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immune responses against severe acute respiratory syndrome coronavirus induced by virus-like particles in mice.virus-like particles (vlps) represent a promising vaccine against severe acute respiratory syndrome coronavirus (sars cov). in this study, recombinant baculovirus vacs and vacme were constructed to express the s protein and the m and e proteins of sars cov, respectively. electron microscope analysis demonstrated the formation of vlps in vacme and vacs coinfected insect cells. mice immunized four times with vlps developed high antibody titres against sars cov. in addition, vlps elicited cell-medi ...200717680799
severe acute respiratory syndrome coronavirus gene 7 products contribute to virus-induced apoptosis.the proteins encoded by gene 7 of the severe acute respiratory syndrome coronavirus (sars-cov) have been demonstrated to have proapoptotic activity when expressed from cdna but appear to be dispensable for virus replication. recombinant sars-covs bearing deletions in gene 7 were used to assess the contribution of gene 7 to virus replication and apoptosis in several transformed cell lines, as well as to replication and pathogenesis in golden syrian hamsters. deletion of gene 7 had no effect on sa ...200717686858
severe acute respiratory syndrome coronavirus gene 7 products contribute to virus-induced apoptosis.the proteins encoded by gene 7 of the severe acute respiratory syndrome coronavirus (sars-cov) have been demonstrated to have proapoptotic activity when expressed from cdna but appear to be dispensable for virus replication. recombinant sars-covs bearing deletions in gene 7 were used to assess the contribution of gene 7 to virus replication and apoptosis in several transformed cell lines, as well as to replication and pathogenesis in golden syrian hamsters. deletion of gene 7 had no effect on sa ...200717686858
selectivity in isg15 and ubiquitin recognition by the sars coronavirus papain-like protease.the severe acute respiratory syndrome coronavirus papain-like protease (sars-cov plpro) carries out n-terminal processing of the viral replicase polyprotein, and also exhibits lys48-linked polyubiquitin chain debranching and isg15 precursor processing activities in vitro. here, we used sds-page and fluorescence-based assays to demonstrate that isg15 derivatives are the preferred substrates for the deubiquitinating activity of the plpro. with k(cat)/k(m) of 602,000 m(-1)s(-1), plpro hydrolyzes is ...200717692280
human cd4(+) memory t-lymphocyte responses to sars coronavirus infection.little is known about cd4(+) t-cell immunity to the severe acute respiratory syndrome (sars) coronavirus. in two sars patients, we examined the memory cd4(+) t-cell responses to peptides derived from sars coronavirus structural proteins. we generated cd4(+) t-cell lines to 3 peptides from the spike (s) protein and defined their hla restriction. in one patient, the predominant memory cd4(+) t-cell response was directed against an epitope outside the s protein receptor-binding domain. in both pati ...200717692881
coronavirus non-structural protein 1 is a major pathogenicity factor: implications for the rational design of coronavirus vaccines.attenuated viral vaccines can be generated by targeting essential pathogenicity factors. we report here the rational design of an attenuated recombinant coronavirus vaccine based on a deletion in the coding sequence of the non-structural protein 1 (nsp1). in cell culture, nsp1 of mouse hepatitis virus (mhv), like its sars-coronavirus homolog, strongly reduced cellular gene expression. the effect of nsp1 on mhv replication in vitro and in vivo was analyzed using a recombinant mhv encoding a delet ...200717696607
functional genomics highlights differential induction of antiviral pathways in the lungs of sars-cov-infected macaques.the pathogenesis of severe acute respiratory syndrome coronavirus (sars-cov) is likely mediated by disproportional immune responses and the ability of the virus to circumvent innate immunity. using functional genomics, we analyzed early host responses to sars-cov infection in the lungs of adolescent cynomolgus macaques (macaca fascicularis) that show lung pathology similar to that observed in human adults with sars. analysis of gene signatures revealed induction of a strong innate immune respons ...200717696609
functional genomics highlights differential induction of antiviral pathways in the lungs of sars-cov-infected macaques.the pathogenesis of severe acute respiratory syndrome coronavirus (sars-cov) is likely mediated by disproportional immune responses and the ability of the virus to circumvent innate immunity. using functional genomics, we analyzed early host responses to sars-cov infection in the lungs of adolescent cynomolgus macaques (macaca fascicularis) that show lung pathology similar to that observed in human adults with sars. analysis of gene signatures revealed induction of a strong innate immune respons ...200717696609
paper of the year 2006: award to pamela hamill. 200717696769
the membrane protein of sars-cov suppresses nf-kappab activation.severe acute respiratory syndrome coronavirus (sars-cov) infects many organs, such as lung, liver, and immune organs and causes life-threatening atypical pneumonia, sars causes high morbidity and mortality rates. the molecular mechanism of sars pathogenesis remains elusive. inflammatory stimuli can activate ikappab kinase (ikk) signalsome and subsequently the nuclear factor kappa b (nf-kappab), which influences gene expression of cyclooxygenase-2 (cox-2) along with other transcription factors. i ...200717705188
priming with sars cov s dna and boosting with sars cov s epitopes specific for cd4+ and cd8+ t cells promote cellular immune responses.cellular immune response plays an important role in antiviral immunity. in our previous study, immunization of mice with severe acute respiratory syndrome coronavirus (sars cov) spike (s) dna vaccine could induce both humoral and cellular immunity in response to a pool of entire overlapping s peptides. identification of functional dominant epitopes in sars cov s protein for t cells is crucial for further understanding of cellular immune responses elicited by sars cov s dna vaccine. in present st ...200717709158
regulation of cell death during infection by the severe acute respiratory syndrome coronavirus and other coronaviruses.both apoptosis and necrosis have been observed in cells infected by various coronaviruses, suggesting that the regulation of cell death is important for viral replication and/or pathogenesis. expeditious research on the severe acute respiratory syndrome (sars) coronavirus, one of the latest discovered coronaviruses that infect humans, has provided valuable insights into the molecular aspects of cell-death regulation during infection. apoptosis was observed in vitro, while both apoptosis and necr ...200717714515
