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

Anna K. Överby, Vsevolod Popov, Matthias Niedrig, Friedemann Weber

Research output: Contribution to journalArticle

82 Citations (Scopus)

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-α/β]) by TBEV. Using strains Neudörfl, Hypr, and Absettarov, we demonstrate that levels of IFN-β 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-β 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 (eIF2α) 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.

Original languageEnglish (US)
Pages (from-to)8470-8483
Number of pages14
JournalJournal of Virology
Volume84
Issue number17
DOIs
StatePublished - Sep 2010

Fingerprint

Tick-borne encephalitis virus
Tick-Borne Encephalitis Viruses
Intracellular Membranes
Double-Stranded RNA
double-stranded RNA
interferons
Interferons
Viral RNA
Interferon Regulatory Factor-3
Flaviviridae
Flavivirus
Interferon-beta
Interferon-alpha
Eukaryotic Initiation Factor-2
Head Start
infection
RNA
interferon-beta
Interferon Type I
interferon-alpha

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Tick-Borne encephalitis virus delays interferon induction and hides its double-stranded RNA in intracellular membrane vesicles. / Överby, Anna K.; Popov, Vsevolod; Niedrig, Matthias; Weber, Friedemann.

In: Journal of Virology, Vol. 84, No. 17, 09.2010, p. 8470-8483.

Research output: Contribution to journalArticle

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