wave-like spread of ebola the past decade the zaire strain of ebola virus (zebov) has emerged repeatedly into human populations in central africa and caused massive die-offs of gorillas and chimpanzees. we tested the view that emergence events are independent and caused by zebov variants that have been long resident at each locality. phylogenetic analyses place the earliest known outbreak at yambuku, democratic republic of congo, very near to the root of the zebov tree, suggesting that viruses causing all other known ...200516231972
lewis x component in human milk binds dc-sign and inhibits hiv-1 transfer to cd4+ t lymphocytes.dc-specific icam3-grabbing non-integrin (dc-sign), which is expressed on dcs, can interact with a variety of pathogens such as hiv-1, hepatitis c, ebola, cytomegalovirus, dengue virus, mycobacterium, leishmania, and candida albicans. we demonstrate that human milk can inhibit the dc-sign-mediated transfer of hiv-1 to cd4+ t lymphocytes as well as viral transfer by both immature and mature dcs. the inhibitory factor directly interacted with dc-sign and prevented the hiv-1 gp120 envelope protein f ...200516239964
[human recombinant antibodies to ebola virus: preparation and characteristics].human recombinant antibodies against a purified ebola virus (ev) lysate were selected from a combinatorial library of scfv-antibodies using the phage display technique. nine unique antibodies were identified after sequencing the vh- and vl-genes encoding the selected antibodies. solid-phase enzyme immunoassay (eia) indicated that these antibodies were able to bind both inactivated and native ev. immunoblotting showed that 6 antibodies identified nucleoprotein (np), one antibody did vp24 and anot ...200516250595
protective cytotoxic t-cell responses induced by venezuelan equine encephalitis virus replicons expressing ebola virus proteins.infection with ebola virus causes a severe disease accompanied by high mortality rates, and there are no licensed vaccines or therapies available for human use. filovirus vaccine research efforts still need to determine the roles of humoral and cell-mediated immune responses in protection from ebola virus infection. previous studies indicated that exposure to ebola virus proteins expressed from packaged venezuelan equine encephalitis virus replicons elicited protective immunity in mice and that ...200516254354
predicted inactivation of viruses of relevance to biodefense by solar radiation.uv radiation from the sun is the primary germicide in the environment. the goal of this study was to estimate inactivation of viruses by solar exposure. we reviewed published reports on 254-nm uv inactivation and tabulated the sensitivities of a wide variety of viruses, including those with double-stranded dna, single-stranded dna, double-stranded rna, or single-stranded rna genomes. we calculated d(37) values (fluence producing on average one lethal hit per virion and reducing viable virus to 3 ...200516254359
developing scientist leaders for tumultuous times.leadership is a quality that can be learned. it is a behavior that one practices, and, after lots of practice, it becomes a habit. this is a lesson i learned from my father, who was a career pilot in the us air force and instilled this into me and my siblings from a very early age. it is also something i have learned in observing others. i have frequently asked why some people from certain disciplinary backgrounds seem to have an advantage in the leadership area. think of the backgrounds of our ...200516261495
laboratory diagnosis of ebola and marburg hemorrhagic fever.the control of filovirus outbreaks can be greatly enhanced by timely laboratory confirmation of infection or the identification of alternative disease processes. the status of current laboratory diagnostics for ebola and marburg virus infections is discussed in terms of the assays available and their interpretation. in addition, the role of field-based laboratory support and its limitations and capabilities in an outbreak response setting, especially in regards to real-time pcr and immunofiltrat ...200516267962
ebola virus circulation in africa: a balance between clinical expression and epidemiological silence.nearly thirty years after the first epidemics, ebola virus (ebov) remains hardly described, its transmission unclear and its reservoir elusive. soon after the ebola fever outbreak and virus discovery in 1976 and in order to investigate the distribution of ebov in central africa, several countries including a range of ecological zones were investigated in the early 1980s, using extensive survey: central african republic (car), cameroon, chad, congo, gabon and equatorial guinea. since 1992, elisa ...200516267963
[clinical management of patients and deceased during the ebola outbreak from october to december 2003 in republic of congo].outbreaks of ebola virus hemorrhagic fever (evhf) have been reported since 2001 in the cuvette ouest department, a forested area located in the western north of congo. at the end of october 2003 a new alarm came from this department which was quickly confirmed as being an epidemic of evhf. the outbreak response was organized by the ministry of health with the assistance of an international team under the aegis of who. the case management of suspect cases was done in an isolation ward set up at t ...200516267964
[multiple ebola virus haemorrhagic fever outbreaks in gabon, from october 2001 to april 2002].outbreaks of ebola virus haemorrhagic fever have been reported from 1994 to 1996 in the province of ogooué ivindo, a forest zone situated in the northeast of gabon. each time, the great primates had been identified as the initial source of human infection. end of november 2001 a new alert came from this province, rapidly confirmed as a evhv outbreak. the response was given by the ministry of health with the help of an international team under the aegis of who. an active monitoring system was imp ...200516267965
medical anthropology and ebola in congo: cultural models and humanistic care.seldom have medical anthropologists been involved in efforts to control high mortality diseases such as ebola hemorrhagic fever (ehf) this paper describes the results of two distinct but complementary interventions during the first phases of an outbreak in the republic of congo in 2003. the first approach emphasized understanding local peoples cultural models and political-economic explanations for the disease while the second approach focused on providing more humanitarian care of patients by i ...200516267966
ebola and great apes in central africa: current status and future needs. 200516267967
recent advances in antiviral nucleoside and nucleotide therapeutics.recent developments in nucleoside/nucleotide therapeutics and antiviral drug targets are described covering progress in the development of nucleoside/nucleotide mimetics for the treatment of influenza virus, human immunodeficiency virus type 1, hepatitis b and c virus, herpes virus infections; including herpes simplex virus, cytomegalovirus and varicella zoster virus infections, and the highly pathogenic poxviruses (variola, vaccinia and monkey pox) and filoviruses (ebola and marburg).200516305526