severe acute respiratory syndrome coronavirus evades antiviral signaling: role of nsp1 and rational design of an attenuated strain.the severe acute respiratory syndrome (sars) epidemic was caused by the spread of a previously unrecognized infectious agent, the sars-associated coronavirus (sars-cov). here we show that sars-cov could inhibit both virus- and interferon (ifn)-dependent signaling, two key steps of the antiviral response. we mapped a strong inhibitory activity to sars-cov nonstructural protein 1 (nsp1) and show that expression of nsp1 significantly inhibited the activation of all three virus-dependent signaling p ...200717715225
specific asparagine-linked glycosylation sites are critical for dc-sign- and l-sign-mediated severe acute respiratory syndrome coronavirus entry.severe acute respiratory syndrome (sars) is caused by a newly emerged coronavirus (cov) designated sars-cov. the virus utilizes angiotensin-converting enzyme 2 (ace2) as the primary receptor. although the idea is less clear and somewhat controversial, sars-cov is thought to use c-type lectins dc-sign and/or l-sign (collectively referred to as dc/l-sign) as alternative receptors or as enhancer factors that facilitate ace2-mediated virus infection. in this study, the function of dc/l-sign in sars- ...200717715238
structure-based design and synthesis of highly potent sars-cov 3cl protease inhibitors. 200717722121
nuclear magnetic resonance structure of the n-terminal domain of nonstructural protein 3 from the severe acute respiratory syndrome coronavirus.this paper describes the structure determination of nsp3a, the n-terminal domain of the severe acute respiratory syndrome coronavirus (sars-cov) nonstructural protein 3. nsp3a exhibits a ubiquitin-like globular fold of residues 1 to 112 and a flexibly extended glutamic acid-rich domain of residues 113 to 183. in addition to the four beta-strands and two alpha-helices that are common to ubiquitin-like folds, the globular domain of nsp3a contains two short helices representing a feature that has n ...200717728234
regulation of irf-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus.severe acute respiratory syndrome coronavirus (sars-cov) is a novel coronavirus that causes a highly contagious respiratory disease, sars, with significant mortality. although factors contributing to the highly pathogenic nature of sars-cov remain poorly understood, it has been reported that sars-cov infection does not induce type i interferons (ifns) in cell culture. however, it is uncertain whether sars-cov evades host detection or has evolved mechanisms to counteract innate host defenses. we ...200717761676
[immunisation strategies for the management of severe acute respiratory syndrome (sars)].most patients with severe acute respiratory syndrome (sars) develop antibodies against the sars coronavirus and survive the infection. this suggests that active or passive immunisation might be an effective option in preventing or treating sars. therefore, the development of sars vaccination strategies belongs to the most important targets of sars research. the present study analyses data-bases for the current knowledge on vaccination strategies. both, passive and active immunisation protocols a ...200717763311
5'-o-masked 2'-deoxyadenosine analogues as lead compounds for hepatitis c virus (hcv) therapeutic agents.on the basis of our previous study on antiviral agents against the severe acute respiratory syndrome (sars) coronavirus, a series of nucleoside analogues whose 5'-hydroxyl groups are masked by various protective groups such as carboxylate, sulfonate, and ether were synthesized and evaluated to develop novel anti-hepatitis c virus (hcv) agents. among these, several 5'-o-masked analogues of 6-chloropurine-2'-deoxyriboside (e.g., 5'-o-benzoyl, 5'-o-p-methoxybenzoyl, and 5'-o-benzyl analogues) were ...200717766124
conductance and amantadine binding of a pore formed by a lysine-flanked transmembrane domain of sars coronavirus envelope protein.the coronavirus responsible for the severe acute respiratory syndrome (sars-cov) contains a small envelope protein, e, with putative involvement in host cell apoptosis and virus morphogenesis. it has been suggested that e protein can form a membrane destabilizing transmembrane (tm) hairpin, or homooligomerize to form a regular tm alpha-helical bundle. we have shown previously that the topology of the alpha-helical putative tm domain of e protein (etm), flanked by two lysine residues at c and n t ...200717766393
prevention and control of emerging infections: a challenge for the 3rd millennium.in the last 30 years, several emerging infections due to novel viruses have been identified, from haemorrhagic fever viruses to hiv, from the sars-coronavirus to avian influenza viruses. ecological and genetic changes are important determinants of the emergence of new viral infections, driving to an increase of r0 (the basic reproductive number) through increasing the probability of transmission. the current h5n1 epidemic may be considered a prepandemic paradigm that needs thorough investigation ...200717802926
rapid multiplex nested pcr for detection of respiratory viruses.respiratory tract infections can be caused by a heterogeneous group of viruses and bacteria that produce similar clinical presentations. specific diagnosis therefore relies on laboratory investigation. this study developed and evaluated five groups of multiplex nested pcr assays that could simultaneously detect 21 different respiratory pathogens: influenza a virus (h1n1, h3n2, and h5n1); influenza b virus; parainfluenza virus types 1, 2, 3, 4a, and 4b; respiratory syncytial virus a and b; human ...200717804659
[three-dimensional structure prediction of the viral protein in the development of anti sars drugs]. 200717824221
bats as a continuing source of emerging infections in humans.amongst the 60 viral species reported to be associated with bats, 59 are rna viruses, which are potentially important in the generation of emerging and re-emerging infections in humans. the prime examples of these are the lyssaviruses and henipavirus. the transmission of nipah, hendra and perhaps sars coronavirus and ebola virus to humans may involve intermediate amplification hosts such as pigs, horses, civets and primates, respectively. understanding of the natural reservoir or introductory ho ...200717042030
genetic distance of sars coronavirus from the recent natural case.phylogenetic analysis of sars coronavirus isolates based on the spike gene and protein sequence using neighbor-joining, maximum likelihood and bayesian inference methods indicated that a recent human sars-cov isolate was closer to some human sars-cov isolates from earlier epidemic phase than to the sars-cov-like viruses isolated from wild animals during previous epidemic phase. a reasonable judgment based on phylogenetic relationship and sequence variations it is likely that the recent human sar ...200717141432
molecular pathogenesis of severe acute respiratory syndrome.the global outbreak in 2002-2003 of severe acute respiratory syndrome (sars) posed a serious threat to public health and had a significant impact on socioeconomic stability. although the global outbreak of sars has been contained, there are serious concerns over its re-emergence and bioterrorism potential, and up to date, no specific treatment exists for this disease. here we review the progress of studies on the pathogenesis of the disease, in particular, studies on the molecular level.200717142081
