WHO kiirehtää: On saatava tietää enemmän post-ebolasyndrooman syystä

Need for more information on post-Ebola syndrome

“We need to understand why these symptoms persist, whether they are caused by the disease or treatment, or perhaps the heavy disinfection,” says Dr Nanyonga who has developed an assessment tool that will be used to establish the most common and disabling symptoms and what can be done to help survivors with these problems.
Dr Andrew Ramsay, field coordinator for WHO in Kenema, says it is essential that potentially disabling physical and psychological problems be diagnosed and, where possible, treated as quickly as possible.
“Eye problems might be caused by damage to the cornea, to the nerves or something else. At this point we do not have enough information to know exactly what is going on. But we need to find out urgently so we can do whatever we can to preserve the eyesight for people who have to try to pick up their lives again.”

OIE- tietoa LYSSA-viruksesta ja rabies taudista.

 

OIE Editorial

Joka kymmenes minuuti joku maailmassa kuolee rabies-tautiin. Siinä on surullinen totuus tämän Lyssa -viruksen nykytilanteesta. Joka vuosi rabies surmaa miltei 70 000 ihmistä, lähinnä lapsia kehitysmaissa. Yli 95% ihmistapauksista on  vesikauhuisen koiran puremasta johtuvaa.  Kuitenkin tämä tauti olisi eliminoitavissa. Tämän taudin suhteen on olemassa kaikki työkalut taudin poisjuurtamiseen maailamsta. Sentakia jokainen ihmistapaus on  liikaa.

Projekti: Ei enää rabieskuolemia!

No more deaths from rabies

Every ten minutes someone in the world dies from rabies. This is the sad reality of the situation even today. Every year, rabies kills nearly 70 000 people, mostly children in developing countries. Over 95% of human cases are caused by the bite of a rabies-infected dog. Yet the disease could be eliminated. Indeed, unlike many other diseases, we already have all the tools needed to eradicate it. Each new victim is therefore one too many.

 http://rabiesalliance.org/

Kuuban lääkäriapu ebolaa vastaan

http://www.hs.fi/ulkomaat/a1414299258662 

Köyhä ja taloussaarron painama Kuuba kerää huomiota panostuksellaan ebolaviruksen vastaiseen taisteluun.
Kuuba on lähettänyt Sierra Leoneen 165 terveydenhuollon ammattilaista.
 Lisäksi 91 kuubalaista lääkäriä ja sairaanhoitajaa on aloittamassa työt Liberiassa ja Guineassa, ja saarivaltio on aikeissa lähettää vielä 200 ammattilaista. Se tarkoittaa, että Kuuba on eniten terveydenhuollon työntekijöitä Länsi-Afrikkaan lähettänyt taho.
Kuuban panos on saanut kiitosta kansainväliseltä yhteisöltä ja medialta. Tunnustusta on antanut jopa Yhdysvallat, jonka suhteet kommunistiseen saarivaltioon ovat jäässä.
27.10.2014

21 päivän karanteeni

HS.fi  27.10.2014
Yhdysvallat panee kaikki Länsi-Afrikassa palvelleet sotilaansa ebolan vuoksi varmuuden vuoksi karanteeniin Italiaan.
Toistakymmentä sotilasta, heidän joukossaan joukkoja komentanut kenraalimajuri Darryl Williams, viettää tiukassa erityksessä enimmillään seuraavat kolme viikkoa.
Eristyksessä olevat sotilaat saavat lähipäivinä seuraa, sillä Länsi-Afrikasta palaa vielä tällä viikolla kymmeniä amerikkalaissotilaita lisää.
Yhdysvaltain puolustusministeriö Pentagon korostaa, ettei sotilailla ole mitään ebolan oireita, vaan karanteeni on puhdas varotoimi.
Amerikkalaissotilaat ovat olleet Länsi-Afrikassa rakentamassa muun muassa liikkuvia testilaboratorioita ja sairaaloita ebolapotilaille.

VSV-EBOV kokeellinen ebola filovirusrokote, joka perustuu muokattuun vesikulaariseen stomatiittivirukseen VSV.

• VSV-EBOV on myös  Rekombinantti Vektori tyyppinen . Se on kehitelty Kanadan kansallisessa mikrobiologian laboratoriossa.  Tämä  rokote perustuu teknisesti  muokatun   vesikulaarisen stomatiitin virukseen (VSV)  ja se on sellaiseski, että se ilmentää  geneettisesti  oikean   ebolan  pinnalla esiintyviä antigeenejä, glykoproteiineja (GP), jotta se  saisi  aikaan immuunivasteen oikeaa ebolavirusta vastaan.

  Tämä rokote tunnetaan  nimillä rVSV-ZEBOV tai rVSV-ZEBOV-GP tai VSVΔG-ZEBOV ( siis: VSV deltaG-ZEBOV) tai BPS1001. Tämä rokotevariantti ilmentää Zairen ebolaviruksen (ZEBOV)  glykoproteiineja.  ZEBOV on se ebolavirus, joka eniten aiheuttaa kuolemantapauksia. 

  Sen sijaan  lähisukuisen  Marburgin filoviruksen (MARV)  glykoproteiineja (GP)  ilmentävät seuraavat rokotevariantit:  rVSV-MARV  tai  rVSV-MARV-GP. 

VSV-EBOV is an experimental vaccine for the Ebola filovirus, developed by scientists at the Canadian National Microbiology Laboratory.^[1][2] VSV-EBOV is based on the vesicular stomatitis virus, which has been genetically engineered to express Ebola glycoproteins so as to provoke an immune response against real Ebola virus. The vaccine variant known as rVSV-ZEBOV, rVSV-ZEBOV-GP, VSVΔG-ZEBOV, or BPSC1001 expresses glycoproteins of the Zaire ebolavirus or ZEBOV, the species causing the highest mortality rate among the ebolaviruses, 
while rVSV-MARV or rVSV-MARV-GP expresses those of the closely related Marburg filovirus or MARV.

From Wikipedia, the free encyclopedia

VSV-EBOV

Vaccine description
Target disease	Ebola virus
Type	Recombinant Vector
Clinical data
Legal status	?
Identifiers
CAS number
ATC code	?

• Yksi ainoa lihakseen annettu EBOV- tai MARV- rokote  sai aikaan  täysin suojaavan immuunivasteen kädellisillä eläimillä,  Jaavanapinoilla ( Jaavan makaki)    ja ilman rokotetta    EBOV tai  vastaavasti MARV virukset olisivat olleet niille letaaleja. Rokotus sinänsä ei aiheuttanut kuumetta eikä muita taudinopireita.  On näyttöä myös siitä, että tämäntyyppinen rokote omaa mahdollisuuksia toimia  hoitona niille, jotka ovat jo infektoituneet.