fruit bats as reservoirs of ebola virus.the first recorded human outbreak of ebola virus was in 1976, but the wild reservoir of this virus is still unknown. here we test for ebola in more than a thousand small vertebrates that were collected during ebola outbreaks in humans and great apes between 2001 and 2003 in gabon and the republic of the congo. we find evidence of asymptomatic infection by ebola virus in three species of fruit bat, indicating that these animals may be acting as a reservoir for this deadly virus.200516319873
taking down goliaths: new vaccines may spell the end for ebola, marburg and lassa virus infections. 200516323509
nonstructural protein 3 of bluetongue virus assists virus release by recruiting escrt-i protein tsg101.the release of bluetongue virus (btv) and other members of the orbivirus genus from infected host cells occurs predominantly by cell lysis, and in some cases, by budding from the plasma membrane. two nonstructural proteins, ns3 and ns3a, have been implicated in this process. here we show that both proteins bind to human tsg101 and its ortholog from drosophila melanogaster with similar strengths in vitro. this interaction is mediated by a conserved psap motif in ns3 and appears to play a role in ...200616352570
the role of reverse genetics systems in determining filovirus pathogenicity.the family filoviridae is comprised of two genera: marburgvirus and ebolavirus. to date minigenome systems have been developed for two ebola viruses (reston ebolavirus and zaire ebolavirus [zebov]) as well as for lake victoria marburgvirus, the sole member of the marburgvirus genus. the use of these minigenome systems has helped characterize functions for many viral proteins in both genera and have provided valuable insight towards the development of an infectious clone system in the case of zeb ...200516355872
internalizing antibodies to the c-type lectins, l-sign and dc-sign, inhibit viral glycoprotein binding and deliver antigen to human dendritic cells for the induction of t cell responses.the c-type lectin l-sign is expressed on liver and lymph node endothelial cells, where it serves as a receptor for a variety of carbohydrate ligands, including icam-3, ebola, and hiv. to consider targeting liver/lymph node-specific icam-3-grabbing nonintegrin (l-sign) for therapeutic purposes in autoimmunity and infectious disease, we isolated and characterized fabs that bind strongly to l-sign, but to a lesser degree or not at all to dendritic cell-specific icam-grabbing nonintegrin (dc-sign). ...200616365436
ebola and marburg viruses: pathogenesis and development of countermeasures.ebola and marburg viruses, family filoviridae, are among the best known examples of emerging and re-emerging pathogens. although outbreaks have been sporadic and geographically restricted to areas of central africa, the hemorrhagic fevers caused by these viruses are remarkably severe and are associated with high case fatality rates often exceeding 80 percent. in addition to humans, these viruses have decimated populations of wild apes in central africa. currently, there are no vaccines or effect ...200516375711
rescue of recombinant marburg virus from cdna is dependent on nucleocapsid protein we report recovery of infectious marburg virus (marv) from a full-length cdna clone. compared to the wild-type virus, recombinant marv showed no difference in terms of morphology of virus particles, intracellular distribution in infected cells, and growth kinetics. the nucleocapsid protein vp30 of marv and ebola virus (ebov) contains a zn-binding motif which is important for the function of vp30 as a transcriptional activator in ebov, whereas its role for marv is unclear. it has been report ...200616379005
[bats, reserves of the ebola virus: the mystery is dissipated]. 200616386226
interferon: ten stories in one. a short review of some of the highlights in the history of an almost quinquagenarian.this short review article on some pertinent observations in the unfolding story of interferon is dedicated to professor ilona béládi on the occasion of her 80th birthday. this by no means covers the whole story on interferon. it just highlights some of the more striking findings made with interferon (or its inducers) over a time span of almost 50 years since its original discovery (in 1957) by isaacs and lindenmann. these observations concern (i) the induction of interferon by synthetic polyanio ...200516400870
new medicines from nature's armamentarium.nature frequently unleashes a barrage of new and frightening diseases against humans--such as hiv, severe acquired respiratory syndrome, ebola virus and avian flu recently--in addition to the seemingly ever-present scourges such as malaria and tuberculosis. fortunately, nature also provides the wherewithal to help conquer the diseases that it sets loose. all that is needed is the human ingenuity to discover, develop and apply the solutions in an optimal fashion. participants at the 9th max tishl ...200616406332
gene-specific countermeasures against ebola virus based on antisense phosphorodiamidate morpholino oligomers.the filoviruses marburg virus and ebola virus (ebov) quickly outpace host immune responses and cause hemorrhagic fever, resulting in case fatality rates as high as 90% in humans and nearly 100% in nonhuman primates. the development of an effective therapeutic for ebov is a daunting public health challenge and is hampered by a paucity of knowledge regarding filovirus pathogenesis. this report describes a successful strategy for interfering with ebov infection using antisense phosphorodiamidate mo ...200616415982
john montgomery's legacy: carbocyclic adenosine analogues as sah hydrolase inhibitors with broad-spectrum antiviral activity.ever since the s-adenosylhomocysteine (adohcy, sah) hydrolase was recognized as a pharmacological target for antiviral agents (j. a. montgomery et al., j. med. chem. 25:626-629, 1982), an increasing number of adenosine, acyclic adenosine, and carbocyclic adenosine analogues have been described as potent sah hydrolase inhibitors endowed with broad-spectrum antiviral activity. the antiviral activity spectrum of the sah hydrolase inhibitors include pox-, rhabdo-, filo-, arena-, paramyxo-, reo-, and ...200516438025
time- and temperature-dependent activation of hepatitis c virus for low-ph-triggered entry.hepatitis c virus (hcv) is an important human pathogen associated with chronic liver disease. recently, based on a genotype 2a isolate, tissue culture systems supporting complete replication and infectious virus production have been developed. in this study, we used cell culture-produced infectious hcv to analyze the viral entry pathway into huh-7.5 cells. bafilomycin a1 and concanamycin a, inhibitors of vacuolar atpases, prevented hcv entry when they were present prior to infection and had mini ...200616439530
