Etsin punkkienkefaliittiviruksen kaavakuvaa, mutta...tässä on toinen flavivirus ZIKV

Näistä flaviviruksista tulee esiin vain Zikaviruksen kuva lähinnä.  Se on kyllä hyvin kartoitettu, mutta olisi pitänyt kartoittaa punkkienkefaliittivirus TBEV  ensin paremmin ja havaita sen evaasiot ja anntiviraalit  potentiaaliset lääkkeet , että voidaan sitten käsitellä Zikavirus, Nyt jää punkkienkefaliittivirus TBEV  jälleen  vähemmälle  huomiolle, vaikka se on oikeastaan  relevantimpi siksi että sen historia on niin pitkä ja  sen mustan  aukon kohdat  tunnistetaan suurin piirtein-  ja  Zika on samannäköinen-  mutta aiheuttaa  jo niin nopeat katastrofaaliset  taudit,  jotta  asia on livennyt hallinnasta jo siihen tasoon, että  ehkä ajatellaan mieluummin " annihiloida maailman itikat".

Tässä ollaan joudutti aikojen bermudaan.

Zikavirus  on flavivirus  kuten puutiaisaivokuumevirus.  TBEV.
Saan ainakin Zikaviruksen kuvan tähän.
http://viralzone.expasy.org/24?outline=all_by_species

Flavivirus

More on Zika virus here

VIRION

Enveloped, spherical, about 50 nm in diameter. The surface proteins are arranged in an icosahedral-like symmetry. Mature virions contain two virus-encoded membrane proteins (M and E), while immature virions contain a membrane protein precursor (prM).
Source: Zhang et al(Pubmed )

GENOME

Monopartite, linear, ssRNA(+) genome of of 10-11 kb. The genome 5' end has a methylated nucleotide cap for canonical cellular translation. The 3' terminus is not polyadenylated but forms a loop structure. This secondary structure leads to the formation of a subgenomic flavivirus RNA (sfRNA) through genomic RNA degradation by host XRN1. sfRNA is essential for pathogenicity , and may play a role in inhibiting host RIG-I antiviral activity as shown for Dengue virus

GENE EXPRESSION

The virion RNA is infectious and serves as both the genome and the viral messenger RNA. The whole genome is translated in a polyprotein, which is processed co- and post-translationally by host and viral proteases.

REPLICATION

1. Attachement of the viral envelope protein E to host receptors mediates internalization into the host cell by clathrin-mediated endocytosis, or by apoptotic mimicry
2. Fusion of virus membrane with host endosomal membrane. RNA genome is released into the cytoplasm.
3. The positive-sense genomic ssRNA is translated into a polyprotein, which is cleaved into all structural and non structural proteins (to yield the replication proteins).
4. Replication takes place at the surface of endoplasmic reticulum in cytoplasmic viral factories. A dsRNA genome is synthesized from the genomic ssRNA(+).
5. The dsRNA genome is transcribed/replicated thereby providing viral mRNAs/new ssRNA(+) genomes.
6. Virus assembly occurs at the endoplasmic reticulum. The virion buds at the endoplasmic reticulum and is transported to the Golgi apparatus.
7. The prM protein is cleaved in the Golgi, thereby maturing the virion which is fusion competent.
8. Release of new virions by exocytosis.

TBE- rokote , Rokote punkkienkefaliittia vastaan

https://www.1177.se/Vastra-Gotaland/Tema/Vaccinationer/Vaccinationer/Vaccination-mot-TBE/?ar=True

Flavivirusrokotteiden tilanne 2017

https://www.ncbi.nlm.nih.gov/pubmed/28486135

Recent advances in human flavivirus vaccines.

Scherwitzl I¹, Mongkolsapaja J², Screaton G³.

Abstract

Dengue (DENV), West Nile (WNV) and Zika (ZIKV) viruses are mosquito-transmitted flaviviruses that cause thousands of human deaths and millions of illnesses each year. In the last decades, epidemic outbreaks of all three flaviviruses emerged and caused a major health and economical problem in many parts of the world. The increasing and expanding burden of flaviviruses has highlighted the need for effective human vaccines against all three viruses. This review provides an overview of the recent progress in DENV, WNV and ZIKV vaccines development with specific focus on candidates in human clinical development.

