Could the unfolded protein response induce Zika virus-associated microcephaly?

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Accumulating evidence within epidemiological studies has revealed that in utero fetal infection with the Zika virus (ZIKV) may lead to microcephaly – an irreversible congenital malformation of the brain, which is characterized by an incomplete development of the cerebral cortex.

Although there is evidence that supports a causal link between ZIKV infection and congenital microcephaly, the mechanism(s) behind this relationship remain unclear.

In a recently published study in Nature Neuroscience, an international team of researchers have tried to understand how ZIKV induces microcephaly by combining analyses of ZIKV-infected human fetuses, cultured human neural stem cells and mouse embryos.

Within their study, they discovered that: “ZIKV triggers endoplasmic reticulum stress and unfolded protein response in the cerebral cortex of infected postmortem human fetuses as well as in cultured human neural stem cells.” They also demonstrated that in mouse embryos, the endoplasmic reticulum stress is triggered in embryonic brains in vivo after intracerebral and intraplacental inoculation of ZIKV.

When ZIKV reaches the brain it infects neuronal stem cells, which leads to the generation of fewer neurons. By inducing chronic stress in the endoplasmic reticulum, this subsequently promotes apoptosis. These two combined mechanisms explain why the cerebral cortex of infected fetuses become deficient in neurons and is therefore smaller in size.

“These discoveries demonstrate a hypothesis that we had made following a basic research study we had just carried out in our laboratory, and thus confirm the physiological importance of the unfolded protein response in control of neurogenesis,” commented Laurent Nguyen (University of Liège, Belgium), who led the study.

Furthermore, the researchers demonstrated that the administration of pharmacological inhibitors of  the unfolded protein response inhibited the development of microcephaly in ZIKV-infected mouse embryos. “Such defects are specific to ZIKV, as they are not observed upon intraplacental injection of other related flaviviruses in mice,” they explained in their study.

To conclude, Marc Lecuit (Institut Pasteur, Paris, France) explained: “These results illustrate how studying fundamental biological processes is an essential step in understanding the mechanisms of infections, and lead to novel therapeutic strategies.”

Sources: Gladwyn-Ng I, Cordón-Barris L, Alfano C et al. Stress-induced unfolded protein response contributes to Zika virus-associated microcephaly. Nat. Neurosci. doi:10.1038/s41593-017-0038-4 (2017) (Epub ahead of print); www.pasteur.fr/en/press-area/press-documents/how-zika-virus-induces-congenital-microcephaly

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