 A single intramuscular injection of the EBOV or MARV vaccine induced completely protective immune responses in nonhuman primates (crab-eating macaques) against corresponding infections with the otherwise typically lethal EBOV or MARV.^[3][4] Also, the vaccination itself did not induce any fever or other symptoms of illness. There is also evidence that this type of vaccine may have potential as a treatment for those already infected.^[5][6]

•  Yksittäinen annos useita ebolaviruksia vastaan  suojaa antavaa  yhdistettyä  rokotetta  voisi ottaa käyttöön tehokkaammin erityisesti  sellaisissa  tapauksissa,  mitä Länsi-Afrikassa esiintyy. Sellaista yhdistettyä  VSV-GP rokotetta , joka ilmensi ZEBOV-GP, SUDV GP ja MARV GP yhtä suurissa pitoisuuksissa, annettiin  yksittäinen annos Jaavanmakakille. Tämä yhdistetty rokote antoi 100%  suojan seuraavia infektioita vastaan: ZEBOV, SUDV ja MARV ja vieläpä Tai Forest Ebola virusta (TAFV) vastaan.

A single-dose blended vaccine capable of protection against several ebolavirus species could be deployed more efficiently, especially in a setting such as Western Africa. Such a blended VSV-GP vaccine expressing ZEBOV GP, SUDV GP, and MARV GP in equal concentrations was administered as a single dose to crab-eating macaques.^[4] This blended vaccine provided 100% protection against a following infection with ZEBOV, SUDV, MARV, or even Taï Forest Ebola virus or TAFV.

• Rokotteen käytännön toteuttaminen laajalti   voisi olla paljon tehokkaampaa,  jos sitä voisi antaa suun kautta tai nenän sisäisesti tai nenätippoina. Tällaisten  antomallien  tehokkuutta mitattiin  VSVΔG-ZEBOV-GP rokotteen avulla käyttämällä koe-eläimenä Jaavanmamakia.  Neljälle eläimelle annettiin suun kautta rokotetta, neljälle nenänsisäisesti ja kahdelle lihakseen pistettynä. 28 päivää sen jälkeen infektoitiin ZEBOV- viruksella  ruiskuttamalla sitä   lihakseen,  mikä jo aiemmin  oli osoittautunut infektion aikaansaamisessa  letaalisemmaksi muodoksi.  Ei mikään  rokotetuista koe-eläimistä kehkeyttänyt mitään  kliinisiä taudinoireita, kun taas kaksi kontrollieläintä menehtyi samaan  infektioon.

Deployment of a vaccine can be even more efficient if it can be administered orally or intranasally as nose-drops. The efficacy of these modes of administration of a VSVΔG-ZEBOV-GP vaccine were assessed, using ten crab-eating macaques.^[7] Four animals received the vaccine orally, four intranasally, and two intramuscularly. Twenty-eight days later, all were infected with ZEBOV via intramuscular injection, already shown to be a more lethal mode of infection. None of the immunized animals developed any symptoms of clinical illness, while two additional control animals succumbed to the same infection.

• Vaikkakin uskotaan, että ebolavirukset eivät leviä luonnon olosuhteissa  aerosolin kautta, bioterrorin alalla  satettaisiin  leivtätä aerosolia, jotta voisi joutua sisäänhengityksen mukana kehoon.  Sentakia  vastaavanlaisen rokotteen tehoa testattiin mamakeilla, joita oli altistettu Ebola ja MArburgvirusten auerosoleille.  Kaikki rokotetut eläimet pysyivät kokeessa hengissä, kun taas rokottamattomat kontrollit kuolivat.

Although filoviruses are not believed to be transmitted by aerosol in a natural setting, a bioterrorist might disperse an aerosol that could be inhaled. Hence the effectiveness of the corresponding vaccine was tested for protection of crab-eating macaques against aerosol challenge with both Ebola and Marburg viruses.^[8] All vaccinated animals survived the exposure, while all control (untreated) animals perished.

• Turvallisuus on  sellaisten rokoteitten  olennaisena vaatimuksena , mitkä   perustuvat  replikaatiokykyisiin  ( eläviin) vektoreihin  tai kantajiin. - tarkoittaen sitä, että niiden ei tule kyetä aiheuttamaan  tauteja, joista  niiden  modifioimaton (luonnollinen)  isäntä  tai substraatti tunnetaan. 
• Tässä tapauksessa  originaalilla  vesikulaarisen stomatiitin viruksen (VSV) kuljettaja lla  on se etu, että  se vain harvoin  aihuttaa flunssan kaltaista  tautia ihmisessä, kun taas karjaeläimillä riski on  merkitsevä. On raportoitu  hermostovirulenssia ( mistä seuraa hermojärjestelmän tauia)  jyrsijöillä,  makakeilla, karjalla, lampailla ja hevosilla.  Tämän takia tehtiin koe josa injisoitiin  rVSV-ZEBOV-GP ja  rVSV-MARV-GP rokotteitä seitsemän terveen jaavanmakakin  thalamukseen ja kolmeen koe-eläimeen  muokakamatont VSV-virusta . Kahdelle nistä  kolmesta ilmentyi  vakavia neurologisia oireita ja kaikilla kolmella oli  suurehkoja vaurioita hermokudoksissa . Toisaalta taas  tautia ja hermovaurioita    ei  ei tullut yhteenkään  niistä 14 rokotetusta  eläimestä  Nämä tulokset tulkittiin niin että on vahvoja  viitteitä isäntäviruksen  alkuperäisen neurovirulenssin eliminoitumisesta muokkauksessa, mikä tukee   pyrkimyksiä     tällaisten   rokotteiden laajaan käyttöön.

A key requirement for such vaccines based on replication-competent (living) vectors or carriers is their safety, meaning their inability to cause the illnesses for which their unmodified ("wild") host or substrate is known. In this case, the original vesicular stomatitis virus carrier has the advantage of only rarely causing (flu-like) illness in humans, although it is a significant risk for farm animals. There have been reports of neurovirulence (causing disease within the nervous system) in rodents, macaques, cattle, sheep, and horses.^[9] Hence both a rVSV-ZEBOV-GP and a rVSV-MARV-GP vaccine were each injected into the thalamus of seven healthy crab-eating macaques, while wild (unmodified) vesicular stomatitis virus was similarly injected into three animals.^[9] Two of the latter three developed severe neurological symptoms, and major lesions were found in neural tissues from all three. On the other hand, none of the fourteen animals that received vaccine developed illness or neural lesions. These results were interpreted to strongly suggest that the original neurovirulence of the host virus is eliminated by the modification to make the vaccine, supporting efforts toward fielding such vaccines.

•  Rokotteen  kestoaika on se jakso rokottamisen jälkeen, jolloin rokotteen tehokkuus pysyy  tallella.
• rVSV-MARV-GP rokoteen kestoaikaa testattiin Jaavanmakakilla.  14 kuukautta rokottamisen jälkeen eläimet altitettiin Marburg virukselle. Niistä yksikään ei osoittanut kliinistä tautia, mikä merkitsee täydellsitä suojaa, kun taas kaksi kontrollieläintä menehtyi  Sellainen tehokkuuden kestoaika on tyypillistä rokotteille, jotka perustuvat  replikaatiokykyisiin vektoreihin.