reversible unfolding of the severe acute respiratory syndrome coronavirus main protease in guanidinium chloride.chemical denaturant sensitivity of the dimeric main protease from severe acute respiratory syndrome (sars) coronavirus to guanidinium chloride was examined in terms of fluorescence spectroscopy, circular dichroism, analytical ultracentrifuge, and enzyme activity change. the dimeric enzyme dissociated at guanidinium chloride concentration of <0.4 m, at which the enzymatic activity loss showed close correlation with the subunit dissociation. further increase in guanidinium chloride induced a rever ...200717142288
inhibition of sars-cov gene expression by adenovirus-delivered small hairpin rna.severe acute respiratory syndrome (sars) is a highly contagious and lethal disease caused by a new type of coronavirus, sars-associated coronavirus (sars-cov). currently, there is no efficient treatment and prevention for this disease. we constructed recombinant adenoviral vectors that can express shrnas, which inhibited the expression of sars-cov genes effectively in mammalian cells.200717139181
derivation of a novel sars-coronavirus replicon cell line and its application for anti-sars drug screening.the severe acute respiratory syndrome (sars) outbreak in 2002, which had a high morbidity rate and caused worldwide alarm, remains untreated today even though sars was eventually isolated and controlled. development and high-throughput screening of efficacious drugs is therefore critical. however, currently there remains a lack of such a safe system. here, the generation and characterization of the first selectable, sars-coronavirus (sars-cov)-based replicon cell line which can be used for scree ...200717098272
palmitoylation of the cysteine-rich endodomain of the sars-coronavirus spike glycoprotein is important for spike-mediated cell fusion.the sars-coronavirus (sars-cov) is the etiological agent of the severe acute respiratory syndrome (sars). the sars-cov spike (s) glycoprotein mediates membrane fusion events during virus entry and virus-induced cell-to-cell fusion. the cytoplasmic portion of the s glycoprotein contains four cysteine-rich amino acid clusters. individual cysteine clusters were altered via cysteine-to-alanine amino acid replacement and the modified s glycoproteins were tested for their transport to cell-surfaces an ...200717134730
inhibition of sars-cov replication cycle by small interference rnas silencing specific sars proteins, 7a/7b, 3a/3b and s.the severe acute respiratory syndrome coronavirus (sars cov) genome has 14 potential open reading frames (orfs). the first orf is translated from the full-length genomic mrna while the remaining orfs are translated from eight subgeomic rnas (sgrnas). in this study, we designed small interference rnas (sirnas) targeting sgrna 2, 3 and 7 and tested their efficiency and specificity in silencing the protein translated from the targeted sgrna. our results demonstrated that sirna 7 could inhibit sgrna ...200717112601
characterizing 56 complete sars-cov s-gene sequences from hong kong.the spike glycoprotein (s) gene of the severe acute respiratory syndrome-associated coronavirus (sars-cov) has been useful in analyzing the molecular epidemiology of the 2003 sars outbreaks.200717112780
severe acute respiratory syndrome coronavirus infection of mice transgenic for the human angiotensin-converting enzyme 2 virus receptor.animal models for severe acute respiratory syndrome (sars) coronavirus infection of humans are needed to elucidate sars pathogenesis and develop vaccines and antivirals. we developed transgenic mice expressing human angiotensin-converting enzyme 2, a functional receptor for the virus, under the regulation of a global promoter. a transgenic lineage, designated ac70, was among the best characterized against sars coronavirus infection, showing weight loss and other clinical manifestations before re ...200717108019
severe acute respiratory syndrome coronavirus open reading frame (orf) 3b, orf 6, and nucleocapsid proteins function as interferon antagonists.the severe acute respiratory syndrome coronavirus (sars-cov) is highly pathogenic in humans, with a death rate near 10%. this high pathogenicity suggests that sars-cov has developed mechanisms to overcome the host innate immune response. it has now been determined that sars-cov open reading frame (orf) 3b, orf 6, and n proteins antagonize interferon, a key component of the innate immune response. all three proteins inhibit the expression of beta interferon (ifn-beta), and further examination rev ...200717108024
a severe acute respiratory syndrome coronavirus that lacks the e gene is attenuated in vitro and in vivo.a deletion mutant of severe acute respiratory syndrome coronavirus (sars-cov) has been engineered by deleting the structural e gene in an infectious cdna clone that was constructed as a bacterial artificial chromosome (bac). the recombinant virus lacking the e gene (rsars-cov-deltae) was rescued in vero e6 cells. the recovered deletion mutant grew in vero e6, huh-7, and caco-2 cells to titers 20-, 200-, and 200-fold lower than the recombinant wild-type virus, respectively, indicating that althou ...200717108030
severe acute respiratory syndrome coronavirus protein 6 accelerates murine coronavirus infections.one or more of the unique 3'-proximal open reading frames (orfs) of the severe acute respiratory syndrome (sars) coronavirus may encode determinants of virus virulence. a prime candidate is orf6, which encodes a 63-amino-acid membrane-associated peptide that can dramatically increase the lethality of an otherwise attenuated jhm strain of murine coronavirus (l. pewe, h. zhou, j. netland, c. tangudu, h. olivares, l. shi, d. look, t. gallagher, and s. perlman, j. virol. 79:11335-11342, 2005). to di ...200717108045
naturally occurring anti-escherichia coli protein antibodies in the sera of healthy humans cause analytical interference in a recombinant nucleocapsid protein-based enzyme-linked immunosorbent assay for serodiagnosis of severe acute respiratory syndrome.we reported the analytical interference of anti-escherichia coli protein (ep) antibodies in human sera and residual ep in a recombinant nucleocapsid protein-based enzyme-linked immunosorbent assay as a possible source of false positives in severe acute respiratory syndrome serodiagnosis. the rate of false positives was significantly reduced by adding mouse anti-ep antiserum in the blocking step.200717108287
insight into the activity of sars main protease: molecular dynamics study of dimeric and monomeric form of enzyme.the phenomenon that sars coronavirus main protease (sars m(pro)) dimer is the main functional form has been confirmed by experiment. however, because of the absence of structural information of the monomer, the reasons for this remain unknown. to investigate it, two molecular dynamics (md) simulations in water for dimer and monomer models have been carried out, using the crystal structure of protomer a of the dimer as the starting structure for the monomer. during the md simulation of dimer, thr ...200717083088
