Zika virus life cycle

The life cycle of ZIKV is similar to other known flaviviruses. Briefly, the E proteins are involved in the attachment of the virus to receptors on the host membrane. Subsequently, the virus gets internalised via endocytosis. The viral RNA is released into the cytoplasm following fusion of the viral and host membranes. The ssRNA is then translated, and the resulting polyprotein further gets cleaved into various structural and non-structural proteins (C, prM, E and NS proteins) [16].

Replication takes place on the ER surface. Transcription and replication of the dsDNA result in the formation of new viral mRNA and ssRNA, respectively. Following viral assembly at the ER, the virion budding utilises the host ESCRT (endosomal sorting complexes required for transport) machinery to transport to the Golgi apparatus. The prM protein is cleaved, and the virion is rendered mature. Finally, the mature virus exits the cell via exocytosis [16].

 

zika virus replication

Fig 5: Viral Replication

 

Host Immune Response [14]

Following viral infection the host’s immune system recognises viral proteins and elicits an antiviral response. Previous studies on flaviviruses showed that both TLR3 and TLR7 (Toll-like receptors) are able to recognise molecules on these pathogens. Following recognition, the TLRs induce the host defence, initiating various signalling pathways, which lead to the production of type I Interferons (IFNs), inflammatory cytokines and chemokines. However, an in vitro study by Hamel et al on human fibroblast cell lines showed that ZIKV infection only enhanced TLR3, but not TLR7. The increased levels of TLR3 were accompanied with the production of IFN-α and IFN-β in the infected cells, a corresponding increase in the transcriptional levels of interferon regulatory factor 7 (IRF7), and the upregulation of expression of several IFN-stimulated genes. Simultaneously, there is an increase in the expression of two chemokines (CXCL10 and CXCL11), which are known to play crucial roles in adaptive as well as innate immunity. Upregulation of CCL5, another chemokine known for its antiviral activity, was also observed. As an antiviral host defence mechanism, the researchers found that both types I and II interferons are capable of inhibiting virus replication.

The Hamel et al study also showed that ZIKV infection triggered autophagy in the infected fibroblasts. Generally, autophagy-mediated degradation of viral proteins prevents the replication of the virus; however, some viruses, including ZIKV, utilise certain components of the autophagy cycle, and promote viral replication and dissemination. Electron microscopic studies also revealed membrane vesicles (70 – 100 nm) in close association with the ER; this indicates that ZIKV replication occurs intimately with the host cell membrane.

 

Conclusion

Considering the global emergence and pathogenic nature of ZIKV, further studies are needed to identify the underlying mechanisms and mode of action of this virus. This will help identify antiviral targets and devise therapies, to fight this globally expanding menace.

 

References

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