development of human monoclonal antibodies against diseases caused by emerging and biodefense-related viruses.polyclonal antibodies have a century-old history of being effective against some viruses; recently, monoclonal antibodies (mabs) have also shown success. the humanized mab synagis (palivizumab), which is still the only mab against a viral disease approved by the us fda, has been widely used as a prophylactic measure against respiratory syncytial virus infections in neonates and immunocompromised individuals. the first fully human mabs against two other paramyxoviruses, hendra and nipah virus, wh ...200616441209
development of treatment strategies to combat ebola and marburg viruses.ebola and marburg viruses are emerging/re-emerging pathogens that pose a significant threat to human health. these naturally occurring viral infections frequently cause a lethal hemorrhagic fever in humans and nonhuman primates. the disastrous consequences of infection with these viruses have been pursued as potential biological weapons. to date, there are no therapeutic options available for the prophylaxis or treatment of infected individuals. the recognition that ebola and marburg viruses may ...200616441210
a single intranasal inoculation with a paramyxovirus-vectored vaccine protects guinea pigs against a lethal-dose ebola virus determine whether intranasal inoculation with a paramyxovirus-vectored vaccine can induce protective immunity against ebola virus (ev), recombinant human parainfluenza virus type 3 (hpiv3) was modified to express either the ev structural glycoprotein (gp) by itself (hpiv3/ebogp) or together with the ev nucleoprotein (np) (hpiv3/ebogp-np). expression of ev gp by these recombinant viruses resulted in its efficient incorporation into virus particles and increased cytopathic effect in vero cells. ...200616474134
vp35 knockdown inhibits ebola virus amplification and protects against lethal infection in mice.phosphorodiamidate morpholino oligomers (pmo) are a class of uncharged single-stranded dna analogs modified such that each subunit includes a phosphorodiamidate linkage and morpholine ring. pmo antisense agents have been reported to effectively interfere with the replication of several positive-strand rna viruses in cell culture. the filoviruses, marburg virus and ebola virus (ebov), are negative-strand rna viruses that cause up to 90% lethality in human outbreaks. there is currently no commerci ...200616495261
development of a cadvax-based bivalent ebola virus vaccine that induces immune responses against both the sudan and zaire species of ebola virus.ebola virus (ebov) causes a severe hemorrhagic fever for which there are currently no vaccines or effective treatments. while lethal human outbreaks have so far been restricted to sub-saharan africa, the potential exploitation of ebov as a biological weapon cannot be ignored. two species of ebov, sudan ebolavirus (sebov) and zaire ebolavirus (zebov), have been responsible for all of the deadly human outbreaks resulting from this virus. therefore, it is important to develop a vaccine that can pre ...200616501083
detection of cell-cell fusion mediated by ebola virus glycoproteins.ebola viruses (ebov) are enveloped rna viruses infecting cells by a ph-dependent process mediated by viral glycoproteins (gp) involving endocytosis of virions and their routing into acidic endosomes. as with well-characterized ph-dependent viral entry proteins, in particular influenza virus hemagglutinin, it is thought that ebov gp require activation by low ph in order to mediate fusion of the viral envelope with the membrane of endosomes. however, it has not yet been possible to confirm the dir ...200616501090
global suppression of the host antiviral response by ebola- and marburgviruses: increased antagonism of the type i interferon response is associated with enhanced virulence.we studied the effect of filovirus infection on host cell gene expression by characterizing the regulation of gene expression responses in human liver cells infected with zaire ebolavirus (zebov), reston ebolavirus (rebov), and marburgvirus (marv), using transcriptional profiling and bioinformatics. expression microarray analysis demonstrated that filovirus infection resulted in the up-regulation of immune-related genes and the down-regulation of many coagulation and acute-phase proteins. these ...200616501110
de novo syntheses of marburg virus antigens from adenovirus vectors induce potent humoral and cellular immune responses.marburg virus (marv) is an african filovirus that causes a deadly hemorrhagic fever in humans, with up to 90% mortality. currently, there are no marv vaccines or therapies approved for human use. we hypothesized that developing a vaccine that induces a de novo synthesis of marv antigens in vivo will lead to strong induction of both a humoral and cell-mediated immune response against marv. here, we develop and characterize three novel gene-based vaccine candidates which express the viral glycopro ...200616530297
developments in antiviral drug design, discovery and development in 2004.this article summarizes key aspects of progress made during 2004 toward the design, discovery and development of antiviral agents for clinical use. important developments in the identification, characterization and clinical utility of inhibitors of human immunodeficiency virus; the hepatitis viruses, hepatitis b, hepatitis c; the herpes family of viruses, herpes simplex viruses 1 and 2, varicella zoster virus, epstein-barr virus and human cytomegalovirus; the respiratory viruses, influenza, resp ...200516535860
[isolated case of haemorrhagic fever observed in gabon during the 2002 outbreak of ebola but distant from epidemic zones].during the last outbreak of ebola virus haemorrhagic fever that occurred concurrently in gabon and congo, several primary foci were identified in the ogooue ivindo province (northeast gabon), where previous outbreaks had occurred. a 48-year-old woman living in franceville located 580 km from the epicentre presented fever with haemorrhagic signs. she was evacuated to libreville where ebola infection was suspected. diagnosis was confirmed at the centre international de recherches médicales of fran ...200516548488
toxicological safety evaluation of dna plasmid vaccines against hiv-1, ebola, severe acute respiratory syndrome, or west nile virus is similar despite differing plasmid backbones or gene-inserts.the vaccine research center has developed a number of vaccine candidates for different diseases/infectious agents (hiv-1, severe acute respiratory syndrome virus, west nile virus, and ebola virus, plus a plasmid cytokine adjuvant-il-2/ig) based on a dna plasmid vaccine platform. to support the clinical development of each of these vaccine candidates, preclinical studies were performed to screen for potential toxicities (intrinsic and immunotoxicities). all treatment-related toxicities identified ...200616569728