receptor-binding domain of sars-cov spike protein induces long-term protective immunity in an animal model.development of effective vaccines against severe acute respiratory syndrome (sars) coronavirus (sars-cov) is still a priority in prevention of re-emergence of sars. our previous studies have shown that the receptor-binding domain (rbd) of sars-cov spike (s) protein elicits highly potent neutralizing antibody responses in the immunized animals. but it is unknown whether rbd can also induce protective immunity in an animal model, a key aspect for vaccine development. in this study, balb/c mice wer ...200717092615
selection of sars-coronavirus-specific b cell epitopes by phage peptide library screening and evaluation of the immunological effect of epitope-based peptides on mice.antibodies to sars-coronavirus (sars-cov)-specific b cell epitopes might recognize the pathogen and interrupt its adherence to and penetration of host cells. hence, these epitopes could be useful for diagnosis and as vaccine constituents. using the phage-displayed peptide library screening method and purified fab fragments of immunoglobulin g (igg fab) from normal human sera and convalescent sera from sars-cov-infected patients as targets, 11 b cell epitopes of sars-cov spike glycoprotein (s pro ...200717055022
a study on antigenicity and receptor-binding ability of fragment 450-650 of the spike protein of sars coronavirus.the spike (s) protein of sars coronavirus (sars-cov) is responsible for viral binding with ace2 molecules. its receptor-binding motif (s-rbm) is located between residues 424 and 494, which folds into 2 anti-parallel beta-sheets, beta5 and beta6. we have previously demonstrated that fragment 450-650 of the s protein (s450-650) is predominantly recognized by convalescent sera of sars patients. the n-terminal 60 residues (450-510) of the s450-650 fragment covers the entire beta6 strand of s-rbm. in ...200717055551
studies on the interactions of ti-containing polyoxometalates (poms) with sars-cov 3clpro by molecular modeling.ti-containing alpha-keggin polyoxometalates (poms) have been proved with properties of both anti-tumor and anti-hiv (human immunodeficiency virus). the potential anti-sars (severe acute respiratory syndrome) activity of the poms [alpha-pti(2)w(10)o(40)](7-) isomers was investigated in this paper by molecular modeling method. the sars 3c like protease, namely the sars 3cl(pro) is the key function protease for virus replication as well as transcription and thus can be taken as one of the key targe ...200717049610
antibodies against trimeric s glycoprotein protect hamsters against sars-cov challenge despite their capacity to mediate fcgammarii-dependent entry into b cells in vitro.vaccine-induced antibodies can prevent or, in the case of feline infectious peritonitis virus, aggravate infections by coronaviruses. we investigated whether a recombinant native full-length s-protein trimer (trispike) of severe acute respiratory syndrome coronavirus (sars-cov) was able to elicit a neutralizing and protective immune response in animals and analyzed the capacity of anti-s antibodies to mediate antibody-dependent enhancement (ade) of virus entry in vitro and enhancement of replica ...200717049691
lethal infection of k18-hace2 mice infected with severe acute respiratory syndrome coronavirus.the severe acute respiratory syndrome (sars), caused by a novel coronavirus (sars-cov), resulted in substantial morbidity, mortality, and economic losses during the 2003 epidemic. while sars-cov infection has not recurred to a significant extent since 2003, it still remains a potential threat. understanding of sars and development of therapeutic approaches have been hampered by the absence of an animal model that mimics the human disease and is reproducible. here we show that transgenic mice tha ...200717079315
the orf7b protein of severe acute respiratory syndrome coronavirus (sars-cov) is expressed in virus-infected cells and incorporated into sars-cov particles.coronavirus replication is facilitated by a number of highly conserved viral proteins. the viruses also encode accessory genes, which are virus group specific and believed to play roles in virus replication and pathogenesis in vivo. of the eight putative accessory proteins encoded by the severe acute respiratory distress syndrome associated coronavirus (sars-cov), only two-open reading frame 3a (orf3a) and orf7a-have been identified in virus-infected cells to date. the orf7b protein is a putativ ...200717079322
lipid rafts play an important role in the early stage of severe acute respiratory syndrome-coronavirus life cycle.lipid rafts are involved in the life cycle of many viruses. in this study, we showed that lipid rafts also play an important role in the life cycle of severe acute respiratory syndrome (sars)-coronavirus (cov). cholesterol depletion by pretreatment of vero e6 cells with methyl-beta-cyclodextrin (mbetacd) inhibited the production of sars-cov particles released from the infected cells. this inhibition was prevented by addition of cholesterol to the culture medium, indicating that the reduction of ...200717194611
severe acute respiratory syndrome in children.severe acute respiratory syndrome (sars) is a febrile, respiratory tract illness caused by infection with the newly identified sars-associated coronavirus. a notable feature of the 2003 global sars outbreak was the relative paucity of cases reported among children. we reviewed the epidemiologic and clinical features of sars in children and discuss implications of these findings for diagnosis, treatment and prevention of sars.200717195709
crystal structures reveal an induced-fit binding of a substrate-like aza-peptide epoxide to sars coronavirus main peptidase.the sars coronavirus main peptidase (sars-cov m(pro)) plays an essential role in the life-cycle of the virus and is a primary target for the development of anti-sars agents. here, we report the crystal structure of m(pro) at a resolution of 1.82 angstroms, in space group p2(1) at ph 6.0. in contrast to the previously reported structure of m(pro) in the same space group at the same ph, the active sites and the s1 specificity pockets of both protomers in the structure of m(pro) reported here are i ...200717196984
development and validation of a high-throughput screen for inhibitors of sars cov and its application in screening of a 100,000-compound library.the authors have developed a high-throughput screen (hts) that allows for the identification of potential inhibitors of the severe acute respiratory syndrome coronavirus (sars cov) from large compound libraries. the luminescent-based assay measures the inhibition of sars cov-induced cytopathic effect (cpe) in vero e6 cells. the assay was validated in 96-well plates in a bsl3 containment facility. the assay is sensitive and robust, with z values > 0.6, signal to background (s/b) > 16, and signal ...200717200104
