IRE1-Mediated Unfolded Protein Response Promotes the Replication of Tick-Borne Flaviviruses in a Virus and Cell-Type Dependent Manner

Abstract

Tick-borne flaviviruses (TBFV) can cause severe neurological complications in humans, but differences in tissue tropism and pathogenicity have been described for individual virus strains. Viral protein synthesis leads to the induction of the unfolded protein response (UPR) within infected cells. The IRE1 pathway has been hypothesized to support flavivirus replication by increasing protein and lipid biogenesis. Here, we investigated the role of the UPR in TBFV infection in human astrocytes, neuronal and intestinal cell lines that had been infected with tick-borne encephalitis virus (TBEV) strains Neudoerfl and MucAr-HB-171/11 as well as Langat virus (LGTV). Both TBEV strains replicated better than LGTV in central nervous system (CNS) cells. TBEV strain MucAr-HB-171/11, which is associated with gastrointestinal symptoms, replicated best in intestinal cells. All three viruses activated the inositol-requiring enzyme 1 (IRE1) pathway via the X-box binding protein 1 (XBP1). Interestingly, the neurotropic TBEV strain Neudoerfl induced a strong upregulation of XBP1 in all cell types, but with faster kinetics in CNS cells. In contrast, TBEV strain MucAr-HB-171/11 failed to activate the IRE1 pathway in astrocytes. The low pathogenic LGTV led to a mild induction of IRE1 signaling in astrocytes and intestinal cells. When cells were treated with IRE1 inhibitors prior to infection, TBFV replication in astrocytes was significantly reduced. This confirms a supporting role of the IRE1 pathway for TBFV infection in relevant viral target cells and suggests a correlation between viral tissue tropism and the cell-type dependent induction of the unfolded protein response.

Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma?

“…Activated IRE1α exhibits its endoribonuclease nature, and excises a small intron from the x-box binding protein 1 (XBP1) mRNA, resulting in a template for the transcription factor-spliced XBP1 (sXBP1) [ 23 ]. sXBP1 is then transported into the nucleus, and orchestrates large transcriptional programs with hundreds of target genes that are involved in lipid biogenesis, chaperone synthesis, cell dormancy, ERAD, and apoptosis [ 24 , 25 , 26 ]. In addition, IRE1 may activate the IRE1-TRAF2 (TNF receptor associated factor 2)-JNK (c-Jun N-terminal kinase) cascade [ 27 ], thereby activating downstream pro-inflammatory transcriptional factors, as well as other mediators of autophagy or apoptosis.…”

Langat virus, a prototypic tick‐borne encephalitis virus, impacts IL‐6 signaling by downregulating gp130 expression

“…For example, type 1 interferon signaling has been found to impact infection and antiviral immunity in the brain 15–17 and to prevent mouse‐to‐mouse transmission 18 (when it is normally transmitted by ticks 19 ). LGTV has also been found to impact universal cellular signaling pathways including the unfolded protein response, 20,21 protein kinase c, 22 and protein kinase r 23 …”

“…LGTV has also been found to impact universal cellular signaling pathways including the unfolded protein response, 20,21 protein kinase c, 22 and protein kinase r. 23 A recently accepted article by the Journal of Medical Virology entitled, "Langat virus inhibits the gp130/JAK/STAT signaling by reducing the gp130 protein level" 24 addresses another gap in the knowledge of LGTV signaling by investigating its impact on the cellular interleukin (IL)-6 pathway. The IL-6 pathway consists of a family of related cytokines, 25 two of which (IL-6 and oncostatin M…”

Live and let die: signaling AKTivation and UPRegulation dynamics in SARS-CoVs infection and cancer

“…In addition, a recent study has revealed that Marburg virus (MARV) regulates IRE1-XBP1 in a time-dependent manner, upregulating the IRE1-XBP1 branch during the first 24 h post infection so as to promote viral replication [ 143 ]. Curiously, another study has shown that replication of Tick-borne Encephalitis flaviviruses (TBEV) in astrocytes was severely reduced when they were treated with IRE1 inhibitors before viral infection [ 144 ] (Supplementary Table 2 ).…”