biodistribution of dna plasmid vaccines against hiv-1, ebola, severe acute respiratory syndrome, or west nile virus is similar, without integration, despite differing plasmid backbones or gene inserts.the vaccine research center has developed a number of vaccine candidates for different diseases/infectious agents (hiv-1, severe acute respiratory syndrome virus, west nile virus, and ebola virus, plus a plasmid cytokine adjuvant-il-2/ig) based on a dna plasmid vaccine platform. to support the clinical development of each of these vaccine candidates, preclinical studies have been performed in mice or rabbits to determine where in the body these plasmid vaccines would biodistribute and how rapidl ...200616569729
functional mapping of the nucleoprotein of ebola 739 amino acids, the nucleoprotein (np) of ebola virus is the largest nucleoprotein of the nonsegmented negative-stranded rna viruses, and like the nps of other viruses, it plays a central role in virus replication. huang et al. (y. huang, l. xu, y. sun, and g. j. nabel, mol. cell 10:307-316, 2002) previously demonstrated that np, together with the minor matrix protein vp24 and polymerase cofactor vp35, is necessary and sufficient for the formation of nucleocapsid-like structures that are mor ...200616571791
role of endosomal cathepsins in entry mediated by the ebola virus glycoprotein.using chemical inhibitors and small interfering rna (sirna), we have confirmed roles for cathepsin b (catb) and cathepsin l (catl) in ebola virus glycoprotein (gp)-mediated infection. treatment of ebola virus gp pseudovirions with catb and catl converts gp1 from a 130-kda to a 19-kda species. virus with 19-kda gp1 displays significantly enhanced infection and is largely resistant to the effects of the catb inhibitor and sirna, but it still requires a low-ph-dependent endosomal/lysosomal function ...200616571833
[ebola and marburg viruses: the humans strike back].ebola and marburg viruses are the causative agents of rapidly progressive hemorrhagic fevers with high mortality rates. pre- or post-exposure treatments against the diseases are currently not available for human use. in the field, establishment of strict quarantine measures preventing further virus transmission are still the only way to fight the infections. however, our knowledge of ebola and marburg viruses has markedly increased as a result of two recent discoveries discussed in this review. ...200616597410
[sphingolipids, vehicle for pathogenic agents and cause of genetic diseases].sphingolipids are present in all eukaryotic cells and share a sphingoid base : sphingosine. they were first discovered in 1884 and for a long time they were thought to participate to membrane structure only. recently it has been established that they are mainly located in particular areas of the membrane called rafts which are signalling platforms. it has also been demonstrated that sphingolipids are receptors and second messengers. they play a crucial role in cellular functioning and are necess ...200616597411
ebola virus glycoprotein gp is not cytotoxic when expressed constitutively at a moderate level.transient expression of ebola virus (ebov) glycoprotein gp causes downregulation of surface proteins, cell rounding and detachment, a phenomenon believed to play a central role in the pathogenicity of the virus. in this study, evidence that moderate expression of gp does not result in such morphological changes was provided. it was shown that gp continuously produced in 293t cells from the kunjin virus replicon was correctly processed and transported to the plasma membrane without affecting the ...200616603527
laboratory diagnostic systems for ebola and marburg hemorrhagic fevers developed with recombinant proteins. 200616603611
antisense treatments for biothreat agents.antisense oligomers (asos) represent a promising technology to treat viral and bacterial infections, and have already been shown to be successful against a variety of pathogens in cell culture studies and nonhuman primate models of infection. for these reasons, antisense technologies are being pursued as treatments against biothreat agents such as ebola virus, dengue virus and bacillus anthracis. several generations of modified oligonucleotides have been developed to maximize nuclease resistance ...200616610760
ebola virus: unravelling pathogenesis to combat a deadly disease.ebola virus (ebov) causes severe haemorrhagic fever leading to up to 90% lethality. increasingly frequent outbreaks and the placement of ebov in the category a list of potential biothreat agents have boosted interest in this virus. furthermore, development of new technologies (e.g. reverse genetics systems) and extensive studies on ebola haemorrhagic fever (ehf) in animal models have substantially expanded the knowledge on the pathogenic mechanisms that underlie this disease. two major factors i ...200616616875
emerging infectious diseases at the beginning of the 21st century.the emergence and re-emergence of infectious diseases involves many interrelated factors. global interconnectedness continues to increase with international travel and trade; economic, political, and cultural interactions; and human-to-human and animal-to-human interactions. these interactions include the accidental and deliberate sharing of microbial agents and antimicrobial resistance and allow the emergence of new and unrecognized microbial disease agents. as the 21st century begins, already ...200616629503
detection of ebola virus in oral fluid specimens during outbreaks of ebola virus hemorrhagic fever in the republic of congo.patients who have refused to provide blood samples has meant that there have been significant delays in confirming outbreaks of ebola virus hemorrhagic fever (evhf). during the 2 evhf outbreaks in the republic of congo in 2003, we assessed the use of oral fluid specimens versus serum samples for laboratory confirmation of cases of evhf.200616652308
ebola virus-like particles produced in insect cells exhibit dendritic cell stimulating activity and induce neutralizing antibodies.recombinant baculoviruses (rbv) expressing ebola virus vp40 (rbv-vp40) or gp (rbv-gp) proteins were generated. infection of sf9 insect cells by rbv-vp40 led to assembly and budding of filamentous particles from the cell surface as shown by electron microscopy. ebola virus-like particles (vlps) were produced by coinfection of sf9 cells with rbv-vp40 and rbv-gp, and incorporation of ebola gp into vlps was demonstrated by sds-page and western blot analysis. recombinant baculovirus infection of inse ...200616678231
immune protection of nonhuman primates against ebola virus with single low-dose adenovirus vectors encoding modified gps.ebola virus causes a hemorrhagic fever syndrome that is associated with high mortality in humans. in the absence of effective therapies for ebola virus infection, the development of a vaccine becomes an important strategy to contain outbreaks. immunization with dna and/or replication-defective adenoviral vectors (rad) encoding the ebola glycoprotein (gp) and nucleoprotein (np) has been previously shown to confer specific protective immunity in nonhuman primates. gp can exert cytopathic effects o ...200616683867