Copyright © 2017 Elsevier B.V. All rights reserved.

PMID:

28486135

DOI:

10.1016/j.coviro.2017.04.002

Punkin aiheuttamista taudeista pahempi: virusenkefaliitti TBE.

Punkki aiheuttaa bakterritautia borrelioosia ja borrelia on spirokeetta. Tähän tehoaa hyvin doksisykliinikuuri.
Mutta punkin syljessä voi tulla kehoon jo  heti TBE-virus.
Katso tämä opettavainen video vuodelta 2014.
 

https://www.youtube.com/watch?v=op77Juegs28

olennaista on kartoittaa, miten virus ja bakteeri tekevät evaasion ihmisen puolustusjärjestelmistä ja taudit pääsevät  muodosotumaan toisilla yksilöillä  pahoiksi. 

Sitä myöten kun kaikki evaasiojärjestelmät selkiävät, löytynea myös jokin uusi terapiamahdollisuus. 

Antivirusstrategia TBEV:: tä vastaan

PubMed haku antaa 7  relevanttia vastausta joka hahmottaa  aikamme tilannetta.

Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects.

Lindqvist R, Mundt F, Gilthorpe JD, Wölfel S, Gekara NO, Kröger A, Överby AK.

J Neuroinflammation. 2016 Oct 24;13(1):277.

Abstract

BACKGROUND: Neurotropic flaviviruses such as tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and Zika virus (ZIKV) are causative agents of severe brain-related diseases including meningitis, encephalitis, and microcephaly. We have previously shown that local type I interferon response within the central nervous system (CNS) is involved in the protection of mice against tick-borne flavivirus infection. However, the cells responsible for mounting this protective response are not defined.

METHODS: Primary astrocytes were isolated from wild-type (WT) and interferon alpha receptor knock out (IFNAR^-/-) mice and infected with neurotropic flaviviruses. Viral replication and spread, IFN induction and response, and cellular viability were analyzed. Transcriptional levels in primary astrocytes treated with interferon or supernatant from virus-infected cells were analyzed by RNA sequencing and evaluated by different bioinformatics tools.

RESULTS:Here, we show that astrocytes control viral replication of different TBEV strains, JEV, WNV, and ZIKV. In contrast to fibroblast, astrocytes mount a rapid interferon response and restrict viral spread. Furthermore, basal expression levels of key interferon-stimulated genes are high in astrocytes compared to mouse embryonic fibroblasts. Bioinformatic analysis of RNA-sequencing data reveals that astrocytes have established a basal antiviral state which contributes to the rapid viral recognition and upregulation of interferons. The most highly upregulated pathways in neighboring cells were linked to type I interferon response and innate immunity. The restriction in viral growth was dependent on interferon signaling, since loss of the interferon receptor, or its blockade in wild-type cells, resulted in high viral replication and virus-induced cytopathic effects. Astrocyte supernatant from TBEV-infected cells can restrict TBEV growth in astrocytes already 6 h post infection, the effect on neurons is highly reinforced, and astrocyte supernatant from 3 h post infection is already protective.

CONCLUSIONS:These findings suggest that the combination of an intrinsic constitutive antiviral response and the fast induction of type I IFN production by astrocytes play an important role in self-protection of astrocytes and suppression of flavivirus replication in the CNS.

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Select item 268192202.

Type I Interferon response in olfactory bulb, the site of tick-borne flavivirus accumulation, is primarily regulated by IPS-1.

Kurhade C, Zegenhagen L, Weber E, Nair S, Michaelsen-Preusse K, Spanier J, Gekara NO, Kröger A, Överby AK.

J Neuroinflammation. 2016 Jan 27;13:22. doi: 10.1186/s12974-016-0487-9.

Abstract

BACKGROUND: Although type I interferons (IFNs)-key effectors of antiviral innate immunity are known to be induced via different pattern recognition receptors (PRRs), the cellular source and the relative contribution of different PRRs in host protection against viral infection is often unclear. IPS-1 is a downstream adaptor for retinoid-inducible gene I (RIG-I)-like receptor signaling. In this study, we investigate the relative contribution of IPS-1 in the innate immune response in the different brain regions during infection with tick-borne encephalitis virus (TBEV), a flavivirus that causes a variety of severe symptoms like hemorrhagic fevers, encephalitis, and meningitis in the human host.

