Outcomes of Congenital Zika Disease Depend on Timing of Infection and Maternal-Fetal Interferon Action

Abstract

SUMMARY Zika virus (ZIKV) infection during pregnancy in humans results in intrauterine growth restriction, spontaneous abortion and microcephaly. Here, we found that fetus-derived type I interferon (IFN-I) signaling can enhance anti-ZIKV responses and provide clinical benefits to the fetus. Since IFN-λ shares signaling cascades and antiviral functions with IFN-I, we investigated the in vivo effects of IFN-λ in ZIKV-infected pregnant mice. IFN-λ administration during mid-pregnancy reduced ZIKV burden in maternal and fetal organs and alleviated placental injuries and fetal demise. In addition, prophylactic and therapeutic treatment of IFN-λ1 in a human trophoblast line, as well as in primary human amniotic epithelial cells, greatly reduced the ZIKV burden. Our data highlight IFN-λ1 as a potential therapeutic useful for women at risk for congenital Zika disease.

Experimental Zika Virus Infection in the Pregnant Common Marmoset Induces Spontaneous Fetal Loss and Neurodevelopmental Abnormalities

“…Rodents, including laboratory mice, are not a natural host of ZIKV infection because their IFN-driven immune responses can inhibit ZIKV replication 7,53,54 . As a result, murine models of ZIKV infection require IFN manipulation and are thus inherently limited in their potential for both translational relevance and mechanisms of congenital pathogenesis 7,39,53,54 . Here we show that ZIKV inoculation of pregnant marmosets causes a maternal asymptomatic infection and seroconversion similar to that seen in humans.…”

“…Only rodents rendered deficient of type I interferon through experimental manipulations are highly susceptible to maternal-fetal transmission and resultant congenital disease 53,54 . It is thus of likely importance to note that in ZIKV-infected pregnant marmoset dams, maximal RNA-seq differential expression between the infected and uninfected state and significant up-regulation of interferon-associated genes in peripheral blood were observed at day 2.…”

“…We are enthused by both the potential relevance and significance of our findings employing pregnant marmosets. First, they show that the marmoset faithfully recapitulates all crucial aspects of human CZS and does not require the exogenous manipulation of interferons, necessary in murine models 7,39,53,54 . Given the capacity for the marmoset to complete multifetal gestations in 143 days and undergo repeat pregnancy within 10 days, this is an efficient model whose reproductive capacity over short time intervals rivals most rodent models.…”

Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome

“…50 Maternal infection during the first trimester of pregnancy is associated with a higher risk of miscarriage, fetal loss or CZS; whereas an infection in late pregnancy seems to have less fetal and early neonatal consequences, with unspecific signs, as for others TORCH infections. 23,35,60,90,91 A recent report of the US Zika Pregnancy and Infant Registry noted a risk of neurodevelopmental abnormality in 9% of infants…”

Cephalotaxine inhibits Zika infection by impeding viral replication and stability

“…For example, ZIKV spread rapidly in 2015 in at least 33 regions and countries in Central and South America, such as Brazil, becoming an epidemic that affected between 0.5 and 1.5 million people [4e7]. ZIKV infection has been associated with several neurological complications, such as Guillain-Barr e syndrome in adults and microcephaly in infants [8,9].…”