ebola virus vp35-vp40 interaction is sufficient for packaging 3e-5e minigenome rna into virus-like particles.the packaging of viral genomic rna into nucleocapsids and subsequently into virions is not completely understood. phosphoprotein (p) and nucleoprotein (np) interactions link np-rna complexes with p-l (polymerase) complexes to form viral nucleocapsids. the nucleocapsid then interacts with the viral matrix protein, leading to specific packaging of the nucleocapsid into the virion. a mammalian two-hybrid assay and confocal microscopy were used to demonstrate that ebola virus vp35 and vp40 interact ...200616698994
ebola virus vp24 binds karyopherin alpha1 and blocks stat1 nuclear accumulation.ebola virus (ebov) infection blocks cellular production of alpha/beta interferon (ifn-alpha/beta) and the ability of cells to respond to ifn-alpha/beta or ifn-gamma. the ebov vp35 protein has previously been identified as an ebov-encoded inhibitor of ifn-alpha/beta production. however, the mechanism by which ebov infection inhibits responses to ifns has not previously been defined. here we demonstrate that the ebov vp24 protein functions as an inhibitor of ifn-alpha/beta and ifn-gamma signaling. ...200616698996
ebola virus vp35 protein binds double-stranded rna and inhibits alpha/beta interferon production induced by rig-i signaling.the ebola virus (ebov) vp35 protein blocks the virus-induced phosphorylation and activation of interferon regulatory factor 3 (irf-3), a transcription factor critical for the induction of alpha/beta interferon (ifn-alpha/beta) expression. however, the mechanism(s) by which this blockage occurs remains incompletely defined. we now provide evidence that vp35 possesses double-stranded rna (dsrna)-binding activity. specifically, vp35 bound to poly(ri) . poly(rc)-coated sepharose beads but not contro ...200616698997
postexposure protection of guinea pigs against a lethal ebola virus challenge is conferred by rna interference.ebola virus (ebov) infection causes a frequently fatal hemorrhagic fever (hf) that is refractory to treatment with currently available antiviral therapeutics. rna interference represents a powerful, naturally occurring biological strategy for the inhibition of gene expression and has demonstrated utility in the inhibition of viral replication. here, we describe the development of a potential therapy for ebov infection that is based on small interfering rnas (sirnas).200616703508
functional expression of mouse relaxin and mouse relaxin-3 in the lung from an ebola virus glycoprotein-pseudotyped lentivirus via tracheal delivery.the peptide hormone relaxin is a known modulator of connective tissue and the extracellular matrix by virtue of its ability to regulate matrix metalloproteinases (mmps). relaxin knockout mice exhibit age-related pulmonary fibrosis, and delivery of recombinant human h2 relaxin ameliorates fibrotic-like conditions in the mouse lung. we investigated whether lentiviral vectors (lvs) engineering the expression of murine relaxins could induce mmp activity in the mouse lung. mouse relaxin and mouse rel ...200616709614
effect of ebola virus proteins gp, np and vp35 on vp40 vlp morphology.recently we described a role for ebola virus proteins, np, gp, and vp35 in enhancement of vp40 vlp budding. to explore the possibility that vlp structure was altered by co-expression of ebov proteins leading to the observed enhancement of vp40 vlp budding, we performed density gradient analysis as well as electron microscopy studies. our data suggest that vp40 is the major determinant of vlp morphology, as co-expression of np, gp and vp35 did not significantly change vlp density, length, and dia ...200616719918
interaction of amsh with escrt-iii and deubiquitination of endosomal cargo.the "class e" vacuolar protein sorting (vps) pathway mediates sorting of ubiquitinated cargo into the forming vesicles of the multivesicular bodies (mvb), and it is essential for down-regulation of signaling by growth factors and budding of enveloped viruses such as ebola and hiv-1. work in yeast has identified doa4 as a gene that is recruited by the class e machinery to remove ubiquitin from the endosomal cargo before it is incorporated into mvb vesicles, but the identity of the mammalian count ...200616760479
reverse genetic generation of recombinant zaire ebola viruses containing disrupted irf-3 inhibitory domains results in attenuated virus growth in vitro and higher levels of irf-3 activation without inhibiting viral transcription or replication.the vp35 protein of zaire ebola virus is an essential component of the viral rna polymerase complex and also functions to antagonize the cellular type i interferon (ifn) response by blocking activation of the transcription factor irf-3. we previously mapped the irf-3 inhibitory domain within the c terminus of vp35. in the present study, we show that mutations that disrupt the irf-3 inhibitory function of vp35 do not disrupt viral transcription/replication, suggesting that the two functions of vp ...200616775331
[chiroptera and zoonosis: an emerging problem on all five continents].zoonosis is the cause of the vast majority of emerging diseases. bats that occupy the second place in the mammal class play an important role. whether they belong to the microchiroptera suborder or to the megachiroptera suborder, bats on all five continents have been implicated in transmission of numerous pathogens including not only viruses such as lyssavirus (e.g. rabies), hepanivirus (e.g. hendra and nipah virus) and recently coronavirus (e.g. sars-like coronavirus and ebola virus) but also f ...200616775933
viral haemorrhagic fevers caused by lassa, ebola and marburg viruses. 200616802617
[scientific progress and new biological weapons].the biological weapons are different from conventional weapons, because living germs hold an extraordinary and predictable potential for multiplication, propagation and genetic variation during their dissemination in a susceptible population. only natural pathogens (1rst generation weapons) have been used in the past (smallpox virus, plague, anthrax, toxins...). however, new threats are emerging, due to the rapid progress of scientific knowledge and its exponential worldwide diffusion. it is pos ...200616457765
[countermeasure against viral hemorrhagic fever at the border in japan].human have struggled against many infectious diseases such as cholera, plague, dysentery and yellow fever for a long time. and we have spent a lot of energy to control these infectious diseases and developed various tool for them. one of these efforts was quarantine system that was established in 14th century in europe. but during recent days, we are suffering from newly emerged diseases. these new infectious diseases are zoonosis and most of them are serious and highly infectious. viral hemorrh ...200516363688