novel beta-barrel fold in the nuclear magnetic resonance structure of the replicase nonstructural protein 1 from the severe acute respiratory syndrome coronavirus.the nonstructural protein 1 (nsp1) of the severe acute respiratory syndrome coronavirus has 179 residues and is the n-terminal cleavage product of the viral replicase polyprotein that mediates rna replication and processing. the specific function of nsp1 is not known. here we report the nuclear magnetic resonance structure of the nsp1 segment from residue 13 to 128, which represents a novel alpha/beta-fold formed by a mixed parallel/antiparallel six-stranded beta-barrel, an alpha-helix covering ...200717202208
recombinant truncated nucleocapsid protein as antigen in a novel immunoglobulin m capture enzyme-linked immunosorbent assay for diagnosis of severe acute respiratory syndrome coronavirus infection.we report the development of an immunoglobulin m (igm) antibody capture enzyme-linked immunosorbent assay (mac-elisa) for severe acute respiratory syndrome coronavirus (sars-cov) by using recombinant truncated sars-cov nucleocapsid protein as the antigen. the newly developed mac-elisa had a specificity and sensitivity of 100% as evaluated by using sera from healthy volunteers and patients with laboratory-confirmed sars. using serial serum samples collected from sars patients, the times to seroco ...200717202310
unique sars-cov protein nsp1: bioinformatics, biochemistry and potential effects on virulence.viruses have evolved a myriad of strategies for promoting viral replication, survival and spread. sequence analysis of the severe acute respiratory syndrome coronavirus (sars-cov) genome predicts several proteins that are unique to sars-cov. the search to understand the high virulence of sars-cov compared with related coronaviruses, which cause lesser respiratory illnesses, has recently focused on the unique nsp1 protein of sars-cov and suggests evolution of a possible new virulence mechanism in ...200717207625
the intracellular sites of early replication and budding of sars-coronavirus.in this study, we analyzed the replication and budding sites of severe acute respiratory syndrome coronavirus (sars-cov) at early time points of infection. we detected cytoplasmic accumulations containing the viral nucleocapsid protein, viral rna and the non-structural protein nsp3. using em techniques, we found that these putative viral replication sites were associated with characteristic membrane tubules and double membrane vesicles that most probably originated from er cisternae. in addition ...200717210170
features discriminating sars from other severe viral respiratory tract infections.this study investigated the discriminatory features of severe acute respiratory syndrome (sars) and severe non-sars community-acquired viral respiratory infection (requiring hospitalization) in an emergency department in hong kong. in a case-control study, clinical, laboratory and radiological data from 322 patients with laboratory-confirmed sars from the 2003 sars outbreak were compared with the data of 253 non-sars adult patients with confirmed viral respiratory tract infection from 2004 in or ...200717219094
a mouse-adapted sars-coronavirus causes disease and mortality in balb/c mice.no single animal model for severe acute respiratory syndrome (sars) reproduces all aspects of the human disease. young inbred mice support sars-coronavirus (sars-cov) replication in the respiratory tract and are available in sufficient numbers for statistical evaluation. they are relatively inexpensive and easily accessible, but their use in sars research is limited because they do not develop illness following infection. older (12- to 14-mo-old) balb/c mice develop clinical illness and pneumoni ...200717222058
utility of the aged balb/c mouse model to demonstrate prevention and control strategies for severe acute respiratory syndrome coronavirus (sars-cov).the causative agent of severe acute respiratory syndrome (sars) was identified as a coronavirus (cov) following the outbreak of 2002-2003. there are currently no licensed vaccines or treatments for sars-cov infections. potential prevention and control strategies that show promise in vitro must be evaluated in animal models. the aged balb/c mouse model for sars supports a high level of viral replication in association with clinical illness and disease that mimics sars in the elderly. we tested tw ...200717227689
ribonucleocapsid formation of severe acute respiratory syndrome coronavirus through molecular action of the n-terminal domain of n protein.conserved among all coronaviruses are four structural proteins: the matrix (m), small envelope (e), and spike (s) proteins that are embedded in the viral membrane and the nucleocapsid phosphoprotein (n), which exists in a ribonucleoprotein complex in the lumen. the n-terminal domain of coronaviral n proteins (n-ntd) provides a scaffold for rna binding, while the c-terminal domain (n-ctd) mainly acts as oligomerization modules during assembly. the c terminus of the n protein anchors it to the vir ...200717229691
generic detection of coronaviruses and differentiation at the prototype strain level by reverse transcription-pcr and nonfluorescent low-density microarray.a nonfluorescent low-cost, low-density oligonucleotide array was designed for detecting the whole coronavirus genus after reverse transcription (rt)-pcr. the limit of detection was 15.7 copies/reaction. the clinical detection limit in patients with severe acute respiratory syndrome was 100 copies/sample. in 39 children suffering from coronavirus 229e, nl63, oc43, or hku1, the sensitivity was equal to that of individual real-time rt-pcrs.200717229859
recombinant protein-based assays for detection of antibodies to severe acute respiratory syndrome coronavirus spike and nucleocapsid proteins.recombinant severe acute respiratory syndrome (sars) nucleocapsid and spike protein-based immunoglobulin g immunoassays were developed and evaluated. our assays demonstrated high sensitivity and specificity to the sars coronavirus in sera collected from patients as late as 2 years postonset of symptoms. these assays will be useful not only for routine sars coronavirus diagnostics but also for epidemiological and antibody kinetic studies.200717229882
impact of severe acute respiratory syndrome care on the general health status of healthcare workers in taiwan.the impact of the outbreak of severe acute respiratory syndrome (sars) was enormous, but few studies have focused on the infectious and general health status of healthcare workers (hcws) who treated patients with sars.200717230391
evidence for quasi species in severe acute respiratory syndrome-associated coronavirus deletion mutants. 200717230423
characterization of the cleavage of signal peptide at the c-terminus of hepatitis c virus core protein by signal peptide peptidase.production of hepatitis c virus (hcv) core protein requires the cleavages of polyprotein by signal peptidase and signal peptide peptidase (spp). cleavage of signal peptide at the c-terminus of hcv core protein by spp was characterized in this study. the spko mutant (mutate a.a. 189-193 from asayq to ppfpf) is more efficient than the a/f mutant (mutate a.a 189 and 191 from a to f) in blocking the cleavage of signal peptide by signal peptidase. the cleavage efficiency of spp is inversely proportio ...200717237979
