Inhibition of autophagy limits vertical transmission of Zika virus in pregnant mice

Abstract

Cao et al. report a new mechanism by which Zika virus maternal-fetal transmission may occur and be limited as autophagy inhibition protects mice from vertical viral transmission. This study suggests that an autophagy-based therapeutic intervention against ZIKV may be warranted.

Novel activities of safe-in-human broad-spectrum antiviral agents

“…We also confirmed previously reported activities of chloroquine against CHIKV and ZIKV, mycophenolic acid against CHIKV and RRV, fluoxetine, pirlindole and dibucaine against EV1, BCX4430, lopinavir and hydroxichloroquine against ZIKV, as well as gemcitabine against EV1, FLUAV, ZIKV and HSV-1 (Cao et al, 2017;Delogu and de Lamballerie, 2011;Delvecchio et al, 2016;Denisova et al, 2012;Julander et al, 2017;Kang et al, 2015;Khan et al, 2011;Kuivanen et al, 2017;Lee et al, 2017;Soderholm et al, 2016;Ulferts et al, 2016;Yuan et al, 2017) (Fig. 4).…”

Manipulation of autophagy by (+) RNA viruses

“…More recently, an important role of the secretory autophagy pathway was implicated in ZIKV vertical transmission as well as cell-to-cell spread of DENV. ZIKV-induced autophagic activity in human trophoblasts restricted by pharmacological inhibition, or by deficiency in an essential autophagy gene, Atg16L1, limited ZIKV vertical transmission and improved placental and fetal outcomes, which supported a role for autophagic secretion in the process [71]. Along the same lines, it was hypothesised that DENV might evade neutralising antibodies and increase viral spread by exploiting autophagic vesicles for delivery to the extracellular medium [72].…”

To Zika and Destroy: An Antimalarial Drug Protects Fetuses from Zika Infection

“…Additionally, ZIKV infection induces autophagic flux in human skin cells, suggesting that autophagy plays a role in ZIKV pathogenesis [9]. We first confirmed that ZIKV also induces autophagy in human trophoblasts in vitro and in mouse placentas in vivo [10]. Next, we showed that upon ZIKV infection, pregnant mice deficient for a key autophagy gene, Atg16L1 (Atg16l1 HM ), had significantly lower ZIKV titers in both the placentas and fetal brains than the wild-type mice.…”

“…Moreover, ZIKV-induced placental damage was prevented by HCQ treatment, and pups from HCQ-treated ZIKV-infected mice were larger than those from untreated ZIKV-infected mice [10]. Finally, our data suggested that the anti-ZIKV effects of HCQ depend on HCQ's ability to inhibit autophagy, as placental and fetal viral titers were equivalent between Atg16l1 HM mice treated with and without HCQ [10]. Our work provides a new perspective in understanding the mechanism of HCQ's anti-ZIKV effects during pregnancy.…”

“…Given that loss of a key autophagy gene reduced placental ZIKV transmission, we tested the autophagy inhibitors bafilomycin A1, 3-methyladenine and chloroquine and found that all three were able to reduce ZIKV titers in human trophoblasts in vitro [10]. Hydroxychloroquine (HCQ), the hydroxyl derivative of chloroquine, was an attractive candidate drug for in vivo tests in mice for several reasons.…”