The "durability" of a vaccine is the time period after vaccination during which it retains its effectiveness. The durability of an rVSV-MARV-GP vaccine was tested in six crab-eating macaques.^[10] Fourteen months after vaccination, the animals were exposed to Marburg virus. None showed any sign of clinical disease, demonstrating complete protection, while two control animals 
 died. Such durability is typical of vaccines based on replication-competent vectors.^[11]

• Kanadan kansanterveysvirasto omaa patentin rVSV-filovirus-GP-tyyppisille rokotteille., mutta se on antanut lisenssin pienelle amerikkalaiselle yhtiölle New Link Genetics, jotta tämä  voi kehitellä  ihmiskäyttöön  rVSV-ZEBOV rokotteen   omistamassaan  BioProtektio järjestelmässä Iowan valtion  tutkimuslaitoksessa  Amesissa. BioProtektio- järjestelmää tukee Amerikan Puolustusministeriö  ja puolustuksellista uhkaa  vähentävä virasto. NewlinkGenetics  yhtion rooli lie  pääasiassa kliinisten kokeitten organisointi Amerikassa, koska sillä ei ole rokotetta tuottavia laitoksia.

The Public Health Agency of Canada holds the patent associated with the rVSV-filovirus-GP type of vaccine, but has licensed a small U.S. company called NewLink Genetics to develop rVSV-ZEBOV for use in humans, in its wholly owned subsidiary BioProtection Systems at the Iowa State University Research Park in Ames, Iowa.^[12] In this work, BioProtection Systems is supported by the U.S. Defense Threat Reduction Agency, of the United States Department of Defense.^[13] The role of Newlink Genetics appears to be mainly the organization of clinical trials in the U.S., as it has no production facilities for the vaccine.^[14] 

•  Kanadalla oli noin 1500 rokotepulloa kliinisiä kokeita varten jo ennen vuoden 2014 L-Afrikan ebolapurkauksen   alkua. Newlinkin lisenssiä on kritisoitu. Amir Attaran,   juridiikan ja kansaterveyden professori Ottawan yliopistosta kehottaa vakavasti kumoamaan    lisenssin, koska  niin pienen yhtiön kokemus  alalla on vähäinen. Lisenssi myönnettiin silloin,  kun ei näyttänyt olevan kiirettä ebolarokotteen kanssa  ja sen takia kiinnostus suurten lääkeyhtiöitten taholta oli vähäinen.

 Canada had roughly 1,500 vials of vaccine made for clinical trials before the 2014 Ebola outbreak began in West Africa. The license with Newlink has come under criticism. Amir Attaran, a professor of law and population health at the University of Ottawa, has urged that the license be cancelled because of the limitations of such a small company with little experience in this area.^[15] The license was awarded when there seemed to be no urgency for an Ebola vaccine, and hence little interest from large pharmaceutical companies.

•  NewLink Genetics alkoi kliiniset kokeet Silver Spirngissä  Armeijan Walter Reed tutkimuslaitoksessa.    rVSV-ZEBOV rokotteella terveille ihmisille  ja arvioi immuunivasteen, tunnistaa kaikki sivuvaikutukset  ja määritelee hyväksyttävän  annoksen.

On October 13, 2014 at the Walter Reed Army Institute of Research in Silver Spring, Md., NewLink Genetics began clinical trials of rVSV-ZEBOV on healthy human subjects to evaluate the immune response, identify any side effects and determine the appropriate dosage.^[13][16][17]

• Amerikkalaisinsituetti NIAID   alkoi rekrytoida  terveitä  vapaaehtoisia  aikuisia 1  faasin kokeisiin, jotka ovat kaksoissokkokokeita, placebokontrolloituja  ja lisäksi annoksen nosto tutkitaan  ja turvallisuus sekä immunogeenisyys selvitään   tässä Prime-Boost VSV  Ebola rokotuksessa 

As of October, 2014, the U.S. National Institute of Allergy and Infectious Diseases (NIAID) was recruiting healthy human volunteers for a "Phase 1 Randomized, Double-Blind, Placebo Controlled, Dose-Escalation Study to Evaluate the Safety and Immunogenicity of Prime-Boost VSV Ebola Vaccine in Healthy Adults".^[18]

• Lokakuun 20 päivä 2014 on kanadan Kansaterveysvirasto lentorahtina kuljettanut 800 annosta VSV-EBOVrokotetta  WHO:lle Geneveen. Tämä rokotemäärä on tarkoitettu käytettäväksi I faasin kliinisissä kokeissa , jotka aloitetaan loppu-lokkususa tai marraskuun alussa  2014.Tästä  päätellään, rokotteen ihmiskäytön  turvallisuus ja jos se osoittautuu turvalliseksi, määritellään sopiva annos. WHO on rekrytoinut 250  vapaaehtoista, jotka ovat jo valmiina alkamaan kliiniset kokeet neljässä eri paikassa: Sveitsissä, Saksassa, Gabonissa ja Keniassa. Jos tästä ja seuraavista kokeista saadaan onnistuneet tulokset, tämän rokotteen käyttöönottoa Länsi-Afrikan kaltaisessa ympäristössä nopeutetaan  - toivottuna  vaatimuksena on,  että   yhden antokerran rokottaminen riittäisi.. Ja koska   kädellisillä eläimillä (non human primates)  altistuksen jälkeinen rokottaminen on ollut tehokasta voitaisiin saada aikaan suojaa  terveydenhoitotyöntekijöille, joitten epäillään  altistuneen virukselle.

On October 20, the Public Health Agency of Canada began air shipment of 800 doses of the VSV-EBOV vaccine to the WHO in Geneva.^[19] This vaccine is intended to be used in Phase I clinical trials, to start in late October or early November. This will determine if the vaccine is safe to use in humans and if so, determine the appropriate dosage. The WHO has recruited 250 volunteers ready to begin clinical trials in four locations: Switzerland, Germany, Gabon and Kenya. If results of this and following trials are positive, the deployment of this vaccine in environments such as West Africa would be facilitated by the expected requirement of only a single dose. Also, its effectiveness in nonhuman primates when administered even after exposure to the virus could help to protect health-care workers after a suspected exposure.

cAd3-ZEBOV ,Kokeellinen ebolavirusrokote, Rekombinantti vektori -tyyppinen rokote

cAd3-ZEBOV ( Wikipedia teksti)

From Wikipedia, the free encyclopedia

CAd3-ZEBOV

Vaccine description
Target disease	Ebola virus
Type	Recombinant Vector
Clinical data
Legal status	?
Identifiers
CAS number
ATC code	?

•  cAd3-ZEBOV tunnetaan myös nimellä NIAID/GSK ebolarokote tai lyhennyksenä cAd3-EBO Z ja se on kokeellinen rokote kahta  ebolatyyppitä Ebola virusta ja Sudan virusta vastaan. 

NIAID  tarkoittaa National Institute of Allergy and Infectious Diseases. Testaukset tehdään tämän isntituutin  alaisuudessa.
GSK tarkoittaa GlaxoSmih Kline. Rokotetta kehittelevät tiedemiehet ovt tästä lääkefirmasta.
Rokote on  johdettu simpanssin adenoviruksesta , ChAd3 , eli Chimpo Adenovirus type 3. Virusta on geneettisesti  muokattu ilmentämään glykoproteiineja, joita Zairen ja Sudanin ebolavirukset kantavat , tarkoitus on saada  kehittymään immuunivaste näille virusantigeeneille.


cAd3-ZEBOV (also known as the NIAID/GSK Ebola vaccine or cAd3-EBO Z) is an experimental vaccine for two ebolaviruses, Ebola virus and Sudan virus, developed by scientists at GlaxoSmithKline (GSK) and tested by National Institute of Allergy and Infectious Disease (NIAID). This vaccine is derived from a chimpanzee adenovirus, Chimp Adenovirus type 3 (ChAd3), genetically engineered to express glycoproteins from the Zaire and Sudan species of ebolavirus to provoke an immune response against them.