chimpanzee adenovirus vaccine protects against zaire ebola virus.this study evaluated the use of a chimpanzee-based adenovirus vaccine in mouse and guinea pigs models of zaire ebola virus (zebov) infection. vaccine vector expressing the envelope glycoprotein of zebov was created from the molecular clone of chimpanzee adenovirus pan7 (adc7). adc7 vaccine stimulated robust t and b cell responses to zebov in naïve mice inducing complete protection to an otherwise lethal challenge of zebov. complete protection to zaire ebola virus was also observed in guinea pigs ...200616356525
activation of triggering receptor expressed on myeloid cells-1 on human neutrophils by marburg and ebola viruses.marburg virus (marv) and ebola virus (ebov), members of the viral family filoviridae, cause fatal hemorrhagic fevers in humans and nonhuman primates. high viral burden is coincident with inadequate adaptive immune responses and robust inflammatory responses, and virus-mediated dysregulation of early host defenses has been proposed. recently, a novel class of innate receptors called the triggering receptors expressed in myeloid cells (trem) has been discovered and shown to play an important role ...200616809329
infection of naive target cells with virus-like particles: implications for the function of ebola virus vp24.infectious virus-like particle (ivlp) systems have recently been established for several negative-strand rna viruses, including the highly pathogenic zaire ebolavirus (zebov), and allow study of the viral life cycle under biosafety level 2 conditions. however, current systems depend on the expression of viral helper nucleocapsid proteins in target cells, thus making it impossible to determine whether ribonucleoprotein complexes transferred by ivlps are able to facilitate initial transcription, a ...200616809331
complex adenovirus-vectored vaccine protects guinea pigs from three strains of marburg virus challenges.the marburg virus (marv), an african filovirus closely related to the ebola virus, causes a deadly hemorrhagic fever in humans, with up to 90% mortality. currently, treatment of disease is only supportive, and no vaccines are available to prevent spread of marv infections. in order to address this need, we have developed and characterized a novel recombinant vaccine that utilizes a single complex adenovirus-vectored vaccine (cadvax) to overexpress a marv glycoprotein (gp) fusion protein derived ...200616820184
gorilla susceptibility to ebola virus: the cost of sociality. 200616824905
a luciferase-based budding assay for ebola virus.the vp40 matrix protein of ebola virus (ebov) is capable of budding from mammalian cells as a virus-like particle (vlp) and is the major protein involved in virus egress. a functional budding assay has been developed based upon this characteristic of vp40 to assess the contributions of vp40 sequences as well as host proteins to the budding process. this well-defined assay has been modified for potential use in a high-throughput format in which the detection and quantification of firefly lucifera ...200616837071
identification of two amino acid residues on ebola virus glycoprotein 1 critical for cell entry.using site-directed mutagenesis and retroviral vector pseudotyping of the wild type or mutated glycoprotein of zaire ebolavirus (zebov), we analyzed 15 conserved residues in the n-terminus of the filovirus glycoprotein 1 (gp1) in order to identify residues critical for cell entry. results from infectivity assays and western blot analyses identified two phenylalanine residues at positions 88 and 159 that appear to be critical for zebov entry in vitro. we extended this observation by introduction ...200616839637
peptides derived from hiv-1, hiv-2, ebola virus, sars coronavirus and coronavirus 229e exhibit high affinity binding to the formyl peptide receptor.peptides derived from the membrane proximal region of fusion proteins of human immunodeficiency viruses 1 and 2, coronavirus 229 e, severe acute respiratory syndrome coronavirus and ebola virus were all potent antagonists of the formyl peptide receptor expressed in chinese hamster ovary cells. binding of viral peptides was affected by the naturally occurring polymorphisms at residues 190 and 192, which are located at second extracellular loop-transmembrane helix 5 interface. substitution of r190 ...200616842982
molecular determinants of ebola virus virulence in mice.zaire ebolavirus (zebov) causes severe hemorrhagic fever in humans and nonhuman primates, with fatality rates in humans of up to 90%. the molecular basis for the extreme virulence of zebov remains elusive. while adult mice resist zebov infection, the mayinga strain of the virus has been adapted to cause lethal infection in these animals. to understand the pathogenesis underlying the extreme virulence of ebola virus (ebov), here we identified the mutations responsible for the acquisition of the h ...200616848640
detection of ebola virus envelope using monoclonal and polyclonal antibodies in elisa, surface plasmon resonance and a quartz crystal microbalance immunosensor.ebola virus (ebov) zaire, sudan, as well as ivory coast are virulent human ebov species. both polyclonal and monoclonal antibodies (mabs) were developed against soluble ebov envelope glycoprotein (gp) for the study of ebov envelope diversity and development of diagnostic reagents. three ebov sudan-gulu gp peptides, from the n-terminus, mid-gp, and c-terminus regions were used to immunize rabbits for the generation of anti-ebov polyclonal antibodies. polyclonal antisera raised against the c-termi ...200616857271
aids: caused by development of resistance to drugs in a non-target intracellular parasite.the origin of acquired immune disorder syndrome (aids) has been the subject of substantial controversy both in the scientific community and in the popular press. the debate involves the mode of transmission of a simian virus (siv) to humans. both major camps in the argument presume that humans are normally free of such viruses and assume that once the simian virus was transmitted, it immediately infected some t-cells and caused the release of toxic agents that killed off bystander (uninfected) t ...200716893612
generation of an adenoviral vaccine vector based on simian adenovirus 21.adenoviral vectors can be used to generate potent humoral and cellular immune responses to transgene products. use of adenoviral vectors based on non-human isolates may allow for their utilization in populations harbouring neutralizing antibodies to common human serotypes. a vector chimera was constructed using simian adenovirus 22 (a serotype belonging to the species human adenovirus e) and simian adenovirus 21 (a serotype belonging to the species human adenovirus b) expressing the ebola (zaire ...200616894185
