Zika Virus Infection of Pregnant Ifnar1 ^−/− Mice Triggers Strain-Specific Differences in Fetal Outcomes

Abstract

Zika virus (ZIKV) is a flavivirus that causes a constellation of adverse fetal outcomes collectively termed Congenital Zika Syndrome (CZS). However, not all pregnancies exposed to ZIKV result in an infant with apparent defects. During the 2015-2016 American outbreak of ZIKV, CZS rates varied by geographic location. The underlying mechanisms responsible for this heterogeneity in outcomes have not been well defined. Therefore, we sought to characterize and compare the pathogenic potential of multiple Asian/American-lineage ZIKV strains in an established Ifnar1 -/- pregnant mouse model. Here, we show significant differences in the rate of fetal demise following maternal inoculation with ZIKV strains from Puerto Rico, Panama, Mexico, Brazil, and Cambodia. Rates of fetal demise broadly correlated with maternal viremia but were independent of fetus and placenta virus titer, indicating that additional underlying factors contribute to fetus outcome. Our results, in concert with those from other studies, suggest that subtle differences in ZIKV strains may have important phenotypic impacts. With ZIKV now endemic in the Americas, greater emphasis needs to be placed on elucidating and understanding the underlying mechanisms that contribute to fetal outcome. IMPORTANCE Zika virus (ZIKV) transmission has been reported in 87 countries and territories around the globe. ZIKV infection during pregnancy is associated with adverse fetal outcomes including birth defects, microcephaly, neurological complications, and even spontaneous abortion. Rates of adverse fetal outcomes vary between regions, and not every pregnancy exposed to ZIKV results in birth defects. Not much is known about how or if the infecting ZIKV strain is linked to fetal outcomes. Our research provides evidence of phenotypic heterogeneity between Asian/American-lineage ZIKV strains and provides insight into the underlying causes of adverse fetal outcomes. Understanding ZIKV strain-dependent pathogenic potential during pregnancy and elucidating underlying causes of diverse clinical sequelae observed during human infections is critical to understanding ZIKV on a global scale.

Congenital Rift Valley fever in Sprague Dawley rats is associated with diffuse infection and pathology of the placenta

“…There was surprisingly little inflammation in any placental structure. Zika virus (ZIKV) infection of pregnant IFNAR1 knockout mice via footpad injection can result in vertical transmission involving severe necrosis of the decidua and basal zone [ 33 , 34 ]; however, decidual necrosis in ZIKV-infected rodents and pregnant women [ 35 ] is not associated with adverse fetal outcomes such as death or microcephaly. Vertical transmission of human immunodeficiency virus in placentas from 1 st and 2 nd trimester abortions is also correlated with necrosis of the decidua [ 36 ].…”

Infection of the maternal-fetal interface and vertical transmission following low-dose inoculation of pregnant rhesus macaques (Macaca mulatta) with an African-lineage Zika virus

“…In contrast to Asian-lineage ZIKV, African-lineage ZIKV infection in pregnant mice is more likely to cause fetal demise than birth defects [ 16 , 17 ]. Aubry et al reported higher rates of fetal reabsorption in mouse pregnancies infected with African-lineage ZIKV, whereas infection with Asian-lineage resulted in varying capacities to cause fetal harm including fetal brain abnormalities as well as fetal death/resorption [ 16 , 20 ].…”

Infection of the maternal-fetal interface and vertical transmission following low-dose inoculation of pregnant rhesus macaques (Macaca mulatta) with an African-lineage Zika virus

“…In contrast to Asian-lineage ZIKV, African- lineage ZIKV infection in pregnant mice is more likely to cause fetal demise than birth defects [17] [18]. Aubry et al reported higher rates of fetal reabsorption in mouse pregnancies infected with African-lineage ZIKV, whereas infection with Asian-lineage resulted in varying capacities to cause fetal harm including fetal brain abnormalities as well as fetal death/resorption [17] [21].…”