METHODS: IPS-1 knockout mice were infected with TBEV/Langat virus (LGTV), and viral burden in the peripheral and the central nervous systems, type I IFN induction, brain infiltrating cells, and inflammatory response was analyzed.

RESULTS: We show that IPS-1 is indispensable for controlling TBEV and LGTV infections in the peripheral and central nervous system. Our data indicate that IPS-1 regulates neuropathogenicity in mice. IFN response is differentially regulated in distinct regions of the central nervous system (CNS) influencing viral tropism, as LGTV replication was mainly restricted to olfactory bulb in wild-type (WT) mice. In contrast to the other brain regions, IFN upregulation in the olfactory bulb was dependent on IPS-1 signaling. IPS-1 regulates basal levels of antiviral interferon-stimulated genes (ISGs) like viperin and IRF-1 which contributes to the establishment of early viral replication which inhibits STAT1 activation. This diminishes the antiviral response even in the presence of high IFN-β levels. Consequently, the absence of IPS-1 causes uncontrolled virus replication, in turn resulting in apoptosis, activation of microglia and astrocytes, elevated proinflammatory response, and recruitment of inflammatory cells into the CNS.

CONCLUSIONS: We show that LGTV replication is restricted to the olfactory bulb and that IPS-1 is a very important player in the olfactory bulb in shaping the innate immune response by inhibiting early viral replication and viral spread throughout the central nervous system. In the absence of IPS-1, higher viral replication leads to the evasion of antiviral response by inhibiting interferon signaling. Our data suggest that the local microenvironment of distinct brain regions is critical to determine virus permissiveness.

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Select item 256618833.

Synthesis and assessment of 4-aminotetrahydroquinazoline derivatives as tick-borne encephalitis virus reproduction inhibitors.

Sedenkova KN, Dueva EV, Averina EB, Grishin YK, Osolodkin DI, Kozlovskaya LI, Palyulin VA, Savelyev EN, Orlinson BS, Novakov IA, Butov GM, Kuznetsova TS, Karganova GG, Zefirov NS.

Org Biomol Chem. 2015 Mar 21;13(11):3406-15. doi: 10.1039/c4ob02649g.

Tick-borne encephalitis virus (TBEV) belonging to Flavivirus genus causes severe infection in humans. The search for therapeutically relevant compounds targeting TBEV requires the exploration of novel chemotypes. A versatile synthesis of previously unknown 4-aminopyrimidines and 4-aminopyrimidine N-oxides based on a fluorosubstituted heterocyclic core is described. A representative series of 4-aminotetrahydroquinazoline derivatives, containing aliphatic and aromatic substituents as well as the adamantane framework, was obtained and their activity against tick-borne encephalitis virus reproduction was studied. Nine compounds were found to inhibit TBEV entry into the host cells. A bulky hydrophobic adamantyl group was identified to be important for the antiviral activity. The developed synthetic route allowed an easy access to a consistent compound library for further structure-activity relationship studies.

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Select item 251227774.

Type I interferon protects mice from fatal neurotropic infection with Langat virus by systemic and local antiviral responses.

Weber E, Finsterbusch K, Lindquist R, Nair S, Lienenklaus S, Gekara NO, Janik D, Weiss S, Kalinke U, Överby AK, Kröger A.

J Virol. 2014 Nov;88(21):12202-12. doi: 10.1128/JVI.01215-14. Epub 2014 Aug 13.

Vector-borne flaviviruses, such as tick-borne encephalitis virus (TBEV), West Nile virus, and dengue virus, cause millions of infections in humans. TBEV causes a broad range of pathological symptoms, ranging from meningitis to severe encephalitis or even hemorrhagic fever, with high mortality. Despite the availability of an effective vaccine, the incidence of TBEV infections is increasing. Not much is known about the role of the innate immune system in the control of TBEV infections. Here, we show that the type I interferon (IFN) system is essential for protection against TBEV and Langat virus (LGTV) in mice. In the absence of a functional IFN system, mice rapidly develop neurological symptoms and succumb to LGTV and TBEV infections. Type I IFN system deficiency results in severe neuroinflammation in LGTV-infected mice, characterized by breakdown of the blood-brain barrier and infiltration of macrophages into the central nervous system (CNS). Using mice with tissue-specific IFN receptor deletions, we show that coordinated activation of the type I IFN system in peripheral tissues as well as in the CNS is indispensable for viral control and protection against virus induced inflammation and fatal encephalitis.

