A study led by Chinese virologists at Southern Medical University (SMU) and Sun Yat-Sen University (SYSU) in Guangzhou has discovered that neural progenitor cell pyroptosis contributes to Zika virus (ZIKV)-induced microcephaly and represents a novel therapeutic target, the authors reported in the September 9, 2020, online edition of Proceedings of the National Academy of Sciences (PNAS).

"This is the first study to show that ZIKV infection causes neural progenitor cell pyroptosis, which links ZIKV to the development and/or progression of microcephaly," said study leader Mengfeng Li.

A flavivirus related to the dengue, yellow fever and Japanese encephalitis viruses, ZIKV is transmitted to humans by Aedes mosquito vectors, predominantly A. aegypti and A. albopictus.

Although most Zika cases are mild, ZIKV infection during pregnancy can cause severe congenital abnormalities, most notably microcephaly, prompting the WHO to declare ZIKV an international health emergency.

"ZIKV infection causes Zika syndrome including microcephaly in an estimated 5-14% of pregnancies," said Li, a professor in the Department of Microbiology at SYSU's Zhongshan School of Medicine and in SMU's Cancer Institute.

However, the mechanisms by which ZIKV disrupts neurogenesis and causes microcephaly remain poorly understood and, as yet, there are no effective ZIKV treatments or vaccines.

"Currently, there are still no specific anti-viral medications or effective vaccines available for the treatment or prevention of ZIKV-associated diseases," Li told BioWorld Science.

This provided the rationale for the new PNAS study, in which researchers led by Li and Xun Zhu, an associate professor in the Department of Microbiology at SYSU's Zhongshan School of Medicine, investigated ZIKV pathogenesis in vitro and in vivo in pregnant mice.

This research revealed that ZIKV exposure caused neural progenitor cell pyroptosis, a highly inflammatory type of programmed cell death similar to apoptosis, and that this was mediated by the activation of the enzyme caspase-1 and the protein gasdermin D (GSDMD), linking ZIKV to the development and progression of microcephaly.

"This conclusion was drawn following studies in in vivo neonatal mouse models and in vitro in a human neural progenitor cell (hNPC) culture model," explained Li.

Caspase-1 deletion via Casp-1 gene knockout (KO) or treatment with the caspase-1 inhibitor VX-765 (belnacasan; Vertex Pharmaceuticals) were both shown to reduce ZIKV-induced inflammatory responses and pyroptosis, and to attenuate neuropathy and brain atrophy in vivo.

"For example, histopathological examination indicated that caspase-1 deletion or inhibition prevented inflammation-induced damage. Moreover, GSDMD cleavage and increased proinflammatory cytokine production were shown to be abolished in mice infected with ZIKV," he said.

"As an in vivo infection model, we used wild-type (WT) mouse pups of immunocompetent mice at postnatal day 3, when rodent brain and immune system development most closely resemble the second and third trimesters of gestation in humans.

"ZIKV-infected control mice gained weight more slowly than mock-infected controls, which did not occur in any of the caspase-1 depletion or inhibition mice. Moreover, severe brain atrophy was drastically abrogated in the Casp1 KO or VX-765-treated mice infected by ZIKV, compared with ZIKV-infected WT controls."

Taken together, "these findings suggest that inhibition of hNPC pyroptosis may be a potentially promising strategy for the treatment of ZIKV diseases," said Li, noting that caspase-1 inhibitors might be promising in this regard.

VX-765

"VX-765 is an orally absorbed pro-drug of VRT-043198, a potent and selective inhibitor of caspase-1 activation, which has been proved to be safe and well tolerated in a human trial against epilepsy, although it has yet to be approved by the FDA for clinical treatment," noted Li.

"Our study results have shown that VX-765 treatment has significant and sustained beneficial effects on ZIKV-associated neuropathy and brain atrophy, so it would be particularly interesting to see whether VX-765 would be clinically effective against ZIVK-associated diseases."

"However, prior to clinical use, it would be necessary to carry out clinical studies of VX-765, especially of its safety profile in pregnant women, as well as for clinical efficacies against ZIKV-associated microcephaly."

Looking ahead, Li said the researchers will use the pregnant mouse model to elucidate the role of pyroptosis in mediating ZIKV-induced abortion and neonatal abnormalities such as microcephaly. "We will also seek to clarify whether VX-765 can cross the placental and blood-brain barriers, then evaluate its therapeutic effects preclinically and clinically," he said (He, Z. et al. Proc Natl Acad Sci USA (PNAS) 2020, Advanced publication).

Belnacasan

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