Characterizing host cell response to viral infection is a valuable step in therapeutic discovery. In light of the current Zika virus outbreak, the review published by Blázquez et al. (2014) of papers investigating these pathways following flavivirus infection is a useful refresher for researchers engaged in world health initiatives.1
Members of the Flavivirus genus are positive single-strand RNA viruses surrounded by a viral envelope. Members of this genus share a common method of replication that involves use of host cell membranes, namely from the endoplasmic reticulum (ER). Most of this group, which includes serious human and animal pathogens such as dengue virus, yellow fever, West Nile virus and tick-borne fever virus in addition to Zika virus, are also classified as arboviruses, since the major route for transmission is by arthropod vectors. In the case of Zika virus, this is mosquitoes of the Aedes genus.
Within the cell, the ER is responsible for protein synthesis quality control (QC), in that it recognizes and targets incorrectly folded molecules for intracellular degradation. This process, known as autophagy, sequesters the misfolded proteins inside ER-created double membrane vesicles and delivers them for destruction as part of the innate and adaptive immune response. When cells are infected, the flavivirus hijacks the unfolded protein response (UPR), altering ER membrane form and function to allow viral replication. The ER then packages viral material into vesicle packets, where viral genomic replication takes place. These virion packages escape detection and traffic through the Golgi body, to be released as mature viruses.
Normally when faced with increasing numbers of misfolded or otherwise aberrant proteins, the ER initiates a stress response to stimulate appropriate genes and transcription factors that decrease overall protein synthesis and increase ER degradation. However, following infection, the flavivirus modifies this process, allowing viral replication to bypass the QC process and thus persist in the cell. As reviewed by Blázquez et al., various viral proteins mediate this response, affecting UPR pathways and signaling molecules. Flavivirus infection appears to modulate all three arms of the UPR pathway, often sequentially, affecting PERK, ATF-6 and IRE-1 to stimulate transcriptional targets and disrupt interferon signaling.
Flavivirus infection also upregulates autophagic pathways within the host cells, although Blázquez et al. note that the association with UPR modulation is unclear. Furthermore, the benefit of this upregulation to viral replication and persistence is unclear. The authors note that in studies stimulating autophagy by external application of drugs, this effect is protective following infection and represents an interesting therapeutic opportunity.
Reviewing available literature, the authors summarize that further characterizing ER-associated pathways could be essential for developing treatments and vaccines against flavivirus infection.
Reference
1. Blázquez, A-B., et al. (2014) “Stress responses in flavivirus-infected cells: Activation of unfolded protein response and autophagy,” Frontiers in Microbiology, 5(266), doi: 10.3389/fmicb.2014.00266
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