IMPORTANCE: The type I interferon (IFN) system is important to control viral infections; however, the interactions between tick-borne encephalitis virus (TBEV) and the type I IFN system are poorly characterized. TBEV causes severe infections in humans that are characterized by fever and debilitating encephalitis, which can progress to chronic illness or death. No treatment options are available. An improved understanding of antiviral innate immune responses is pivotal for the development of effective therapeutics. We show that type I IFN, an effector molecule of the innate immune system, is responsible for the extended survival of TBEV and Langat virus (LGTV), an attenuated member of the TBE serogroup. IFN production and signaling appeared to be essential in two different phases during infection. The first phase is in the periphery, by reducing systemic LGTV replication and spreading into the central nervous system (CNS). In the second phase, the local IFN response in the CNS prevents virus-induced inflammation and the development of encephalitis.

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Select item 226240015.

An analogue of the antibiotic teicoplanin prevents flavivirus entry in vitro.

De Burghgraeve T, Kaptein SJ, Ayala-Nunez NV, Mondotte JA, Pastorino B, Printsevskaya SS, de Lamballerie X, Jacobs M, Preobrazhenskaya M, Gamarnik AV, Smit JM, Neyts J.

PLoS One. 2012;7(5):e37244. doi: 10.1371/journal.pone.0037244. Epub 2012 May 18.

There is an urgent need for potent inhibitors of dengue virus (DENV) replication for the treatment and/or prophylaxis of infections with this virus. We here report on an aglycon analogue of the antibiotic teicoplanin (code name LCTA-949) that inhibits DENV-induced cytopathic effect (CPE) in a dose-dependent manner. Virus infection was completely inhibited at concentrations that had no adverse effect on the host cells. These findings were corroborated by quantification of viral RNA levels in culture supernatant. Antiviral activity was also observed against other flaviviruses such as the yellow fever virus and the tick-borne encephalitis virus (TBEV). In particular, potent antiviral activity was observed against TBEV. Time-of-drug-addition experiments indicated that LCTA-949 inhibits an early stage in the DENV replication cycle; however, a virucidal effect was excluded. This observation was corroborated by the fact that LCTA-949 lacks activity on DENV subgenomic replicon (that does not encode structural proteins) replication. Using a microscopy-based binding and fusion assay employing DiD-labeled viruses, it was shown that LCTA-949 targets the early stage (binding/entry) of the infection. Moreover, LCTA-949 efficiently inhibits infectivity of DENV particles pre-opsonized with antibodies, thus potentially also inhibiting antibody-dependent enhancement (ADE). In conclusion, LCTA-949 exerts in vitro activity against several flaviviruses and does so (as shown for DENV) by interfering with an early step in the viral replication cycle.Free PMC Article

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Select item 163065826.

Humoral and cellular immune response to RNA immunization with flavivirus replicons derived from tick-borne encephalitis virus.

Aberle JH, Aberle SW, Kofler RM, Mandl CW.

J Virol. 2005 Dec;79(24):15107-13.

A new vaccination principle against flaviviruses, based on a tick-borne encephalitis virus (TBEV) self-replicating noninfectious RNA vaccine that produces subviral particles, has recently been introduced (R. M. Kofler, J. H. Aberle, S. W. Aberle, S. L. Allison, F. X. Heinz, and C. W. Mandl, Proc. Natl. Acad. Sci. USA 7:1951-1956, 2004).
 In this study, we evaluated the potential of the self-replicating RNA vaccine in mice in comparison to those of live, attenuated vaccines and a formalin-inactivated whole-virus vaccine (ImmunInject). For this purpose, mice were immunized using gene gun-mediated application of the RNA vaccine and tested for CD8+ T-cell responses, long-term duration, neutralizing capacity, and isotype profile of specific antibodies and protection against lethal virus challenge. We demonstrate that the self-replicating RNA vaccine induced a broad-based, humoral and cellular (Th1 and CD8+ T-cell response) immune response comparable to that induced by live vaccines and that it protected mice from challenge. Even a single immunization with 1 microg of the replicon induced a long-lasting antibody response, characterized by high neutralizing antibody titers, which were sustained for at least 1 year. Nevertheless, it was possible to boost this response further by a second injection with the RNA vaccine, even in the presence of a concomitant CD8+ T-cell response. In this way it was possible to induce a balanced humoral and cellular immune response, similar to infection-induced immunity but without the safety hazards of infectious agents. The results also demonstrate the value of TBEV replicon RNA for inducing protective long-lasting antiviral responses.