•  Viime kuussa , syyskuussa 2014 alkoivat samanaikaisesti I faasin kokeet Oxfordissa ja Bethesdassa - rokotetta  annetaan  vapaaehtoisille. Lokakuun aikana rokotetta annetaan isommalle vapaaehtoisryhmälle Malissa.  Jos tämä I faasi päättyy onnellisesti, rokote pääsee käyttöön Länsi-Afrikan epidemiassa.  Tähän valmistautuessan  GSK  tuottaa  10 000 annoksen varastoa.

 Simultaneous phase 1 trials of this vaccine commenced in September 2014, being administered to volunteers in Oxford and Bethesda.^[1] During October the vaccine is being administered to a further group of volunteers in Mali. If this phase is completed successfully, the vaccine will be fast tracked for use in the Ebola virus epidemic in West Africa. In preparation for this, GSK is preparing a stockpile of 10,000 doses.^[2][3]

 Ensimmäinen brittikoe

 Kun  kymmenen amerikkalaista oli ollut koerokotettavana   niin Ruth Atkins  ( syntynyt 1966) Oxfordshirestä ( Brittiläisen kansallisen terveydenhoidon ent. sairaanhoitaja) oli ensimmäinen brittiläinen vapaaehtoinen ja hän sai koekeellista rokotetta 12.9 2014  Oxfordissa  tehdyssä  rokotekokeilussa . Kokeilua rahoittaa  Wellcome Trust ja  Brittiläinen hallitus Tämä rokotevariantti on kaavailtu antamaan suojaa vain Ebolavirusta vastaan, mutta ei Sudan virusta vastaan.

First British trial

Following ten Americans who received the vaccine in a trial, Ruth Atkins (born 1966)^[4] of Oxfordshire, a former nurse with the British National Health Service, was the first British volunteer to receive the experimental vaccine (on September 17, 2014) in a vaccine trial run by Oxford University researchers and funded by the Wellcome Trust and the UK government. This variant was only designed to protect against Ebola virus and not Sudan virus.^[5]
See also

• VSV-EBOV
• ZMapp

References

1. "Experimental Ebola Vaccine Processed in Maryland". Drug Discov. Dev. Associated Press. 2 October 2014.
2. "First British volunteer injected with trial Ebola vaccine in Oxford". Guardian. 17 September 2014. Retrieved 17 September 2014.
3. "An Ebola vaccine was given to 10 volunteers, and there are ‘no red flags’ yet". Washington Post. 16 September 2014. Retrieved 17 September 2014.
4. First volunteer receives new Ebola vaccine in UK trial
5. First British volunteer injected with trial Ebola vaccine in Oxford, The Guardian, Wednesday 17 September 2014 12.01 EDT, accessed 09/17/2014

VLP partikkeli rokote EBOV:ia vastaan

Genome Medicine 2011, 3:5  doi:10.1186/gm219

The electronic version of this article is the complete one and can be found online at: http://genomemedicine.com/content/3/1/5


Viruksenkaltaisia partikkeleita (VLP)  sisältävät rokotteet 

Virus-like particle (VPL)  vaccines

•  Näitä viruksen kaltaisia partikkeleita generoituu yhdestä tai useammasta virusproteiinista ja ne matkivat luonnollisen virionin muotoa, muta eivät sisälttä geneettistä amteriaalia.  EBOV  VLP:t kehkeytyvät samaan aikaan kun ZEBOV ilmentää  GP, NP, VP40 kudosviljelysoluissa. Jos sitä kombinoi Ribi adjuvantin kanssa ja annostaa kolmasti  ei-ihmiskädellisille , seuraa  suojaa ZEBOV altistusta kohtaan.
• Toinen rokotekandidaatti oli replikaatiovajeinen ZEBOV, josta VP30 puuttui.  kaksi tällaista rokotetta  antoi hiirelle  ja  marsulle  suojaa letaalia ZEBOV virusta vastaan  viruslatistuksessa.

VLPs are particles generated by the expression of one or more viral proteins and mimic the natural viral conformation but do not contain viral genetic material. EBOV VLPs were generated by simultaneously expressing GP, NP and VP40 of ZEBOV in 293T cells, combined with Ribi adjuvant and administered three times to NHPs, resulting in protection against homologous ZEBOV challenge [71].  Another vaccine candidate recently investigated was a replication-deficient ZEBOV lacking the VP30 gene. Two vaccinations with this virus protected mice and guinea pigs from lethal ZEBOV challenge [72].

•  Vaikka on lupaavia rokotekandidaatteja,  EBOV infektion vastaiset suojavaikutukset ovat kuitenkin   korrelaatioiltaan  vielä selvittämättä.

Although there are now promising vaccine candidates, the correlates of protection from EBOV infection are still poorly understood. 

•  Kun yhdistää  olemassaolevat rokotteet    tutkimuksen osoittamiin protektioihin  ja  kun soveltaa genomisia strategioita, pitäisi tuloksena olla  rokottamistehon paraneminen ja parempi altistuksen jälkeinen hoito ja/tai   kaikilta neljältä  Afrikan alueen  EBOV virukselta  kattavasti  suojaava rokote

Combining existing vaccine candidates with research into the correlates of protection and applying genomics strategies should result in improved vaccines effective as post-exposure treatment and/or vaccines that cross-protect against all four African EBOV.s. 

27.10.12014 

Saatavilla olevaa interventioterapiaa : antisense antivirusyhdisteitä

http://www.google.com/patents/US8703735
TÄMÄ ARTIKKELI NÄYTTÄÄ SELVTTÄVÄN  TÄMÄN STRATEGIAN PERUSTEELLISESTI:
Lue koko artikkeli perusteellisesti.  Sitten voi hakea myös luonnosta molekyylejä, jotka muistuttavat  luotuja  antisense antiviraaliyhdisteitä.
(Huomaa yhdisteiden piperaziinitumaa muistuttava ydin, sillä piperaziini  on Hexahydropyrazine; Piperazidine; Diethylenediamine, siis niissä on  kaksi typpeä, mutta näissä yhdisteissä on toinen korvattu hapella- Piperaziinitumaa on muokattu muutenkin monenlaisiksi lääkkeiksi: http://en.wikipedia.org/wiki/Piperazine)
Näissä antivirusmolekyyleissä piperaxiinin rooli on luoda hyvin linkkiytynyt runko, joka muistuttaa aika paljon genomista  ketjurakennetta ja sen takai pystyy tekemään inteaktion haluttuun genomisen koodin kohtaan.

 

Antisense antiviral compounds and methods for treating a filovirus infection
US 8703735 B2

YHTEENVETO

• Artikkeli käsittää  inventaarion  antivrus- yhdisteistä, niitten koostumuksesta  ja  niiden käyttömetodeista ja tuotannosta- mitkä  keskittyvät lähinnä Filo-virusten- Ebola ja Marburg virus mukaanluettuina- replikaation estoon. Näitä  myös  katsotaan  suhteessa sekä nisäkkäitten että kädellisten  Ebola ja Marburgvirusinfektioitten hoitoon.