anthrax in western and central african great apes.during the period of december 2004 to january 2005, bacillus anthracis killed three wild chimpanzees (pan troglodytes troglodytes) and one gorilla (gorilla gorilla gorilla) in a tropical forest in cameroon. while this is the second anthrax outbreak in wild chimpanzees, this is the first case of anthrax in gorillas ever reported. the number of great apes in central africa is dramatically declining and the populations are seriously threatened by diseases, mainly ebola. nevertheless, a considerable ...200616900500
permeabilization of the plasma membrane by ebola virus gp2.the glycoprotein (gp) of ebola virus (ebov) is a multifunctional protein known to play a role in virus attachment and entry, cell rounding and cytotoxicity, down-regulation of host surface proteins, and enhancement of virus assembly and budding. ebov gp is synthesized as a precursor which is subsequently cleaved to yield two disulfide-linked subunits: gp1 (surface-exposed [su] subunit) and gp2 (membrane-anchored [tm] subunit). we sought to determine the effect of membrane-anchored gp2 protein ex ...200716927113
[hematological and immunological parameters during ebola virus passages in guinea-pigs].the trend in hematological and immunological parameters during ebola virus passages in guinea-pigs indicated that pathophysiological changes occurred just during the second passage and further became stronger. the increase of some parameters and their correlation with the occurrence of fatal outcomes allowed the authors to reveal the most significant changes as increased juvenile platelets, whole blood virus appearance, higher echinocytes, a rise in the pro mil of blast cells and megakaryocytes ...200616929596
structure-function analysis of the soluble glycoprotein, sgp, of ebola addition to the transmembrane protein, gp(1,2), the ebola virus glycoprotein gene encodes the soluble glycoproteins sgp and delta-peptide. two more soluble proteins, gp(1) and gp(1,2deltatm), are generated from gp(1,2) as a result of disulfide-bond instability and proteolytic cleavage, respectively, and are shed from the surface of infected cells. the sgp glycoprotein is secreted as a disulfide-linked homodimer, but there have been conflicting reports on whether it is arranged in a parallel o ...200616977667
release of cellular proteases into the acidic extracellular milieu exacerbates ebola virus-induced cell damage.ebola virus is highly cytopathic through mechanisms that are largely unknown. we present evidence that progressive acidification of the extracellular milieu by ebola virus-infected cells combined with reduced levels of natural cysteine protease inhibitor makes the cells vulnerable to uncontrolled proteolysis of extracellular matrix components by released active endosomal cathepsins, thereby exacerbating ebola virus-induced cell destruction. the cell surface microenvironment was shown to be cruci ...200716982079
emergency medicine and the public's health: emerging infectious recent years, multiple global forces have contributed to the emergence and widespread distribution of previously unknown disease entities. this article discusses ebola virus, west nile virus, and hantavirus as representative emerging infectious diseases. smallpox is discussed along with concerns about the safety of the smallpox vaccine, given the uncertain risk of bioterrorism and smallpox exposure. ed physicians must become familiar with the presentation, management, and public health impact ...200616982350
a dna vaccine for ebola virus is safe and immunogenic in a phase i clinical trial.ebola viruses represent a class of filoviruses that causes severe hemorrhagic fever with high mortality. recognized first in 1976 in the democratic republic of congo, outbreaks continue to occur in equatorial africa. a safe and effective ebola virus vaccine is needed because of its continued emergence and its potential for use for biodefense. we report the safety and immunogenicity of an ebola virus vaccine in its first phase i human study. a three-plasmid dna vaccine encoding the envelope glyco ...200616988008
characterization of marburg virus glycoprotein in viral major determinant of host tropism for filoviruses is viral glycoprotein (gp), which is involved in receptor binding and viral entry. compared to ebola gp (egp), marburg gp (mgp) is less well characterized in viral entry. in this study, using a human immunodeficiency virus-based pseudotyped virus as a surrogate system, we have characterized the role of mgp in viral entry. we have shown that like egp, the mucin-like region of mgp (289-501) is not essential for virus entry. we have developed a ...200716989883
understanding the dynamics of ebola epidemics.ebola is a highly lethal virus, which has caused at least 14 confirmed outbreaks in africa between 1976 and 2006. using data from two epidemics [in democratic republic of congo (drc) in 1995 and in uganda in 2000], we built a mathematical model for the spread of ebola haemorrhagic fever epidemics taking into account transmission in different epidemiological settings. we estimated the basic reproduction number (r0) to be 2.7 (95% ci 1.9-2.8) for the 1995 epidemic in drc, and 2.7 (95% ci 2.5-4.1) ...200716999875
mutation of ymyl in the nipah virus matrix protein abrogates budding and alters subcellular localization.matrix (m) proteins reportedly direct the budding of paramyxoviruses from infected cells. in order to begin to characterize the assembly process for the highly lethal, emerging paramyxovirus nipah virus (niv), we have examined the budding of niv m. we demonstrated that expression of the niv m protein is sufficient to produce budding virus-like particles (vlps) that are physically and morphologically similar to niv. we identified in niv m a sequence, ymyl, with similarity to the ypdl late domain ...200617005661
tyro3 family-mediated cell entry of ebola and marburg viruses.filoviruses, represented by the genera ebolavirus and marburgvirus, cause a lethal hemorrhagic fever in humans and in nonhuman primates. although filovirus can replicate in various tissues or cell types in these animals, the molecular mechanisms of its broad tropism remain poorly understood. here we show the involvement of members of the tyro3 receptor tyrosine kinase family-axl, dtk, and mer-in cell entry of filoviruses. ectopic expression of these family members in lymphoid cells, which otherw ...200617005688
bile salt-stimulated lipase from human milk binds dc-sign and inhibits human immunodeficiency virus type 1 transfer to cd4+ t cells.a wide range of pathogens, including human immunodeficiency virus type 1 (hiv-1), hepatitis c virus, ebola virus, cytomegalovirus, dengue virus, mycobacterium, leishmania, and helicobacter pylori, can interact with dendritic cell (dc)-specific icam3-grabbing nonintegrin (dc-sign), expressed on dcs and a subset of b cells. more specifically, the interaction of the gp120 envelope protein of hiv-1 with dc-sign can facilitate the transfer of virus to cd4+ t lymphocytes in trans and enhance infection ...200617005819
