera in haiti in 2010. 201121266767
severe acute respiratory syndrome coronavirus papain-like protease suppressed alpha interferon-induced responses through downregulation of extracellular signal-regulated kinase 1-mediated signalling pathways.severe acute respiratory syndrome coronavirus (sars-cov) papain-like protease (plpro), a deubiquitinating enzyme, reportedly blocks poly i?:?c-induced activation of interferon regulatory factor 3 and nuclear factor kappa b, reducing interferon (ifn) induction. this study investigated type i ifn antagonist mechanism of plpro in human promonocytes. plpro antagonized ifn-a-induced responses such as interferon-stimulated response element- and ap-1-driven promoter activation, protein kinase r, 2'-5'- ...201121270289
epithelial cells lining salivary gland ducts are early target cells of severe acute respiratory syndrome coronavirus infection in the upper respiratory tracts of rhesus macaques.the shedding of severe acute respiratory syndrome coronavirus (sars-cov) into saliva droplets plays a critical role in viral transmission. the source of high viral loads in saliva, however, remains elusive. here we investigate the early target cells of infection in the entire array of respiratory tissues in chinese macaques after intranasal inoculations with a single-cycle pseudotyped virus and a pathogenic sars-cov. we found that angiotensin-converting enzyme 2-positive (ace2(+)) cells were wid ...201121289121
epithelial cells lining salivary gland ducts are early target cells of severe acute respiratory syndrome coronavirus infection in the upper respiratory tracts of rhesus macaques.the shedding of severe acute respiratory syndrome coronavirus (sars-cov) into saliva droplets plays a critical role in viral transmission. the source of high viral loads in saliva, however, remains elusive. here we investigate the early target cells of infection in the entire array of respiratory tissues in chinese macaques after intranasal inoculations with a single-cycle pseudotyped virus and a pathogenic sars-cov. we found that angiotensin-converting enzyme 2-positive (ace2(+)) cells were wid ...201121289121
development of anti-viral agents using molecular modeling and virtual screening techniques.computational chemistry has always played a key role in anti-viral drug development. the challenges and the quickly rising public interest when a virus is becoming a threat has significantly influenced computational drug discovery. the most obvious example is anti-aids research, where hiv protease and reverse transcriptase have triggered enormous efforts in developing and improving computational methods. methods applied to anti-viral research include (i) ligand-based approaches that rely on know ...201121303343
the leader proteinase of foot-and-mouth disease virus negatively regulates the type i interferon pathway by acting as a viral deubiquitinase.the leader proteinase (l(pro)) of foot-and-mouth disease virus (fmdv) is a papain-like proteinase that plays an important role in fmdv pathogenesis. previously, it has been shown that l(pro) is involved in the inhibition of the type i interferon (ifn) response by fmdv. however, the underlying mechanisms remain unclear. here we demonstrate that fmdv lb(pro), a shorter form of l(pro), has deubiquitinating activity. sequence alignment and structural bioinformatics analyses revealed that the catalyt ...201121307201
identification and characterization of three novel small interference rnas that effectively down-regulate the isolated nucleocapsid gene expression of sars coronavirus.nucleocapsid (n) protein of severe acute respiratory syndrome-associated coronavirus (sars-cov) is a major pathological determinant in the host that may cause host cell apoptosis, upregulate the proinflammatory cytokine production, and block innate immune responses. therefore, n gene has long been thought an ideal target for the design of small interference rna (sirna). sirna is a class of small non-coding rnas with a size of 21-25nt that functions post-transcriptionally to block targeted gene e ...201121317844
down-regulation of granulocyte-macrophage colony-stimulating factor by 3c-like proteinase in transfected a549 human lung carcinoma cells.severe acute respiratory syndrome (sars) is a severe respiratory illness caused by a novel virus, the sars coronavirus (sars-cov). 3c-like protease (3clpro) of sars-cov plays a role in processing viral polypeptide precursors and is responsible of viral maturation. however, the function of 3clpro in host cells remains unknown. this study investigated how the 3clpro affected the secretion of cytokines in the gene-transfected cells.201121324206
distinct severe acute respiratory syndrome coronavirus-induced acute lung injury pathways in two different nonhuman primate species.acute lung injury (ali) and acute respiratory distress syndrome (ards), caused by influenza a virus h5n1 and severe acute respiratory syndrome coronavirus (sars-cov), supposedly depend on activation of the oxidative-stress machinery that is coupled with innate immunity, resulting in a strong proinflammatory host response. inflammatory cytokines, such as interleukin 1ß (il-1ß), il-8, and il-6, play a major role in mediating and amplifying ali/ards by stimulating chemotaxis and activation of neutr ...201121325418