Sammanfattning

The present invention provides antisense antiviral compounds, compositions, and methods of their use and production, mainly for inhibiting the replication of viruses of the Filoviridae family, including Ebola and Marburg viruses.  The compounds, compositions, and methods also relate to the treatment of viral infections in mammals including primates by Ebola and Marburg viruses. 

•  Antisense- antivirusyhdistyksiin kuuluu fosforodiamidaatti- morfolino-oligonukleotidit (PMOplus)  joilla on  nukleaasille vastustuskykyinen runkorakenne, noin 15- 40  nukleotidiemästä, joissa ainakin kaksi mutta yleensä useampi,  ei  kuitenkaan yli puolet niitten määrästä  omaa  piperaziinin sisältävän,   alayksikköjen välisen sidoksen ja kohdistavan sekvenssin, jonka kohteena on  AUG- startti -alue  Ebolaviruksen  VP35, VP24, Marburg viruksen  VP24 tai Marbugviruksen  NP proteiineja    koodaavissa jaksoissa.

The antisense antiviral compounds include phosphorodiamidate morpholino oligonucleotides (PMOplus) having a nuclease resistant backbone, about 15-40 nucleotide bases, at least two but typically no more than half piperazine-containing intersubunit linkages, and a targeting sequence that is targeted against the AUG start site region of Ebola virus VP35, Ebola virus VP24, Marburg virus VP24, or Marburg virus NP, including combinations and mixtures thereof.

EBOV virusinfektiossa heti altistumisen jälkeen annettu adjuvantti mAb-perusteinen terapia plus antisense antivirusterapia

Volume 22, Issue 8, August 2014, Pages 456–463

Review

Post-exposure therapy of filovirus infections

• Gary Wong^{1, 2},
• Xiangguo Qiu¹,
• Gene G. Olinger³,
• Gary P. Kobinger^{1, 2, 4, 5}

DOI: 10.1016/j.tim.2014.04.002

Get rights and content

---

Highlights

•

Interventions given 1 hour after Ebola virus exposure were ineffective in nonhuman primates (NHPs), with the exception of monoclonal antibody (mAb)-based therapy and BCX4430.

Adjuvanted mAb therapy offers 100% protection for up to 72 hours after Ebola virus infection.

•

mAb therapy is effective even after positive confirmation by reverse transcription-quantitative PCR (RT-qPCR) and fever.

---

Filovirus infections cause fatal hemorrhagic fever characterized by the initial onset of general symptoms before rapid progression to severe disease; the most virulent species can cause death to susceptible hosts within 10 days after the appearance of symptoms. Before the advent of monoclonal antibody (mAb) therapy, infection of nonhuman primates (NHPs) with the most virulent filovirus species was fatal if interventions were not administered within minutes.
+
 A novel nucleoside analogue, BCX4430, has since been shown to also demonstrate protective efficacy with a delayed treatment start.

This review summarizes and evaluates the potential of current experimental candidates for treating filovirus disease with regard to their feasibility and use in the clinic, and assesses the most promising strategies towards the future development of a pan-filovirus medical countermeasure.

Keywords

• filovirus;
• Ebola;
• Marburg;
• monoclonal antibodies;
• immunotherapy;
• post-exposure

Ebola rokote 2015 GSK and NewLink

News Feature | October 6, 2014

GSK, NewLink Race To Bring Ebola Vaccines Online By 2015

By Estel Grace Masangkay

The World Health Organization revealed that pharmaceutical companies GlaxoSmithKline and NewLink Genetics are working double time to ramp up their capacity to produce Ebola vaccine candidates. The companies hope to bring an effective Ebola vaccine online by 2015, reports Reuters.

Both companies are currently conducting Phase 1 trials of their vaccine candidates in healthy volunteers. GSK dosed its first healthy volunteer in the U.K. last month as part of its safety trials to test its vaccine against the Zaire strain of Ebola virus. The study will assess whether GSK’s vaccine is safe and able to stimulate the production of antibodies to fight the deadly virus. A total of 60 volunteers will be enrolled for the trial, which is expected to be completed by the end of year. GSK expects to deploy the vaccines on an emergency basis shortly after the trials’ conclusion.

Last month, biopharmaceutical company NewLink Genetics announced that the U.S. Food and Drug Administration (FDA) had given the green light for the initiation of its own Phase1 trial for its Ebola vaccine candidate. The vaccine was originally developed by the Public Health Agency of Canada (PHAC) and is currently licensed to NewLink’s subsidiary, BioProtection Systems. The vaccine targets the protein coating of the virus and stimulates antibody response for virus neutralization. Approximately 40 healthy volunteers will be given the vaccine in the trial, which will investigate different dosing schedules and methods of extending the drug to other vulnerable populations.

“Both [GSK and NewLink] are working to augment their manufacturing capacity. The goal is a very significant increase in scale during the first half of 2015. The next step is to make these vaccines available as soon as possible – and in sufficient quantities – to protect critical frontline workers and to make a difference in the epidemic’s future evolution,” the WHO stated in its two-day meeting.

With the first report of Ebola’s presence in the U.S. following its recent outbreak in Africa, the urgency to quickly test and manufacture Ebola vaccines has intensified. Time reports that one of the ways clinical trials can be accelerated is through the ‘wedge’ approach. The goal is to study a “slice” or “wedge” of a target population for the first step of the trial. Investigators then apply the insights gathered from that first stage on to the the next as a new population “slice” is studied. Such methods can help speed up clinical trials for the vaccines, which normally takes a few years to go through the development program and secure regulatory approval.

26.10.2014
Lisäys  EBOLA virus epitoopeista tietoa


http://cdn.f1000.com/posters/docs/311

WHO 26 Oct 2014 . Now: 10 141 EVD cases in the world,. mortality ca 49%.

World Health Organization: Ebola Cases In Africa Top 10,000

Doug Mataconis   ·   Sunday, October 26, 2014   ·   2 Comments

The World Health Organization has upped the number of people known to be infected with Ebola in Africa to over 10,000:

GENEVA — The number of people infected with Ebola in three West African countries has exceeded 10,000, the World Health Organization reported Saturday.
A total of 10,141 people had contracted the disease worldwide, the organization said in its latest update on the progress of the epidemic, and the number reported to have died rose to 4,922.  ( Mortality 48,55% )

The W.H.O. acknowledged that its figures understated the reality of Ebola’s spread.
All but 27 of the infections and all but three of the deaths have occurred in the West African countries of Guinea, Liberia and Sierra Leone, according to report.
A fourth country, Mali, has reported its first confirmed Ebola case, the death of a 2-year-old child from the disease on Friday.
The group said it was treating the situation as an emergency because the child was displaying symptoms when he rode hundreds of miles by public bus from neighboring Guinea, which presented “multiple opportunities for exposures — including high-risk exposures — involving many people.”
Malian authorities have isolated 43 people, including 10 health care workers who had contact with the child in the town of Kayes, where she was taken for treatment, the W.H.O. said.
But the authorities face the daunting task of tracing other people who were exposed to the child during her lengthy journey, which included a stop over of several hours in Mali’s capital, Bamako.
Mali, one of Africa’s poorest nations, had appeared to be highly vulnerable to a spillover of the Ebola virus from neighboring countries still struggling to contain the epidemic, which began nine months ago. It has limited infrastructure and a fragile central government weakened by years of internal conflict.

