Gestational Stage and IFN-λ Signaling Regulate ZIKV Infection In Utero

Abstract

SUMMARY Although Zika virus (ZIKV)-induced congenital disease occurs more frequently during early stages of pregnancy, its basis remains undefined. Using established type I interferon (IFN)-deficient mouse models of ZIKV transmission in utero, we found that the placenta and fetus were more susceptible to ZIKV infection at earlier gestational stages. Whereas ZIKV infection at embryonic day 6 (E6) resulted in placental insufficiency and fetal demise, infections at midstage (E9) resulted in reduced cranial dimensions, and infection later in pregnancy (E12) caused no apparent fetal disease. In addition, we found that fetuses lacking type III IFN-λ signaling had increased ZIKV replication in the placenta and fetus when infected at E12, and reciprocally, treatment of pregnant mice with IFN-λ2 reduced ZIKV infection. IFN-λ treatment analogously diminished ZIKV infection in human midgestation fetal- and maternal-derived tissue explants. Our data establish a model of gestational stage-dependence of ZIKV pathogenesis and IFN-λ-mediated immunity at the maternal-fetal interface.

Zika virus–related neurotropic flaviviruses infect human placental explants and cause fetal demise in mice

“…2A-D), similar to that seen during congenital ZIKV infection (8). However, we did not observe evidence of severe damage, necrosis, or loss of structural integrity, as the junctional and labyrinth layers remained intact in CHIKV- or WNV-infected placentas (Fig.…”

“…Because ZIKV replicated inefficiently in immunocompetent wild-type (WT) mice, most studies in pregnant mice have used animals with genetic or acquired deficiencies in type I interferon (IFN) receptor signaling ( 7, 8, 10 ). Alternatively, injection of WT dams via intravenous or intrauterine routes with high doses of ZIKV can bypass peripheral immunity, resulting in transplacental transmission and fetal injury ( 9, 11 ).…”

Consequences of congenital Zika virus infection

“…The most commonly used mouse model of congenital ZIKV infection involves subcutaneous or intravaginal inoculation of ZIKV in pregnant dams lacking the type I IFN receptor ( Ifnar1 −/− mice) crossed to immunocompetent wild-type (WT) sires. This allows efficient ZIKV replication in the pregnant dam to facilitate infection of heterozygous Ifnar1 +/− fetuses that have an intact type I IFN response [6,63,65]. In this Ifnar1 −/− mouse model of congenital infection, intravaginal or subcutaneous inoculation at early gestational dates (e.g., embryonic day (E) 6.5) results in high viral burden in the fetus and placenta, which leads to IUGR and fetal demise [6,65].…”

“…This allows efficient ZIKV replication in the pregnant dam to facilitate infection of heterozygous Ifnar1 +/− fetuses that have an intact type I IFN response [6,63,65]. In this Ifnar1 −/− mouse model of congenital infection, intravaginal or subcutaneous inoculation at early gestational dates (e.g., embryonic day (E) 6.5) results in high viral burden in the fetus and placenta, which leads to IUGR and fetal demise [6,65]. After infection at early gestational dates, IUGR and fetal demise likely result from damage and insufficiency of the placenta, leading to fetal death [6].…”

“…After infection at early gestational dates, IUGR and fetal demise likely result from damage and insufficiency of the placenta, leading to fetal death [6]. By contrast, infection at later gestational dates (E9.5) resulted in diminished viral burden in the placenta and fetus, which caused microcephaly but not fetal demise [65]. Finally, infection of mice at even later gestational time points (E11.5) resulted in even lower viral burden in the fetus without any appreciable clinical effect in the fetus or the placenta [65].…”