distinct severe acute respiratory syndrome coronavirus-induced acute lung injury pathways in two different nonhuman primate species.acute lung injury (ali) and acute respiratory distress syndrome (ards), caused by influenza a virus h5n1 and severe acute respiratory syndrome coronavirus (sars-cov), supposedly depend on activation of the oxidative-stress machinery that is coupled with innate immunity, resulting in a strong proinflammatory host response. inflammatory cytokines, such as interleukin 1ß (il-1ß), il-8, and il-6, play a major role in mediating and amplifying ali/ards by stimulating chemotaxis and activation of neutr ...201121325418
evidence that tmprss2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response.the spike (s) protein of the severe acute respiratory syndrome coronavirus (sars-cov) can be proteolytically activated by cathepsins b and l upon viral uptake into target cell endosomes. in contrast, it is largely unknown whether host cell proteases located in the secretory pathway of infected cells and/or on the surface of target cells can cleave sars s. we along with others could previously show that the type ii transmembrane protease tmprss2 activates the influenza virus hemagglutinin and the ...201121325420
benefits of random-priming: exhaustive survey of a cdna library from lung tissue of a sars patient.the severe acute respiratory syndrome (sars) leads to severe injury in the lungs with multiple factors, though the pathogenesis is still largely unclear. this paper describes the particular analyses of the transcriptome of human lung tissue that was infected by sars-associated coronavirus (sars-cov). random primers were used to produce ests from total rna samples of the lung tissue. the result showed a high diversity of the transcripts, covering much of the human genome, including loci which do ...201121328370
validation of assays to monitor immune responses in the syrian golden hamster (mesocricetus auratus).the syrian golden hamster (mesocricetus auratus) is a valuable but under-utilized animal model for studies of human viral pathogens such as bunyaviruses, arenaviruses, flaviviruses, henipaviruses, and sars-coronavirus. a lack of suitable reagents and specific assays for monitoring host responses has limited the use of this animal model to clinical observations, pathology and humoral immune responses. the objective of this study was to establish and validate assays to monitor host immune response ...201121334343
validation of assays to monitor immune responses in the syrian golden hamster (mesocricetus auratus).the syrian golden hamster (mesocricetus auratus) is a valuable but under-utilized animal model for studies of human viral pathogens such as bunyaviruses, arenaviruses, flaviviruses, henipaviruses, and sars-coronavirus. a lack of suitable reagents and specific assays for monitoring host responses has limited the use of this animal model to clinical observations, pathology and humoral immune responses. the objective of this study was to establish and validate assays to monitor host immune response ...201121334343
inhibition of severe acute respiratory syndrome coronavirus replication in a lethal sars-cov balb/c mouse model by stinging nettle lectin, urtica dioica agglutinin.urtica dioica agglutinin (uda) is a small plant monomeric lectin, 8.7 kda in size, with an n-acetylglucosamine specificity that inhibits viruses from nidovirales in vitro. in the current study, we first examined the efficacy of uda on the replication of different sars-cov strains in vero 76 cells. uda inhibited virus replication in a dose-dependent manner and reduced virus yields of the urbani strain by 90% at 1.1 ± 0.4 µg/ml in vero 76 cells. then, uda was tested for efficacy in a lethal sars-c ...201121338626
emodin inhibits current through sars-associated coronavirus 3a protein.the open-reading-frame 3a of sars coronavirus (sars-cov) had been demonstrated previously to form a cation-selective channel that may become expressed in the infected cell and is then involved in virus release. drugs that inhibit the ion channel formed by the 3a protein can be expected to inhibit virus release, and would be a source for the development of novel therapeutic agents. here we demonstrate that emodin can inhibit the 3a ion channel of coronavirus sars-cov and hcov-oc43 as well as viru ...201121356245
plp2 of mouse hepatitis virus a59 (mhv-a59) targets tbk1 to negatively regulate cellular type i interferon signaling pathway.coronaviruses such as severe acute respiratory syndrome (sars) coronavirus (scov) and mouse hepatitis virus a59 (mhv-a59) have evolved strategies to disable the innate immune system for productive replication and spread of infection. we have previously shown that papain-like protease domain 2 (plp2), a catalytic domain of the nonstructural protein 3 (nsp3) of mhv-a59, encodes a deubiquitinase (dub) and inactivates ifn regulatory factor 3 (irf3) thereby the type i interferon (ifn) response.201121364999