Once again, this demonstrates the importance of fighting the battle against Ebola in western Africa.

Muistiin MALIN ensimmäinen keisi dg 23.10: Tarttuttavien 2 henkilön matka Guineasta ebolapotilaan hautajaisista 19..10. bussilla Maliin

 Suomen Huvudstadsbladet kirjoitaa ruotsinkielellä:

 http://hbl.fi/nyheter/2014-10-25/672771/who-varnar-ebola-i-mali

WHO antaa varoituksia: 

Mali confirms its first case of Ebola

Ebola situation assessment - 24 October 2014

Mali’s Ministry of Health has confirmed the country’s first case of Ebola virus disease. The Ministry received positive laboratory results, from PCR testing, on Thursday and informed WHO immediately. In line with standard procedures, samples are being sent to a WHO-approved laboratory for further testing and diagnostic work.

Details about the case

In telephone conversation on Thursday night, health officials gave WHO the following details about the case, which is currently undergoing intense investigation.
The patient is a two-year-old girl, who recently arrived from Guinea accompanied by her grandmother. The child’s first contact with the country’s health services occurred on 20 October, when she was examined by a health care worker at Quartier Plateau in Kayes, a city in western Mali on the Senegal River.
Kayes has a population of around 128 000 people. It is located about 600 kilometres from the capital city of Bamako and lies near the border between Mali and Senegal.
The health-care worker referred the grandmother and child to the Fousseyni Daou Hospital, in the same city, where she was admitted to the paediatric ward on the following day, on 21 October. Symptoms on admission included a fever of 39°C, cough, bleeding from the nose, and blood in the stools.
Test results were negative for malaria, but positive for typhoid fever. The child received paracetamol, but did not improve. Further testing at the country’s SEREFO laboratory confirmed Ebola virus as the causative agent on 23 October.
Initial investigation of this case – the first confirmed in Mali – has revealed the extensive travel history of the child and her grandmother. The grandmother travelled from her home in Mali to attend a funeral in the town of Kissidougou, in southern Guinea.
WHO is seeking confirmation of media reports that the funeral was for the child’s mother, who is said to have shown Ebola-like symptoms before her death. These and other facts will be communicated as they are confirmed.

Additional facts communicated to WHO

On 19 October, the grandmother left Guinea to return to Mali, taking the child with her. The case history revealed that bleeding from the nose began while both were still in Guinea, meaning that the child was symptomatic during their travels through Mali.
Travel was by public transport through Keweni, Kankan, Sigouri, and Kouremale to Bamako. The two stayed in Bamako for two hours before travelling on to Kayes. Multiple opportunities for exposure occurred when the child was visibly symptomatic.

Prompt emergency response

WHO is treating the situation in Mali as an emergency. The child’s symptomatic state during the bus journey is especially concerning, as it presented multiple opportunities for exposures – including high-risk exposures - involving many people.
Continued high-level vigilance is essential, as the government is fully aware.
The child is being treated in isolation and staff have received training in appropriate procedures for safe management. The initial investigation identified 43 close and unprotected contacts, including 10 health-care workers, who are also being monitored in isolation.
The authorities in Mali have acted swiftly, also in communicating their immediate needs to WHO. These needs include training in infection prevention and control, adequate supplies of personal protective equipment, and assistance with contact tracing and overall investigation of the event.
Fortunately, key staff from WHO and the US Centers for Disease Control and Prevention (CDC) were already in Mali assisting with the country’s preparedness measures, should an imported case occur.
The WHO team already on the ground includes an infection control expert and a logistician. These and other staff are now being repurposed to assist in a surge response to the outbreak. WHO is urgently deploying a rapid response team comprising experts in clinical management, epidemiology, contact tracing, logistics and social mobilization.
WHO and the Ministry of Health see a need to accelerate the completion of an isolation facility in Bamako, and WHO has offered its support. In addition, the public needs to be informed of the situation as it evolves, including facts about the emergency actions already under way.
Outbreaks in other parts of West Africa have demonstrated how fear and anxiety, fuelled by misinformation and disinformation, if left unchecked, can be a major barrier to even the best-orchestrated containment efforts.
Both Senegal and Nigeria, two countries now declared free of Ebola virus transmission, used effective community information and education initiatives, often conducted as house-to-house campaigns, as an integral component of the outbreak response.

KTN- domeenitutkimus EBOV matrixproteiinissa VP40 ja sen konformaatiomuutoksista

• LÄHDE 1.

Novel Strategies to Combat Ebolavirus

books.google.se/books?isbn=0549803394 - Översätt den här sidan

Peter J. Halfmann - 2008

Viral matrix proteins interact with various cellular cargo proteins from the ESCRT ... Ebolavirus VP40 possesses two overlapping late domains, PTAPPEY, in its ...

•  LÄHDE 2. 

EBOV matrixproteiini VP40 kokoontuu ihmisen solun plasmakalvon sisälehteen säätelemään siinä viruksen  silmukoitumista ulos solusta.  VP40 voi siinä kohtaa tuotta myös viruksen kaltaisia partikkeleita VLP, joisa ei ole muita EBOV proteiineja mukana.  Mekanistiset yksityiskohdat kuitenkin tässä  viruksen vapautumiselle tärkeässä VP40-interaktiossa ja proteiini-proteiinivuorovaikutuksessa ovat kuitenkin ollet  selvittämistä vailla.  Nyt tutkijat mutatoivat  N-terminaalisen KTN domaanin AAA- domaaniksi ja katsoivat mikä merkitys KTN-domaanilla oli tähän VP40 toimintaan.

KTN- domeenin mutatointi. vaikutti  konformaatioplastisuuteen, VP40 -oligomerisoitumiseen ja viruksen kaltaisten partikkelien (VLP) vapautumiseen , sillä modifiointi vähensi  matrixproteiinin VP40  asettautumista plasmakalvoon.  

 

Viruses. 2014 Oct 17;6(10):3837-54. doi: 10.3390/v6103837.A Loop Region in the N-Terminal Domain of Ebola Virus VP40 Is Important in Viral Assembly, Budding, and Egress.

Adu-Gyamfi E¹, Soni SP², Jee CS³, Digman MA⁴, Gratton E⁵, Stahelin RV⁶.

 It is well established that VP40 assembles on the inner leaflet of the plasma membrane of human cells to regulate viral budding where VP40 can produce virus like particles (VLPs) without other Ebola virus proteins present. The mechanistic details, however, of VP40 lipid-interactions and protein-protein interactions that are important for viral release remain to be elucidated.
Here, we mutated a loop region in the N-terminal domain of VP40 (Lys127, Thr129, and Asn130) and find that mutations (K127A, T129A, and N130A) in this loop region reduce plasma membrane localization of VP40. Additionally, using total internal reflection fluorescence microscopy and number and brightness analysis we demonstrate these mutations greatly reduce VP40 oligomerization.
 Lastly, VLP assays demonstrate these mutations significantly reduce VLP release from cells. Taken together, these studies identify an important loop region in VP40 that may be essential to viral egress.