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Select item 126153097.

Tick-borne encephalitis.

Gritsun TS, Lashkevich VA, Gould EA.

Antiviral Res. 2003 Jan;57(1-2):129-46. Review.

Abstract Tick-borne encephalitis (TBE) is one of the most dangerous human infections occurring in Europe and many parts of Asia. The etiological agent Tick-borne encephalitis virus (TBEV), is a member of the virus genus Flavivirus, of the family Flaviviridae. TBEV is believed to cause at least 11,000 human cases of encephalitis in Russia and about 3000 cases in the rest of Europe annually. Related viruses within the same group, Louping ill virus (LIV), Langat virus (LGTV) and Powassan virus (POWV), also cause human encephalitis but rarely on an epidemic scale. Three other viruses within the same group, Omsk hemorrhagic fever virus (OHFV), Kyasanur Forest disease virus (KFDV) and Alkhurma virus (ALKV), are closely related to the TBEV complex viruses and tend to cause fatal hemorrhagic fevers rather than encephalitis. This review describes the clinical manifestations associated with TBEV infections, the main molecular-biological properties of these viruses, and the different factors that define the incidence and severity of disease. The role of ticks and their local hosts in the emergence of new virus variants with different pathogenic characteristics is also discussed. This review also contains a brief history of vaccination against TBE including trials with live attenuated vaccine and modern tendencies in developing of vaccine virus strains.

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Puutiaisaivotulehdus, Punkkienkefaliitti TBE

https://www.thl.fi/sv/web/infektiotaudit/taudit-ja-mikrobit/virustaudit/puutiaisaivotulehdus

Puutiaisaivotulehdus

Mikä on puutiaisaivotulehdus?

Puutiaisaivotulehdus (tick borne encephalitis, TBE, Kumlingen tauti, puutiaisaivokuume) on flaviviruksiin kuuluvan TBE-viruksen aiheuttama enkefaliitti eli aivotulehdus. Puutiaisaivotulehdusta esiintyy Keski-Euroopasta Siperian läpi Japaniin asti ulottuvalla leveällä vyöhykkeellä. TBE-virusta on kolmea eri tyyppiä: läntinen, siperialainen ja Kaukoidän tyyppi.
Punkit levittävät myös borrelioosia eli Lymen tautia, joka on eri sairaus kuin puutiaisaivotulehdus.

Miten puutiaisaivotulehdus tarttuu?

TBE-virus leviää Ixodes-puutiaisen pureman välityksellä. TBE-virus tarttuu muutamassa minuutissa punkin syljestä jo pureman alkuvaiheessa. Myös punkkien nymfit ja toukat voivat levittää virusta, niiden puremaa ei yleensä havaita. Baltian maissa tartuntoja on kuvattu tapahtuneen myös pastöroimattoman maidon välityksellä.

Mitkä ovat puutiaisaivotulehduksen oireet?

Puutiaisaivotulehdus on taudinkuvaltaan kaksivaiheinen. Oireita ilmenee vain 10─30 prosentilla tartunnan saaneista. Aika puremasta ensimmäisiin oireisiin voi vaihdella 4─28 vrk välillä. Yleensä noin viikon kuluttua puremasta potilaalla on kuumeilua ja epämääräistä pahaa oloa ja sairauden tunnetta. Tämä vaihe kestää yleensä noin 4─7 päivää ja valtaosa infektioista päättyy tähän.
Noin viikon (3–21 vuorokauden) kuumeettoman jakson jälkeen 20─30 prosenttia sairastuneista saa varsinaisen aivotulehduksen. Aivotulehdusjakson aikana potilaalla on kuumetta, päänsärkyä, niskajäykkyyttä, valon arkuutta, pahoinvointia ja mahdollisesti muita neurologisia oireita, kuten tajunnanhäiriöitä, kouristuksia tai halvausoireita.