longitudinal profiles of immunoglobulin g antibodies against severe acute respiratory syndrome coronavirus components and neutralizing activities in recovered patients.immunological memory is the basis for vaccination. currently, the longitudinal profiles of antibody responses in recovered severe acute respiratory syndrome (sars) patients have not been fully characterized.201121366405
the solution structure of coronaviral stem-loop 2 (sl2) reveals a canonical cuyg tetraloop fold.the transcription and replication of the severe acute respiratory syndrome (sars) coronavirus (sars-cov) is regulated by specific viral genome sequences within 5'- and 3'-untranslated regions (5'-utr and 3'-utr). here we report the solution structure of 5'-utr derived stem-loop 2 (sl2) of sars-cov determined by nmr spectroscopy. the highly conserved pentaloop of sl2 is stacked on 5-bp stem and adopts a canonical cuyg tetraloop fold with the 3' nucleotide (u51) flipped out of the stack. the signi ...201121382373
dynamically-driven inactivation of the catalytic machinery of the sars 3c-like protease by the n214a mutation on the extra domain.despite utilizing the same chymotrypsin fold to host the catalytic machinery, coronavirus 3c-like proteases (3clpro) noticeably differ from picornavirus 3c proteases in acquiring an extra helical domain in evolution. previously, the extra domain was demonstrated to regulate the catalysis of the sars-cov 3clpro by controlling its dimerization. here, we studied n214a, another mutant with only a doubled dissociation constant but significantly abolished activity. unexpectedly, n214a still adopts the ...201121390281
crystallization and diffraction analysis of the sars coronavirus nsp10-nsp16 complex.to date, the sars coronavirus is the only known highly pathogenic human coronavirus. in 2003, it was responsible for a large outbreak associated with a 10% fatality rate. this positive rna virus encodes a large replicase polyprotein made up of 16 gene products (nsp1-16), amongst which two methyltransferases, nsp14 and nsp16, are involved in viral mrna cap formation. the crystal structure of nsp16 is unknown. nsp16 is an rna-cap adomet-dependent (nucleoside-2'-o-)-methyltransferase that is only a ...201121393853
a virus-binding hot spot on human angiotensin-converting enzyme 2 is critical for binding of two different coronaviruses.how viruses evolve to select their receptor proteins for host cell entry is puzzling. we recently determined the crystal structures of nl63 coronavirus (nl63-cov) and sars coronavirus (sars-cov) receptor-binding domains (rbds), each complexed with their common receptor, human angiotensin-converting enzyme 2 (hace2), and proposed the existence of a virus-binding hot spot on hace2. here we investigated the function of this hypothetical hot spot using structure-guided biochemical and functional ass ...201121411533
development and rna-synthesizing activity of coronavirus replication structures in the absence of protein synthesis.the rna replication and transcription complex of coronaviruses is associated with an elaborate reticulovesicular network (rvn) of modified endoplasmic reticulum. using cycloheximide and puromycin, we have studied the effect of translation inhibition on the rna synthesis of severe acute respiratory syndrome coronavirus and mouse hepatitis virus. both inhibitors prevented the usual exponential increase in viral rna synthesis, with immunofluorescence and electron microscopy indicating that rvn deve ...201121430047
an optimal cis-replication stem-loop iv in the 5' untranslated region of the mouse coronavirus genome extends 16 nucleotides into open reading frame 1.the 288-nucleotide (nt) 3' untranslated region (utr) in the genome of the bovine coronavirus (bcov) and 339-nt 3' utr in the severe acute respiratory syndrome (sars) coronavirus (scov) can each replace the 301-nt 3' utr in the mouse hepatitis coronavirus (mhv) for virus replication, thus demonstrating common 3' cis-replication signals. here, we show that replacing the 209-nt mhv 5' utr with the ~63%-sequence-identical 210-nt bcov 5' utr by reverse genetics does not yield viable virus, suggesting ...201121430057
improved prediction of mhc class i binders/non-binders peptides through artificial neural network using variable learning rate: sars corona virus, a case study.fundamental step of an adaptive immune response to pathogen or vaccine is the binding of short peptides (also called epitopes) to major histocompatibility complex (mhc) molecules. the various prediction algorithms are being used to capture the mhc peptide binding preference, allowing the rapid scan of entire pathogen proteomes for peptide likely to bind mhc, saving the cost, effort, and time. however, the number of known binders/non-binders (bnb) to a specific mhc molecule is limited in many cas ...201121431562