• LÄHDE3. 

EBOV  matrixproteiinilla on konformaatioplastisuutta. Se voi muuttua  monomeeristä, dimeeriksi, trimeeriksi, oligomeeriksi joka on hexameeri tai RNA:ta sitovaksi oktameeriksi.   Tämä  konformaatioplastisuus,   viruksen elinsyklinvaiheen mukainen plastinen sopeutuvuus-  vaaditaan viruksen elinsykliin, joten tässä tarjoutuu mahdollisuus kehittää VP40 spesifisiä lääkkeitä. Tällaisella  konformaatioplastisuudella virus korvaa genominsa pientä kokoa, mikä rajoittaa viruksen adaptoitumista.

Protein Sci. 2014 Aug 26. doi: 10.1002/pro.2541. [Epub ahead of print] Conformational plasticity of the Ebola virus matrix protein.

Radzimanowski J¹, Effantin G, Weissenhorn W.

Filoviruses are the causative agents of a severe and often fatal hemorrhagic fever with repeated outbreaks in Africa. They are negative sense single stranded enveloped viruses that can cross species barriers from its natural host bats to primates including humans. The small size of the genome poses limits to viral adaption, which may be partially overcome by conformational plasticity. Here we review the different conformational states of the Ebola virus (EBOV) matrix protein VP40 that range from monomers, to dimers, hexamers, and RNA-bound octamers. This conformational plasticity that is required for the viral life cycle poses a unique opportunity for development of VP40 specific drugs.
 Furthermore, we compare the structure to homologous matrix protein structures from Paramyxoviruses and Bornaviruses and we predict that they do not only share the fold but also the conformational flexibility of EBOV VP40.© 2014 The Protein Society.

KEYWORDS:  Ebola virus; VP40; assembly; budding

Ebola Reston virus

Evolutionary characteristics of a UTR in Ebolavirus

 http://www.linkedin.com/pub/robert-anthony-ricketson/41/816/38a

June 2011 – Present

Pseudoknots within RNA virus genomes are felt to be involved in regulatory function. In the nucleoprotein 5' UTR, a pseudoknot is identified by RNAStructure and Pseudoviewer in RESTV, TAFV, and BDBG apart from the known transcription regulatory sequence. This structure is absent in the more virulent Zaire and Sudan ebolavirus.

EBOV-interaktomitutkimus vahvisti DNA topoisomeraasin TOP1:n cofaktoriosan EBOLreplikaatiossa

22 lokakuuta 2014 
http://acceleratingscience.com/proteomics/mass-spectrometry-analysis-for-co-factors-involved-in-ebola-virus-replication/

 LC-MS/MS analysis identified 65 candidate proteins that co-precipitated as the EBOL interactome. Of these, the researchers chose nuclear protein DNA topoisomerase 1 (TOP1) for further investigation because previous studies had implicated this enzyme in RNA viral replication. TOP1 first unwinds the nucleic acid helical structure to allow transcription and replication by cleaving phosphodiester bridges, and it then repairs the cut ends. To begin, Takahashi and co-authors used Western blotting to confirm that TOP1 co-precipitated with EBOL. They also revealed cellular location with immunofluorescence—demonstrating that, following treatment with Venus-EBOL, TOP1 co-localized in the cytoplasm as well as in the nucleus.

To study the effect of TOP1 on viral replication, the team infected cells with an EBOV mutant in the presence or absence of small interfering TOP1 RNA (siTOP1). They found that treatment with siTOP1 downregulated TOP1 and reduced viral replication. Treatment did not, however, affect in vitro infection using two other viruses, vesicular stomatitis virus (VSV) or influenza virus, suggesting the response was EBOV-specific. Furthermore, using a mini-genome assay to investigate RNA-dependent polymerase activity, the scientists found that knockdown of TOP1 reduced EBOV enzyme activity but not that of the influenza virus.
In order to understand and further confirm the interaction between EBOL and the host cell protein, Takahashi et al. next examined whether TOP1’s DNA and RNA phosphodiester bridge-cleaving action was involved in promoting viral replication. Using mutant TOP1 constructs, the researchers found that following siTOP1 downregulation of cellular EBOL polymerase, transfection with a TOP1 mutant containing the phosphodiester bridge-cleaving activity restored activity of the viral enzyme. For further confirmation of the EBOL co-factor in EBOV replication, the researchers saw that treating infected HEK293 cells with irinotecan (CPT-11) and topotecan, inhibitors of TOP1, also reduced specific polymerase activity.
The authors propose that information arising from the characterization of the EBOV interactome in host cells will aid in drug discovery for the treatment of this deadly disease.

Linkkejä Ebolavirukssta

http://allie.dbcls.jp/pubmed/EBOV;Ebola+virus.html

EBOV struktuurin yksityiskohdat

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306676/

 

DNA topoisomeraasien estäjiä etsitään onkologian alalla

Dalton Trans. 2014 Oct 15. [Epub ahead of print] Dual inhibition of topoisomerases I and IIα by ruthenium(ii) complexes containing asymmetric tridentate ligands.

Du K¹, Liang J, Wang Y, Kou J, Qian C, Ji L, Chao H.

Abstract

Five novel ruthenium(ii) complexes, [Ru(dtzp)(dppt)]²⁺ (), [Ru(dtzp)(pti)]²⁺ (), [Ru(dtzp)(ptn)]²⁺ (), [Ru(dtzp)(pta)]²⁺ () and [Ru(dtzp)(ptp)]²⁺ () (where dtzp = 2,6-di(thiazol-2-yl)pyridine, dppt = 3-(1,10-phenanthroline-2-yl)-5,6-diphenyl-as-triazine), pti = 3-(1,10-phenanthroline-2-yl)-as-triazino-[5,6-f]isatin, ptn = 3-(1,10-phenanthroline-2-yl)-as-triazino[5,6-f]naphthalene, pta = 3-(1,10-phenanthroline-2-yl)-as-triazino[5,6-f]acenaphthylene, and ptp = 3-(1,10-phenanthroline-2-yl)-as-triazino[5,6-f]-phenanthrene), were synthesised and characterised. The structures of complexes were determined by X-ray diffraction. The DNA binding behaviours of the complexes were studied by spectroscopic and viscosity measurements. The results suggested that the Ru(ii) complexes, except for complex , bind to DNA in an intercalative mode. Topoisomerase inhibition and DNA strand passage assay confirmed that Ru(ii) complexes , , and acted as efficient dual inhibitors of topoisomerases I and IIα. In vitro cytotoxicity assays indicated that these complexes exhibited anticancer activity against various cancer cell lines. Ruthenium(ii) complexes were confirmed to preferentially accumulate in the nucleus of cancer cells and induced DNA damage. Flow cytometric analysis and AO/EB staining assays indicated that these complexes induced cell apoptosis. With the loss of the mitochondrial membrane potential, the Ru(ii) complexes induce apoptosis via the mitochondrial pathway.