the psychological effect of severe acute respiratory syndrome on emergency department staff.the severe acute respiratory syndrome (sars) outbreak in 2003 affected 29 countries. the sars outbreak was unique in its rapid transmission and it resulted in heavy stress in first-line healthcare workers, particularly in the emergency department.200717183035
the cytoplasmic tail of the severe acute respiratory syndrome coronavirus spike protein contains a novel endoplasmic reticulum retrieval signal that binds copi and promotes interaction with membrane protein.like other coronaviruses, severe acute respiratory syndrome coronavirus (sars cov) assembles at and buds into the lumen of the endoplasmic reticulum (er)-golgi intermediate compartment (ergic). accumulation of the viral envelope proteins at this compartment is a prerequisite for virus assembly. previously, we reported the identification of a dibasic motif (kxhxx) in the cytoplasmic tail of the sars cov spike (s) protein that was similar to a canonical dilysine er retrieval signal. here we demons ...200717166901
participation of both host and virus factors in induction of severe acute respiratory syndrome (sars) in f344 rats infected with sars coronavirus.to understand the pathogenesis and develop an animal model of severe acute respiratory syndrome (sars)-associated coronavirus (sars-cov), the frankfurt 1 sars-cov isolate was passaged serially in young f344 rats. young rats were susceptible to sars-cov but cleared the virus rapidly within 3 to 5 days of intranasal inoculation. after 10 serial passages, replication and virulence of sars-cov were increased in the respiratory tract of young rats without clinical signs. by contrast, adult rats infec ...200717151094
trends in the development and approval of monoclonal antibodies for viral infections.monoclonal antibodies (mabs) developed for either the prevention or treatment of viral diseases represent a small, but valuable, class of products. since 1985, commercial firms have initiated clinical studies involving a total of 28 mabs. to date, one product (palivizumab) has been approved and eight candidates are currently in clinical study. most commercial mabs studied as antiviral agents in the clinic have either directly or indirectly targeted human immunodeficiency virus, respiratory syncy ...200717263584
children's vaccines do not induce cross reactivity against sars-cov.in contrast with adults, children infected by severe acute respiratory syndrome-corona virus (sars-cov) develop milder clinical symptoms. because of this, it is speculated that children vaccinated with various childhood vaccines might develop cross immunity against sars-cov. antisera and t cells from mice immunised with various vaccines were used to determine whether they developed cross reactivity against sars-cov. the results showed no marked cross reactivity against sars-cov, which implies th ...200717264247
inhibitor design for sars coronavirus main protease based on "distorted key theory".in order to find effective peptide inhibitors against sars cov m(pro), an analysis was performed for 11 oligo-peptides that can be cleaved by the sars coronavirus main protease (cov m(pro), or 3cl(pro)). flexible molecular alignments of the 11 cleavable peptides have provided useful insights into the chemical properties of their amino acid residues close to the cleavage site. moreover, it was found through the ligand-receptor docking studies that of the 11 cleavable peptides, nh2-atlq / aias-coo ...200717266617
spike protein of sars-cov stimulates cyclooxygenase-2 expression via both calcium-dependent and calcium-independent protein kinase c pathways.we have previously shown that the nucleocapsid protein of sars-associated coronavirus (sars-cov) activated cyclooxygenase-2 (cox-2) expression. in this study, we identified another viral protein, the spike of sars-cov, which played an important role in virus-stimulated cox-2 expression after screening all genes from the sars-cov genome. we found that an upstream calcium-dependent pkc isozyme pkc alpha that modulates the downstream erk/nf-kappab pathway through an influx of extracellular ca2+ is ...200717267381
evolutionary insights into the ecology of coronaviruses.although many novel members of the coronaviridae have recently been recognized in different species, the ecology of coronaviruses has not been established. our study indicates that bats harbor a much wider diversity of coronaviruses than any other animal species. dating of different coronavirus lineages suggests that bat coronaviruses are older than those recognized in other animals and that the human severe acute respiratory syndrome (sars) coronavirus was directly derived from viruses from wil ...200717267506
inhibition of infection caused by severe acute respiratory syndrome-associated coronavirus by equine neutralizing antibody in aged mice.the high susceptibility of elderly to severe acute respiratory syndrome-associated coronavirus (sars-cov) indicates how crucial it is to protect the elderly by various strategies. aged balb/c mice displayed a high susceptibility to sars-cov and have been a valuable platform for evaluation of strategies against sars-cov infection. in this study, we confirmed the validity of this model using various methods, and verified that equine anti-sars-cov f(ab')(2) can prevent aged animals from sars-cov in ...200717276898
enhancement of cytotoxicity against vero e6 cells persistently infected with sars-cov by mycoplasma fermentans.we previously reported that cells with persistent severe acute respiratory syndrome coronavirus (sars-cov) infection were established after apoptotic events. in the present study, we investigated the cytopathic effects of dual infection with sars-cov and mycoplasma fermentans on vero e6 cells. dual infection completely killed cells and prevented the establishment of persistent sars-cov infection. m. fermentans induced inhibition of cell proliferation, but the cells remained alive. apoptosis was ...200717277901
the immunobiology of sars*.severe acute respiratory syndrome (sars) presented as an atypical pneumonia that progressed to acute respiratory distress syndrome in approximately 20% of cases and was associated with a mortality of about 10%. the etiological agent was a novel coronavirus (cov). angiotensin-converting enzyme 2 is the functional receptor for sars-cov; dc-sign and cd209l (l-sign) can enhance viral entry. although the virus infects the lungs, gastrointestinal tract, liver, and kidneys, the disease is limited to th ...200717243893
[avian influenza and the severe acute respiratory syndrome (sars) - experiences and perspectives].new respiratory viruses associated with pneumonia have in the past few years been detected in humans. the sudden appearance of the severe acute respiratory syndrome (sars) in 2003 demonstrated that an emerging and highly infectious disease caused by a hitherto unknown virus was able to spread rapidly, but could finally be contained by stringent measures. the avian influenza a-h5n1-virus of high pathogenicity has crossed in multiple instances the species barriers between humans, mammals, and bird ...200717253209
