Editors' ChoiceInfectious Disease

Zika–associated microcephaly: Reduce the stress and race for the treatment

See allHide authors and affiliations

Science Translational Medicine  10 Jan 2018:
Vol. 10, Issue 423, eaar7514
DOI: 10.1126/scitranslmed.aar7514


Inhibition of the endoplasmic reticulum stress pathway may hold the key to Zika virus–associated microcephaly treatment.

The preparation for the 2016 Olympic games in Brazil was characterized by the widely discussed Zika virus (ZIKV) outbreak. Although no cases of Zika infection were reported during the Rio Olympics, the attention drawn to this virus has noticeably grown since then. Increasing evidence suggests that ZIKV-infected pregnant mothers can pass the virus to the fetus, causing brain developmental defects resulting in a brain smaller than normal (microcephaly); however, the molecular mechanisms underlying these defects remain still largely unknown.

Gladwyn-Ng and colleagues observed that Zika-infected neural progenitor cells presented signatures of endoplasmic reticulum (ER) stress response and proposed that reducing the activation of this pathway may lead to prevention of ZIKV-associated microcephaly.

The group of researchers began by noticing that gene expression profiles derived from human cortical samples obtained from postmortem ZIKV-infected fetuses showed signatures of ER stress and activation of the unfolded protein response (UPR) pathway. The authors further validated this observation employing infected neural stem cell cultures and mouse embryos exposed to the virus either by intracerebroventricular or intraplacental injections. The activation of the ER stress and UPR pathways further correlated with neurogenesis deficits. Specifically, infected neural progenitor cells preferentially generated neuronal cells directly rather than producing intermediate progenitors first. As a consequence, the number of intermediate progenitors, as well as the final count of neurons, diminished dramatically, resulting in a smaller cerebral cortex. Apparently noninfected neural stem cells in the vicinity of ZIKV-infected cells also seemed to show proliferation defects, implying either that ZIKV infection below detection limit was sufficient to induce the phenotype or that cell nonautonomous mechanisms were at play.

Most importantly, the authors showed that administration of an inhibitor of the UPR pathway corrected the aberrant neural stem cell proliferation and rescued brain size. Thus, although the finish line is still far away, pharmacological inhibitors of the UPR pathway may have just entered the race to develop pharmacological treatments for ZIKV-infected embryos.

Highlighted Article

Stay Connected to Science Translational Medicine

Navigate This Article