viral infections in workers in hospital and research laboratory settings: a comparative review of infection modes and respective biosafety aspects.to compare modes and sources of infection and clinical and biosafety aspects of accidental viral infections in hospital workers and research laboratory staff reported in scientific articles.201121497126
subcellular location and topology of severe acute respiratory syndrome coronavirus envelope protein.severe acute respiratory syndrome (sars) coronavirus (cov) envelope (e) protein is a transmembrane protein. several subcellular locations and topological conformations of e protein have been proposed. to identify the correct ones, polyclonal and monoclonal antibodies specific for the amino or the carboxy terminus of e protein, respectively, were generated. e protein was mainly found in the endoplasmic reticulum-golgi intermediate compartment (ergic) of cells transfected with a plasmid encoding e ...201121524776
the adp-ribose-1"-monophosphatase domains of sars-coronavirus and human coronavirus 229e mediate resistance to antiviral interferon responses.several plus strand rna viruses encode proteins containing macrodomains. these domains possess adp-ribose-1-phosphatase (adrp) activity and/or bind poly(adp-ribose), poly(a), or poly(g). the relevance of these activities in the viral life cycle has not yet been resolved. here, we report that genetically engineered mutants of sars-coronavirus (sars-cov) and human coronavirus 229e (hcov-229e) expressing adrp-deficient macrodomains displayed an increased sensitivity to the antiviral effect of inter ...201121525212
comparative pathogenesis of three human and zoonotic sars-cov strains in cynomolgus macaques.the severe acute respiratory syndrome (sars) epidemic was characterized by increased pathogenicity in the elderly due to an early exacerbated innate host response. sars-cov is a zoonotic pathogen that entered the human population through an intermediate host like the palm civet. to prevent future introductions of zoonotic sars-cov strains and subsequent transmission into the human population, heterologous disease models are needed to test the efficacy of vaccines and therapeutics against both la ...201121533129
activation and maturation of sars-cov main protease.the worldwide outbreak of the severe acute respiratory syndrome (sars) in 2003 was due to the transmission of sars coronavirus (sars-cov). the main protease (m(pro)) of sars-cov is essential for the viral life cycle, and is considered to be an attractive target of anti-sars drug development. as a key enzyme for proteolytic processing of viral polyproteins to produce functional non-structure proteins, m(pro) is first auto-cleaved out of polyproteins. the monomeric form of m(pro) is enzymatically ...201121533772
locapep: localization of epitopes on protein surfaces using peptides from phage display libraries.the use of peptides from a phage display library selected by binding to a given antibody is a widespread technique to probe epitopes of antigenic proteins. however, the identification of interaction sites mimicked by these peptides on the antigen surface is a difficult task. locapep is a computer program developed to localize epitopes using a new clusters algorithm that focuses on protein surface properties. the program is constructed with the aim of providing a flexible computational tool for p ...201121539309
interference of ribosomal frameshifting by antisense peptide nucleic acids suppresses sars coronavirus replication.the programmed -1 ribosomal frameshifting (-1 prf) utilized by eukaryotic rna viruses plays a crucial role for the controlled, limited synthesis of viral rna replicase polyproteins required for genome replication. the viral rna replicase polyproteins of severe acute respiratory syndrome coronavirus (sars-cov) are encoded by the two overlapping open reading frames 1a and 1b, which are connected by a -1 prf signal. we evaluated the antiviral effects of antisense peptide nucleic acids (pnas) target ...201121549154
using a pan-viral microarray assay (virochip) to screen clinical samples for viral pathogens.the diagnosis of viral causes of many infectious diseases is difficult due to the inherent sequence diversity of viruses as well as the ongoing emergence of novel viral pathogens, such as sars coronavirus and 2009 pandemic h1n1 influenza virus, that are not detectable by traditional methods. to address these challenges, we have previously developed and validated a pan-viral microarray platform called the virochip with the capacity to detect all known viruses as well as novel variants on the basi ...201121559002