Kuolleisuus puutiaisaivotulehdukseen on hyvin pieni, noin 0,5─1 prosenttia. Suurelle osalle varsinaiseen aivokuumeeseen sairastuneista jää kuitenkin pitkäkestoisia ja 2─10 prosentille jopa pysyviä keskushermosto-oireita. Jälkioireista tavallisia ovat ärtyneisyys, muisti- ja keskittymisvaikeudet, kuulovauriot, raajan halvaukset ja lihasheikkous.

Miten puutiaisaivotulehdus todetaan?

Tuoreessa puutiaisaivotulehduksessa muodostuu TBE-virusvasta-aineita, jotka voidaan todeta verikokeella. Myös selkäydinnesteestä voidaan tutkia vasta-aineet. Kerran sairastettu tauti jättää elinikäisen suojan eli immuniteetin.

Miten puutiaisaivotulehdusta hoidetaan?

Puutiaisaivotulehdus on virustauti eikä siihen ole tarjolla lääkehoitoa. Aivotulehduksen hoito vaatii sairaalahoitoa.

Miten puutiaisaivotulehduksen tarttuminen ehkäistään?

Suojaudu ja käytä karkoitteita

Liikuttaessa luonnossa puutiaisaivotulehdusalueella, tulisi pukeutua pitkähihaiseen ja -lahkeiseen vaatetukseen, ja käyttää esimerkiksi Punkki-OFFia paljaaksi jäävälle ihoalueelle. Perinteinen punkkisyyni kerran vuorokaudessa ei auta puutiaisaivotulehduksen ehkäisyssä, mutta se on tarpeen borrelioosin tarttumisen estämisessä. 

Rokote

Puutiaisaivotulehdusta vastaan on olemassa rokote, ks. rokotukset.

Päivitetty:  18.9.2015

Evaasiostrategiaa TBEV viruksella. IFN viive.

VIIVE antiviraaliseen  IFN-järjestelmään

Euroopassa ja Aasiassa aiheutuu vuosittain noin 10 000 vakavaa punkkisyntyistä enkefaliittia (TBE) , punkin aiheuttamaa aivotulehdusta.

 Tässä tutkimuksessa tarkastettiin TBE-viruksen tapoja  vaikuttaa antivirustyyppistä interferonia IFN- alfa/beta- esiintyikö sitä ollenkaan?  Tiedetään että tämä virus käyttää monta evaasiomenetelmää ihmis-isäntänsä suhteen. 

Tutkimuksessa käytettiin viruskantoja Neudörfl, Hypr ja Absettarov ja havaittiin, että IFN-beta transkriptit ja viruksen RNA korreloivat tarkasti keskenään. Lisäksi IFN-indusoituminen TBEV viruksesta riippui IFN-transkriptiotekijän säätelyfaktorista IRF-3. Kuitenkin jopa vahvimmin IFN-indusoitumisaktiivisuutta ja korkeimpia RNA-pituisuuksia omaava kanta osoitti  huomattavaa viivettä IRF-3:n aktivoitumisessa. Tästä johtuen TBEV saattoi pitää matalia, kynnyksen alla olevia IFN-transkriptitasoja, joten solut eivät kyenneet vapauttamaan tuottunutta  IFN interferonia. Vasta 24 tunnin päästä oli kumuloitunut sen verran riittävästi IFN- transkriptejä että saattoi tuottua havaittavia määriä erittyneitä interferoneja. 

Tämä viive IFN-induktiossa ei näytä aiheutuvan spesifisestä virusproteiinista, koska TBEV C, E, NS2A, NS2B, NS3, NS4A, NS4B, NS5 ja NS2B-NS3 sekä myös TBEV infektio itse eivät ilmennä mitään vaikutusta spesifiseen IFN-beta induktioon.