PMID:

25315107

[PubMed - as supplied by publisher]

Isäntäsolun Karyopherin alfa 1, johon EBOV VP24 kiinnittyy

Kuva esittääkysymyksen: meneekö VP24 itse  tuolla karyopherin-alfa-osoitelapulla  tuman puoellle.Violetti  dimeeri kuvaa isäntäsolun PY-STAT1 tekijää, joka koetaa  saada osoitelappua tuman suuntaan, muta Ebov tekijä( kolmio) nappaa signaalin ja  ehkä menee itse tumaan. tuman puolelle,arvelee kuvan tekijä.  Toisaalta on osoitettu että  VP24 tekijää  myös hyäkkää suoraan STAT1 kimppuun.
Mitä se VP24  siellä tumassa tekisi ??

• Minkälainen on Karyopherin alpha 1, isäntäsolun molekyyli, tumaan johdattava signaali.

From Wikipedia, the free encyclopedia

Karyopherin alpha 1 (importin alpha 5)
PDB rendering based on 2jdq.
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	KPNA1 ; IPOA5; NPI-1; RCH2; SRP1
External IDs	OMIM: 600686 MGI: 103560 HomoloGene: 55642 GeneCards: KPNA1 Gene
[show]Gene ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3836	16646
Ensembl	ENSG00000114030	ENSMUSG00000022905
UniProt	P52294	Q60960
RefSeq (mRNA)	NM_002264	NM_008465
RefSeq (protein)	NP_002255	NP_032491
Location (UCSC)	Chr 3: 122.14 – 122.23 Mb	Chr 16: 35.98 – 36.04 Mb
PubMed search	[1]	[2]

Importin subunit alpha-1 is a protein that in humans is encoded by the KPNA1 gene.^[1]
Recombination activating proteins RAG1 and RAG2 regulate and mediate V(D)J recombination, the process by which genes for immunoglobulins and T-cell receptors are generated. Several other ubiquitously expressed proteins are thought to be recruited in the recombination process. Among these are the genes affected in severe combined immune deficiency and genes involved in ds-DNA break repair. The protein encoded by this gene interacts with RAG1 and may play a role in V(D)J recombination^[2]

Interactions

Karyopherin alpha 1 has been shown to interact with KPNB1^[3][4] and UBR
Tähän voi siis lisätä: EBOV VP24  ja  PY-STAT1
 

EBOV sammuttaa tehokkaasti antivirusjärjestelmän. VP35 ja VP24 avulla.

Nsinnäkin  Ebolavirusproteiini VP24 sitoutuu karyoferiinialfa1:een ja blokeeraa STAT1 tumakertymän. 

LÄHDE: 
http://jvi.asm.org/content/80/11/5156.abstract
 Tietoa vodelta 2005
Ebola Virus VP24 Binds Karyopherin α1 and Blocks STAT1 Nuclear Accumulation

1. St. Patrick Reid1,†,
2. Lawrence W. Leung1,†, et al.

1. ¹Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029
2. ²Special Pathogens Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, MS G-14, Atlanta, Georgia 30329
3. ³Filovirus Laboratory, University Claude Bernard Lyon-1, INSERM U412, 69007 Lyon, France

Suomennosta

•  Ebolavirusinfektio blokeeraa  solun alfa/beeta interferonituotannon  ja  solujen kyvyn vastata alfa/beeta tai gamma-interferoniin. 

Jo aiemmin on osoitettu että ebolaviruksen VP35 on  EBOV:in koodamaa  IFNalfa/beeta-tuotannon inhibiittori. Kuitenkin se mekanismi, jolla EBOV estää interferonin vasteita ei ennen  vuotta 2004-5  oltu  määritelty

Ebola virus (EBOV) infection blocks cellular production of alpha/beta interferon (IFN-α/β) and the ability of cells to respond to IFN-α/β or IFN-γ. The EBOV VP35 protein has previously been identified as an EBOV-encoded inhibitor of IFN-α/β production. However, the mechanism by which EBOV infection inhibits responses to IFNs has not previously been defined. 

•  Tutkijaryhm tässä työssään osoittavat , että ebolaviruksen VP24  toimii IFN-alfa/beeta ja IFN-gammasignaloinnin estäjänä.   VP24 ilmenemä johtaa IFN- indusoimien geenien  expression  estymään  ja täten  interferonien kyvyttömyyteen  saada aikaan antivirusvalmiustila kehossa.

Here we demonstrate that the EBOV VP24 protein functions as an inhibitor of IFN-α/β and IFN-γ signaling. Expression of VP24 results in an inhibition of IFN-induced gene expression and an inability of IFNs to induce an antiviral state. 

•  VP24 välitteinen interferonien soluvasteiden estymä korreloi  tyrosiinifosforyloidun  STAT1 (PY-STATI) tekijän   huonontuneeseen  kertymiseen tuman puolelle. Fosforyloitunut STAT1 on avainaskel sekä IFNalfa/beeta että IFN-gamma signaloinnissa. 

The VP24-mediated inhibition of cellular responses to IFNs correlates with the impaired nuclear accumulation of tyrosine-phosphorylated STAT1 (PY-STAT1), a key step in both IFN-α/β and IFN-γ signaling. 

•  Yhtäpitäen  tämän VP24:n oletetun  funktion kanssa EBOV-infektoituneissa soluissa  havaitaan myös  blokeerautuminen IFN- indusoituvassa PY-STAT1:n tumaan kertymisessä.

Consistent with this proposed function for VP24, infection of cells with EBOV also confers a block to the IFN-induced nuclear accumulation of PY-STAT1.

•  Sitten havaittiin lisäksi, että  VP24 erityisesti vuorovaikuttaa karyoferiini alfa1:n kanssa, joka on  NLS-reseptori  eli tumaan paikallistava signaalireseptori PY-STAT1:proteiinissa.  Mutta VP24 ei  tehnyt interaktiota  muihin karyoferiineihin ( alfa2, alfa3 tai alfa4) .

Jos VP24  oli yliexpressoituneena,  erkani  karyoferiini alfa1-PY-STAT1- keskinen  interaktio, mikä  viittaa siihen, että VP24-karyoferiini alfa1 interaktio vaikuttaa oman osansa interferonisignaloinnin blokeerautumiseen.

 Nämä tiedot viittaavat siihen, että VP24 on todennäköisesti tärkeä  virulenssin merkitsijä, joka sallii EBOV  viruksen  välttää interferonien (IFN) antivirusvaikutukset.

 Further, VP24 is found to specifically interact with karyopherin α1, the nuclear localization signal receptor for PY-STAT1, but not with karyopherin α2, α3, or α4. Overexpression of VP24 results in a loss of karyopherin α1-PY-STAT1 interaction, indicating that the VP24-karyopherin α1 interaction contributes to the block to IFN signaling. These data suggest that VP24 is likely to be an important virulence determinant that allows EBOV to evade the antiviral effects of IFNs.

• Received 7 November 2005. 
• Kommentti: Jos solun interferonijärjestelmä voisi vapaasti virittää solulle antivirusvalmiustilan,   se saattaisi aktivoida yli 100 antivirusfunktiota omaavaa geeniä. Tämän EBOV tehokkaasti estää. VP35 ja VP24 proteiineillaan.