sars-cov accessory protein 3b induces ap-1 transcriptional activity through activation of jnk and erk pathways.the outbreak of severe acute respiratory syndrome (sars) in 2003 in china, characterized by atypical pneumonia, was associated with the emergence of a novel coronavirus named severe acute respiratory syndrome coronavirus (sars-cov). eight accessory proteins of sars coronavirus were the suspected players in the pathogenesis of the virus. among them, protein 3b localizes to the nucleus and behaves as an interferon antagonist by inhibiting irf3 activation. however, the effect of 3b on the activity ...201121561061
angiotensin-converting enzyme 2 ectodomain shedding cleavage-site identification: determinants and constraints.adam17, also known as tumor necrosis factor α-converting enzyme, is involved in the ectodomain shedding of many integral membrane proteins. we have previously reported that adam17 is able to mediate the cleavage secretion of the ectodomain of human angiotensin-converting enzyme 2 (ace2), a functional receptor for the severe acute respiratory syndrome coronavirus. in this study, we demonstrate that purified recombinant human adam17 is able to cleave a 20-amino acid peptide mimetic corresponding t ...201121563828
lack of peripheral memory b cell responses in recovered patients with severe acute respiratory syndrome: a six-year follow-up study.six years have passed since the outbreak of severe acute respiratory syndrome (sars). previous studies indicated that specific abs to sars-related coronavirus (sars-cov) waned over time in recovered sars patients. it is critical to find out whether a potential anamnestic response, as seen with other viral infections, exists to protect a person from reinfection in case of another sars outbreak. recovered sars patients were followed up to 6 y to estimate the longevity of specific ab. the specific ...201121576510
protocol for recombinant rbd-based sars vaccines: protein preparation, animal vaccination and neutralization detection.based on their safety profile and ability to induce potent immune responses against infections, subunit vaccines have been used as candidates for a wide variety of pathogens (1-3). since the mammalian cell system is capable of post-translational modification, thus forming properly folded and glycosylated proteins, recombinant proteins expressed in mammalian cells have shown the greatest potential to maintain high antigenicity and immunogenicity (4-6). although no new cases of sars have been repo ...201121587153
identification of rna pseudoknot-binding ligand that inhibits the -1 ribosomal frameshifting of sars-coronavirus by structure-based virtual screening.programmed -1 ribosomal frameshifting (-1 rf) is an essential regulating mechanism of translation used by sars-cov (severe acute respiratory syndrome coronavirus) to synthesize the key replicative proteins encoded by two overlapping open reading frames. the integrity of rna pseudoknot stability and structure in -1 rf site is an important for efficient -1 rf. thus, small molecules interacting with high affinity and selectivity with the rna pseudoknot in -1 rf site of sars-cov (sars-pseudoknot), w ...201121591761
fully human monoclonal antibody directed to proteolytic cleavage site in severe acute respiratory syndrome (sars) coronavirus s protein neutralizes the virus in a rhesus macaque sars model.background. there is still no effective method to prevent or treat severe acute respiratory syndrome (sars), which is caused by sars coronavirus (cov). in the present study, we evaluated the efficacy of a fully human monoclonal antibody capable of neutralizing sars-cov in vitro in a rhesus macaque model of sars. methods. the antibody 5h10 was obtained by vaccination of km mice bearing human immunoglobulin genes with escherichiacoli-producing recombinant peptide containing the dominant epitope of ...201121592986
fully human monoclonal antibody directed to proteolytic cleavage site in severe acute respiratory syndrome (sars) coronavirus s protein neutralizes the virus in a rhesus macaque sars model.background. there is still no effective method to prevent or treat severe acute respiratory syndrome (sars), which is caused by sars coronavirus (cov). in the present study, we evaluated the efficacy of a fully human monoclonal antibody capable of neutralizing sars-cov in vitro in a rhesus macaque model of sars. methods. the antibody 5h10 was obtained by vaccination of km mice bearing human immunoglobulin genes with escherichiacoli-producing recombinant peptide containing the dominant epitope of ...201121592986
inhibitors of sars-3cl(pro): virtual screening, biological evaluation, and molecular dynamics simulation studies.sars-cov from the coronaviridae family has been identified as the etiological agent of severe acute respiratory syndrome (sars), a highly contagious upper respiratory disease that reached epidemic status in 2002. sars-3cl(pro), a cysteine protease indispensible to the viral life cycle, has been identified as one of the key therapeutic targets against sars. a combined ligand and structure-based virtual screening was carried out against the asinex platinum collection. multiple low micromolar inhib ...201121604711