 Kuitenkin tutkijaryhmä havaitsi, että tämän  viruksen dsRNA sinänsä  on vahva IFN- vasteen esiin liipaisija, mutta sitä muotoa on vain intrasellulaarisen kalvon aitioiden sisällä. Siitä huolimatta IFN:n indusoitumisen riippuvuus IFN-promoottorin 1 stimulaatiosta ( IPS-1) samoin kuin eukaryooottisen aloitusfaktorin alfa-alayksiköstä (eIF2alpha) viittaisi jonkinlaiseen sytoplasmiseen altistumiseen jollekin määrälle viruksen dsRNA muotoa infektion myöhäisvaiheessa. 

Tutkijat pystyivät osoittamaan tällä viruksella TBEV kuten muillakin flaviviruksilla , että se järjestelee uudestaan  solunsisäisiä kalvojaan. Viruspartikkelit ja membraaniin yhteydessä olevat rakkulat ( jotka todennäköisesti edustavat virusRNA-synteesikohtia) olivat  havaittavissa endoplasmisen retikulumin sisällä. Täten ilmeisesti TBEV järjestelee uudestaan solun sisäisiä kalvoja tarjoten aitiota omalle dsRNA:lleen , joka on suurimmalta osaltaan saavuttamattomissa sytoplasmisten patogeenireseptorien tunnistamissyrityksiltä. Tämä viivyttää IFN-induktion alkuunpanoa sen verran riittävästi, että salliutuu progeniittoripartikkeleitten tuotannon alkuunpääsy noin 24 tunninkohdalla.

LÄHDE:

https://www.ncbi.nlm.nih.gov/pubmed/20554782/

J Virol. 2010 Sep;84(17):8470-83. doi: 10.1128/JVI.00176-10. Epub 2010 Jun 16.

Tick-borne encephalitis virus delays interferon induction and hides its double-stranded RNA in intracellular membrane vesicles.

Overby AK¹, Popov VL, Niedrig M, Weber F.

Author information

Abstract

Tick-borne encephalitis virus (TBEV) (family Flaviviridae, genus Flavivirus) accounts for approximately 10,000 annual cases of severe encephalitis in Europe and Asia. Here, we investigated the induction of the antiviral type I interferons (IFNs) (alpha/beta IFN [IFN-alpha/beta]) by TBEV. Using strains Neudörfl, Hypr, and Absettarov, we demonstrate that levels of IFN-beta transcripts and viral RNA are strictly correlated. Moreover, IFN induction by TBEV was dependent on the transcription factor IFN regulatory factor 3 (IRF-3). However, even strain Hypr, which displayed the strongest IFN-inducing activity and the highest RNA levels, substantially delayed the activation of IRF-3. As a consequence, TBEV can keep the level of IFN transcripts below the threshold value that would permit the release of IFN by the cell. Only after 24 h of infection have cells accumulated sufficient IFN transcripts to produce detectable amounts of secreted IFNs. The delay in IFN induction appears not to be caused by a specific viral protein, since the individual expressions of TBEV C, E, NS2A, NS2B, NS3, NS4A, NS4B, NS5, and NS2B-NS3, as well as TBEV infection itself, had no apparent influence on specific IFN-beta induction.

We noted, however, that viral double-stranded RNA (dsRNA), an important trigger of the IFN response, is immunodetectable only inside intracellular membrane compartments. Nonetheless, the dependency of IFN induction on IFN promoter stimulator 1 (IPS-1) as well as the phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) suggest the cytoplasmic exposure of some viral dsRNA late in infection. Using ultrathin-section electron microscopy, we demonstrate that, similar to other flaviviruses, TBEV rearranges intracellular membranes. Virus particles and membrane-connected vesicles (which most likely represent sites of virus RNA synthesis) were observed inside the endoplasmic reticulum. Thus, apparently, TBEV rearranges internal cell membranes to provide a compartment for its dsRNA, which is largely inaccessible for detection by cytoplasmic pathogen receptors. This delays the onset of IFN induction sufficiently to give progeny particle production a head start of approximately 24 h.

PMID:

20554782

PMCID:

PMC2919015

DOI:

10.1128/JVI.00176-10

[Indexed for MEDLINE]

Free PMC Article

Suomennos 8.9. 2017