molecular pathology in the lungs of severe acute respiratory syndrome patients.severe acute respiratory syndrome (sars) is a novel infectious disease with disastrous clinical consequences, in which the lungs are the major target organs. previous studies have described the general pathology in the lungs of sars patients and have identified some of the cell types infected by sars coronavirus (sars-cov). however, at the time of this writing, there were no comprehensive reports of the cellular distribution of the virus in lung tissue. in this study, we have performed double la ...200717255322
expression, purification and characterization of recombinant severe acute respiratory syndrome coronavirus non-structural protein 1.the coronavirus (cov) responsible for severe acute respiratory syndrome (sars), sars-cov, encodes two large polyproteins (pp1a and pp1ab) that are processed by two viral proteases to yield mature non-structural proteins (nsps). many of these nsps have essential roles in viral replication, but several have no assigned function and possess amino acid sequences that are unique to the cov family. one such protein is sars-cov nsp1, which is processed from the n-terminus of both pp1a and pp1ab. the ma ...200717187987
production of authentic sars-cov m(pro) with enhanced activity: application as a novel tag-cleavage endopeptidase for protein overproduction.the viral proteases have proven to be the most selective and useful for removing the fusion tags in fusion protein expression systems. as a key enzyme in the viral life-cycle, the main protease (m(pro)) is most attractive for drug design targeting the sars coronavirus (sars-cov), the etiological agent responsible for the outbreak of severe acute respiratory syndrome (sars) in 2003. in this study, sars-cov m(pro) was used to specifically remove the gst tag in a new fusion protein expression syste ...200717189639
the synergistic interaction of interferon types i and ii leads to marked reduction in severe acute respiratory syndrome-associated coronavirus replication and increase in the expression of mrnas for interferon-induced proteins.interferon (ifn)-alpha, -beta and -gamma have been shown to be only marginally effective against severe acute respiratory syndrome coronavirus (sars-cov) replication in vero cell lines. we investigated the combination of type i ifns (ifn-alpha or -beta) and ifn-gamma for antiviral activity and found that such combinations synergistically inhibited sars-cov replication in vero cells, using yield reduction assay and the isobologram and combination index methods of chou and talalay for evaluation. ...200717191018
microarray-in-a-tube for detection of multiple viruses.the detection of multiple viruses is important for pathogenic diagnosis and disease control. microarray detection is a good method, but requires complex procedures for multiple virus detection.200717158198
generation and characterization of human monoclonal neutralizing antibodies with distinct binding and sequence features against sars coronavirus using xenomouse.passive therapy with neutralizing human monoclonal antibodies (mabs) could be an effective therapy against severe acute respiratory syndrome coronavirus (sars-cov). utilizing the human immunoglobulin transgenic mouse, xenomouse, we produced fully human sars-cov spike (s) protein specific antibodies. antibodies were examined for reactivity against a recombinant s1 protein, to which 200 antibodies reacted. twenty-seven antibodies neutralized 200tcid(50) sars-cov (urbani). additionally, 57 neutrali ...200717161858
[lessons from sars].given that viruses may not have adapted to human-to-human transmission during their initial emergence in humans, they may thus be easier to control; accordingly, early detection by surveillance of unusual outbreaks is essential. our healthcare systems are very vulnerable to viruses with a particular tropism for hospital personnel. international collaboration by teams of epidemiologists as well as virologists was the key to success against sars (severe acute respiratory syndrome). we were lucky i ...200717258678
exosomal vaccines containing the s protein of the sars coronavirus induce high levels of neutralizing antibodies.infection with the sars-associated coronavirus (sars-cov) induces an atypical pulmonary disease with a high lethality rate. although the initial sars epidemic was contained, sporadic outbreaks of the disease still occur, suggesting a continuous need for a vaccine against this virus. we therefore explored exosome-based vaccines containing the spike s proteins of sars-cov. s-containing exosomes were obtained by replacing the transmembrane and cytoplasmic domains of the s protein by those of vsv-g. ...200717258782
establishment of a reference panel for the detection of anti-sars-cov antibodies.the immunological assays for detection of antibodies against sars-cov were developed in-house and some of them are available commercially. however, the antigens used in these assays differed. in order to validate the reliability of these assays, the standard panel should be established. in this study, we have expressed and purified severe acute respiratory syndrome (sars) structural proteins and their fragments and developed indirect enzyme-linked immunosorbent assays (elisas) that detect antibo ...200717261372
natural mutations in the receptor binding domain of spike glycoprotein determine the reactivity of cross-neutralization between palm civet coronavirus and severe acute respiratory syndrome coronavirus.the severe acute respiratory syndrome (sars) outbreak of 2002 and 2003 occurred as a result of zoonotic transmission. coronavirus (cov) found in naturally infected palm civet (civet-cov) represents the closest genetic relative to sars-cov, but the degree and the determinants of cross-neutralization among these viruses remain to be investigated. studies indicate that the receptor binding domain (rbd) of the sars-cov spike (s) glycoprotein contains major determinants for viral entry and neutraliza ...200717314167
group 2 coronaviruses prevent immediate early interferon induction by protection of viral rna from host cell recognition.many viruses encode antagonists to prevent interferon (ifn) induction. infection of fibroblasts with the murine hepatitis coronavirus (mhv) and sars-coronavirus (sars-cov) did not result in nuclear translocation of interferon-regulatory factor 3 (irf3), a key transcription factor involved in ifn induction, and induction of ifn mrna transcription. furthermore, mhv and sars-cov infection could not prevent ifn induction by poly (i:c) or sendai virus, suggesting that these covs do not inactivate irf ...200717316733