virucidal activity of a scorpion venom peptide variant mucroporin-m1 against measles, sars-cov and influenza h5n1 viruses.outbreaks of sars-cov, influenza a (h5n1, h1n1) and measles viruses in recent years have raised serious concerns about the measures available to control emerging and re-emerging infectious viral diseases. effective antiviral agents are lacking that specifically target rna viruses such as measles, sars-cov and influenza h5n1 viruses, and available vaccinations have demonstrated variable efficacy. therefore, the development of novel antiviral agents is needed to close the vaccination gap and silen ...201121620914
sars-cov 9b protein diffuses into nucleus, undergoes active crm1 mediated nucleocytoplasmic export and triggers apoptosis when retained in the nucleus.background: 9b is an accessory protein of the sars-cov. it is a small protein of 98 amino acids and its structure has been solved recently. 9b is known to localize in the extra-nuclear region and has been postulated to possess a nuclear export signal (nes), however the role of nes in 9b functioning is not well understood. principal findings/methodology: in this report, we demonstrate that 9b in the absence of any nuclear localization signal (nls) enters the nucleus by passive transport. using va ...201121637748
crystal structure and functional analysis of the sars-coronavirus rna cap 2'-o-methyltransferase nsp10/nsp16 complex.cellular and viral s-adenosylmethionine-dependent methyltransferases are involved in many regulated processes such as metabolism, detoxification, signal transduction, chromatin remodeling, nucleic acid processing, and mrna capping. the severe acute respiratory syndrome coronavirus nsp16 protein is a s-adenosylmethionine-dependent (nucleoside-2'-o)-methyltransferase only active in the presence of its activating partner nsp10. we report the nsp10/nsp16 complex structure at 2.0 å resolution, which ...201121637813
engineering t cells specific for a dominant sars coronavirus cd8 t cell epitope.severe acute respiratory syndrome (sars) is a highly contagious and life threatening disease, with a fatality rate of almost 10%. the etiologic agent is a novel coronavirus, sars-cov, with animal reservoirs found in bats and other wild animals and thus the possibility of re-emergence. in this study, we first investigated whether sars-specific memory t cells persist in sars-recovered individuals 6 years post-infection, demonstrating that recovered patients still possess polyfunctional sars-specif ...201121813600
on the treatment of airline travelers in mathematical models.the global spread of infectious diseases is facilitated by the ability of infected humans to travel thousands of miles in short time spans, rapidly transporting pathogens to distant locations. mathematical models of the actual and potential spread of specific pathogens can assist public health planning in the case of such an event. models should generally be parsimonious, but must consider all potentially important components of the system to the greatest extent possible. we demonstrate and disc ...201121799782
a conserved rna pseudoknot in a putative molecular switch domain of the 3'-untranslated region of coronaviruses is only marginally stable.the 3'-untranslated region (utr) of the group 2 coronavirus mouse hepatitis virus (mhv) genome contains a predicted bulged stem-loop (designated p0ab), a conserved cis-acting pseudoknot (pk), and a more distal stem-loop (designated p2). base-pairing to create the pseudoknot-forming stem (p1(pk)) is mutually exclusive with formation of stem p0a at the base of the bulged stem-loop; as a result, the two structures cannot be present simultaneously. herein, we use thermodynamic methods to evaluate th ...201121799029
under-three minute pcr: probing the limits of fast amplification.nucleic acid amplification is enormously useful to the biotechnology and clinical diagnostic communities; however, to date point-of-use pcr has been hindered by thermal cycling architectures and protocols that do not allow for near-instantaneous results. in this work we demonstrate pcr amplification of synthetic sars respiratory pathogenic targets and bacterial genomic dna in less than three minutes in a hardware configuration utilizing convenient sample loading and disposal. instead of sample m ...201121796289
expression, crystallization and preliminary crystallographic study of the c-terminal half of nsp2 from sars coronavirus.sars coronavirus (sars-cov) is the aetiological agent of the highly infectious severe acute respiratory syndrome (sars). to gain a better understanding of sars-cov replication and transcription proteins, a preliminary x-ray crystallographic study of the c-terminal domain of sars-cov nonstructural protein 2 (nsp2) is reported here. the c-terminal domain of sars-cov nsp2 was cloned, overexpressed, purified and crystallized using polyethylene glycol 5000 monomethyl ether as the precipitant; the cry ...201121795795