morbidity and mortality of wild animals in relation to outbreaks of ebola haemorrhagic fever in gabon, 1994-2003.antibody to ebola virus was found in 14 (1.2%) of 1147 human sera collected in gabon in 1981-1997. six seropositive subjects were bled in the northeast in 1991, more than 3 years prior to recognition of the first known outbreak of ebola haemorrhagic fever (ehf), whilst eight came from the southwest where the disease has not been recognised. it has been reported elsewhere that 98 carcasses of wild animals were found in systematic studies in northeastern gabon and adjoining northwestern republic o ...200717010400
evaluation of promed-mail as an electronic early warning system for emerging animal diseases: 1996 to identify emerging animal and zoonotic diseases and associated geographic distribution, disease agents, animal hosts, and seasonality of reporting in the program for monitoring emerging diseases (promed)-mail electronic early warning system.200617014355
implication of a retrovirus-like glycoprotein peptide in the immunopathogenesis of ebola and marburg viruses.ebola and marburg viruses can cause hemorrhagic fever (hf) outbreaks with high mortality in primates. whereas marburg (marv), ebola zaire (zebov), and ebola sudan (sebov) viruses are pathogenic in humans, apes, and monkeys, ebola reston (rebov) is pathogenic only in monkeys. early immunosuppression may contribute to pathogenesis by facilitating viral replication. lymphocyte depletion, intravascular apoptosis, and cytokine dysregulation are prominent in fatal cases. here we functionally character ...200617023517
[properties of the ebola virus glycoprotein].in central and west africa, ebola virus, a member of the filovirus group, has produced sporadic outbreaks of lethal disease. this virus causes hemorrhagic fever in humans and nonhuman primates, resulting in mortality rates of up to 90%. although there are no satisfactory biologic explanations for this extreme virulence, it has been suggested that functions of the envelope glycoprotein are likely to play important roles in the pathogenicity of ebola virus.200617038820
zoonotic viral diseases and the frontier of early diagnosis, control and prevention.public awareness of the human health risks of zoonotic infections has grown in recent years. currently, concern of h5n1 flu transmission from migratory bird populations has increased with foci of fatal human cases. this comes on the heels of other major zoonotic viral epidemics in the last decade. these include other acute emerging or re-emerging viral diseases such as severe acute respiratory syndrome (sars), west-nile virus, ebola virus, monkeypox, as well as the more inapparent insidious slow ...200617040245
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
protective efficacy of neutralizing antibodies against ebola virus infection.ebola virus causes lethal hemorrhagic fever in humans and nonhuman primates, but no effective antiviral compounds are available for the treatment of this infection. the surface glycoprotein (gp) of ebola virus is an important target of neutralizing antibodies. although passive transfer of gp-specific antibodies has been evaluated in mouse and guinea pig models, protection was achieved only by treatment shortly before or after virus challenge. using these animal models, we evaluated the protectiv ...200717055127
the vp35 protein of ebola virus inhibits the antiviral effect mediated by double-stranded rna-dependent protein kinase pkr.the vp35 protein of ebola virus is a viral antagonist of interferon. it acts to block virus or double-stranded rna-mediated activation of interferon regulatory factor 3, a transcription factor that facilitates the expression of interferon and interferon-stimulated genes. in this report, we show that the vp35 protein is also able to inhibit the antiviral response induced by alpha interferon. this depends on the vp35 function that interferes with the pathway regulated by double-stranded rna-depend ...200717065211
recent common ancestry of ebola zaire virus found in a bat reservoir. 200617069458
[hemorrhagic (marburg, ebola, lassa, and bolivian) fevers: epidemiology, clinical pictures, and treatment].the evaluation of the biological and epidemiological properties of ebola, marburg, lassa, and machupo viruses suggests that they are of social importance for health care authorities. the studies have created prerequisites to the development of reliable biosafety means against these pathogens. particular emphasis is laid on the methods for infection diagnosis and on the studies to design specific protective agents--immunoglobulins and inactivated vaccines.200617087059
progress towards the treatment of ebola haemorrhagic fever.being highly pathogenic for human and nonhuman primates and the subject of former weapon programmes makes ebola virus one of the most feared pathogens worldwide today. due to a lack of licensed pre- and postexposure intervention, the current response depends on rapid diagnostics, proper isolation procedures and supportive care of case patients. consequently, the development of more specific countermeasures is of high priority for the preparedness of many nations. over the past years, enhanced re ...200617107278
the erk mitogen-activated protein kinase pathway contributes to ebola virus glycoprotein-induced cytotoxicity.ebola virus is a highly lethal pathogen that causes hemorrhagic fever in humans and nonhuman primates. among the seven known viral gene products, the envelope glycoprotein (gp) alone induces cell rounding and detachment that ultimately leads to cell death. cellular cytoxicity is not seen with comparable levels of expression of a mutant form of gp lacking a mucin-like domain (gpdeltamuc). gp-induced cell death is nonapoptotic and is preceded by downmodulation of cell surface molecules involved in ...200717108034
computational prediction and identification of hla-a2.1-specific ebola virus ctl epitopes.ebola virus (ebov) is known to cause a severe hemorrhagic fever resulting in high mortality. although the precise host defense mechanism(s) that afford protection against ebov is not completely understood, t cell-mediated immune responses is believed to play a pivotal role in controlling virus replication and ebov infection. there have been no reports on mapping of mhc class i-binding ctl epitopes for ebov till to date. in this study, we identified five hla-a2-binding 9-mer peptides of ebov nucl ...200717123567
structural studies of algal lectins with anti-hiv activity.a number of antiviral lectins, small proteins that bind carbohydrates found on viral envelopes, are currently in pre-clinical trials as potential drugs for prevention of transmission of human immunodeficiency virus (hiv) and other enveloped viruses, such as the ebola virus and the coronavirus responsible for severe acute respiratory syndrome (sars). lectins of algal origin whose antiviral properties make them candidate agents for prevention of viral transmission through topical applications incl ...200617128290
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