the sars-coronavirus membrane protein induces apoptosis through modulating the akt survival pathway.a number of viral gene products are capable of triggering apoptotic cell death through interfering with cellular signaling cascades, including the akt kinase pathway. in this study, the pro-apoptotic role of the sars-cov membrane (m) structural protein is described. we found that the sars-cov m protein induced apoptosis in both hek293t cells and transgenic drosophila. we further showed that m protein-induced apoptosis involved mitochondrial release of cytochrome c protein, and could be suppresse ...200717306213
[expression of predicted b cell epitope peptide in s2 subunit of sars coronavirus spike protein in e.coli and identification of its mimic antigenicity].to study the expression of predicted b cell epitope peptide in s2 subunit of sars coronavirus spike protein in e.coli and its mimic antigenicity to s2 protein.200717286901
development of vaccines and passive immunotherapy against sars corona virus using scid-pbl/hu mouse models.we have investigated novel vaccine strategies against severe acute respiratory syndrome (sars) cov using cdna constructs encoding the structural antigens: (s), (m), (e), or (n) protein, derived from sars cov. pbl from healthy human volunteers were administered i.p. into il-2 receptor gamma-chain disrupted scid mice, and scid-pbl/hu mice were constructed. these mice can be used to analyze the human immune response in vivo. sars m dna vaccine and n dna vaccine induced human ctl specific for sars c ...200717289225
the potential of targeted antibody prophylaxis in sars outbreak control: a mathematic analysis.severe acute respiratory syndrome (sars) coronavirus-like viruses continue to circulate in animal reservoirs. if new mutants of sars coronavirus do initiate another epidemic, administration of prophylactic antibodies to risk groups may supplement the stringent isolation procedures that contained the first sars outbreak.200717298911
severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection.before the emergence of severe acute respiratory syndrome (sars) coronavirus (sars-cov) in 2003, only 12 other animal or human coronaviruses were known. the discovery of this virus was soon followed by the discovery of the civet and bat sars-cov and the human coronaviruses nl63 and hku1. surveillance of coronaviruses in many animal species has increased the number on the list of coronaviruses to at least 36. the explosive nature of the first sars epidemic, the high mortality, its transient reeme ...200717934078
co-circulation of human metapneumovirus and sars-associated coronavirus during a major nosocomial sars outbreak in hong kong.the clinico-epidemiological significance of human metapneumovirus (hmpv) detected during the sars outbreak is unknown.200717936066
human monoclonal antibodies by immortalization of memory b cells.the administration of hyper immune sera to prevent or treat life-threatening infections is a remarkable milestone in medicine and biotechnology that has been achieved more than a century ago. yet, the therapeutic use of monoclonal antibodies in this field has developed slowly over the last decades. here we compare and contrast current methods to generate human monoclonal antibodies and highlight the advantages of exploiting the human antibody repertoire using a novel method that allows efficient ...200718063358
heterologous expression of sars-cov orf10 and x5 genes in e. coli and streptomyces lividans tk24.in previous studies a variety of novel accessory genes has been identified that were interspersed among the structural genes of the sars-cov (severe acute respiratory syndrome coronavirus) genome. the predicted unknown proteins (pups) encoded by the accessory genes, which are considered to be unique to the sars-cov genome, might play important roles in the sars-cov infection. two of these genes, called orf10 and x5, were synthesized and introduced into e. coli and streptomyces lividans tk24, res ...200718069252
[development and application of a safe sars-cov neutralization assay based on lentiviral vectors pseudotyped with sars-cov spike protein].the severe acute respiratory syndrome-associated coronavirus (sars-cov) spike protein (s) is a major target for neutralizing antibody. to develop and apply a safe neutralization assay for sars-cov, lentiviral sars-cov s pseudotypes had been constructed based on a three plasmid system, which contained pvrc8304 (harboring codon optimized full-length sars-cov s protein), pcmv delta 8. 2 (hiv-1 gag/pol construct) and phr'cmv egfp (the green fluorescent protein reporter construct). the pseudo-typed l ...200718092680
comparison of effectiveness of whole viral, n and n199 proteins by elisa for the rapid diagnosis of severe acute respiratory syndrome coronavirus.although severe acute respiratory syndrome (sars) has been controlled, the subsequently emerging sporadic cases in 2004 emphasize the necessity of developing a rapid diagnostic method, which would be of great help in clinical diagnosis and also wild host screening. this study aims to establish an effective and rapid serological tool for the diagnosis of sars-cov by comparison among whole viral, n and n199 proteins by elisa.200718167201
duration of antibody responses after severe acute respiratory syndrome.among 176 patients who had had severe acute respiratory syndrome (sars), sars-specific antibodies were maintained for an average of 2 years, and significant reduction of immunoglobulin g-positive percentage and titers occurred in the third year. thus, sars patients might be susceptible to reinfection >or=3 years after initial exposure.200718258008
[bad bats?].for many centuries, man is fascinated by bats, the only flying mammals. probably because of their particular immune system, bats can be considered an important reservoir for new emerging viral diseases like sars-coronavirus, marburg fever, ebola fever and nipah virus encephalitis. during closer contact, they can transmit rabies and probably other nonviral infectious diseases. bats get closer to man due to ecological modifications like deforestation, so that transmission of new infectious agents ...200717985603
[preparation and characterization of the epitopes of sars coronavirus spike protein].to prepare the recombinant epitopes of sars-cov spike protein and study their antigenic property to spike protein.200717988578
evaluation of the safety, immunogenicity and pharmacokinetics of equine anti-sars-cov f(ab')(2) in macaque.to warrant potential clinical testing, the equine anti-sars-cov f(ab')(2) requires evaluation in as many animal models as possible and a safety test in a primate model. in this study, we evaluated the pharmacokinetics, tolerance and immunity of this kind of antibody in macaques and rats. results showed that the f(ab')(2) fragments had a normal metabolism in injected animals. the general physiological indexes did not differ between animals injected with anti-sars-cov f(ab')(2) or saline. however, ...200717996696
safety and immunogenicity from a phase i trial of inactivated severe acute respiratory syndrome coronavirus vaccine.emergence of severe acute respiratory syndrome (sars) from the winter of 2002 to the spring of 2003 has caused a serious threat to public health.200718018769
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