anti-sars-cov spike antibodies trigger infection of human immune cell via a ph- and cysteine protease-independent fc{gamma}r pathway.public health measures successfully contained outbreaks of the severe acute respiratory syndrome coronavirus (sars-cov). however, the precursor of the sars-cov remains in its natural bat reservoir and re-emergence of a human-adapted sars-like coronavirus remains a plausible public health concern. vaccination is a major strategy for containing resurgence of sars in humans and a number of vaccine candidates have been tested in experimental animal models. we previously reported that antibody elicit ...201121775467
emerging theme: cellular pdz proteins as common targets of pathogenic viruses.more than a decade ago three viral oncoproteins - adenovirus type 9 e4-orf1, human t-lymphotropic virus type 1 tax, and high-risk human papillomavirus e6 - were found to encode a related carboxyl-terminal pdz domain-binding motif (pbm) that mediates interactions with a select group of cellular pdz proteins. recent studies have shown that many other viruses also encode pbm-containing proteins that bind to cellular pdz proteins. interestingly, these recently recognized viruses include not only som ...201121775458
recent developments in anti-severe acute respiratory syndrome coronavirus chemotherapy.severe acute respiratory syndrome coronavirus (sars-cov) emerged in early 2003 to cause a very severe acute respiratory syndrome, which eventually resulted in a 10% case-fatality rate. owing to excellent public health measures that isolated focus cases and their contacts, and the use of supportive therapies, the epidemic was suppressed to the point that further cases have not appeared since 2005. however, despite intensive research since then (over 3500 publications), it remains an untreatable d ...201121765859
sars-coronavirus ancestor's foot-prints in south-east asian bat colonies and the refuge theory.one of the great challenges in the ecology of infectious diseases is to understand what drives the emergence of new pathogens including the relationship between viruses and their hosts. in the case of the emergence of severeacute respiratory syndrome coronavirus (sars-cov), several studies have shown coronavirus diversity in bats as well as the existence of sars-cov infection in apparently healthy bats, suggesting that bats may be a crucial host in the genesis of this disease. to elucidate the b ...201121763784
sars-coronavirus ancestor's foot-prints in south-east asian bat colonies and the refuge theory.one of the great challenges in the ecology of infectious diseases is to understand what drives the emergence of new pathogens including the relationship between viruses and their hosts. in the case of the emergence of severeacute respiratory syndrome coronavirus (sars-cov), several studies have shown coronavirus diversity in bats as well as the existence of sars-cov infection in apparently healthy bats, suggesting that bats may be a crucial host in the genesis of this disease. to elucidate the b ...201121763784
chimeric severe acute respiratory syndrome coronavirus (sars-cov) s glycoprotein and influenza matrix 1 efficiently form virus-like particles (vlps) that protect mice against challenge with sars-cov.sars-cov was the cause of the global pandemic in 2003 that infected over 8000 people in 8 months. vaccines against sars are still not available. we developed a novel method to produce high levels of a recombinant sars virus-like particles (vlps) vaccine containing the sars spike (s) protein and the influenza m1 protein using the baculovirus insect cell expression system. these chimeric sars vlps have a similar size and morphology to the wild type sars-cov. we tested the immunogenicity and protec ...201121762752
cyclosporin a inhibits the replication of diverse coronaviruses.low micromolar, non-cytotoxic concentrations of cyclosporin a (csa) strongly affected the replication of sars-coronavirus (sars-cov), human coronavirus 229e, and mouse hepatitis virus in cell culture, as was evident from the strong inhibition of green fluorescent protein reporter gene expression and up to 4 log reduced progeny titres. upon high-multiplicity infection, csa treatment rendered sars-cov rna and protein synthesis almost undetectable, suggesting an early block in replication. sirna-me ...201121752960
the immune responses of hla-a*0201 restricted sars-cov s peptide-specific cd8(+) t cells are augmented in varying degrees by cpg odn, polyi:c and r848.the induction of antigen specific memory cd8(+) t cells in vivo is very important to new vaccines against infectious diseases. in the present study, we aimed to evaluate the immune responses of peptide-specific cd8(+) t cells induced by hla-a*0201 restricted severe acute respiratory syndrome-associated coronavirus (sars-cov) s epitopes plus cpg oligodeoxynucleotide (cpg odn), polyi:c and r848 as adjuvants. furthermore, the generation, distribution and phenotype of long-lasting peptide-specific m ...201121745520
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