Spondweni virus infection in pregnant rhesus macaques causes placental pathology without apparent fetal harm

Abstract

The 2015-2016 Zika virus (ZIKV) epidemic revealed the potential of flaviviruses to emerge rapidly, cause severe disease, and affect pregnancy outcomes. In 2016, Spondweni virus (SPOV), the closest known relative of ZIKV, was detected in mosquitoes in Haiti, suggesting it may also have the potential to emerge in the Western Hemisphere. The risks that close relatives of ZIKV pose to pregnant individuals are not well understood. Previously, we showed that SPOV can cause fetal demise, placental pathology, and vertical transmission in a mouse model. Here we report SPOVs pathogenic potential in pregnant rhesus macaques. We inoculated four macaques with SPOV at gestational day 30 (early first trimester) and compared their viral loads and fetal outcomes with those of macaques infected in the first trimester with either African-lineage ZIKV (ZIKV-DAK) or an Asian-lineage ZIKV isolate from Puerto Rico (ZIKV-PR) in previous studies. Plasma viremia persisted 10-31 days in SPOV-inoculated dams, whereas viremia resolved within 10-17 days for ZIKV-DAK and 5-52 days for ZIKV-PR. Cesarean deliveries near term (gestational day 152-157) revealed no demise, premature birth, or gross abnormalities in fetuses of dams inoculated with SPOV or ZIKV-PR. In contrast, under near-identical conditions, all ZIKV-DAK-inoculated dams experienced fetal demise between 12 and 20 days post-inoculation. At cesarean section, we did not detect SPOV RNA above the limit of detection in maternal (e.g., spleen, liver), placental, or fetal tissues, in contrast to previous findings with ZIKV-PR. Histological analysis revealed mononuclear/lymphohistiocytic villitis in all placentas of SPOV-exposed macaques, along with other pathological changes in individual placentas. Our findings suggest that SPOV infection of macaques in early pregnancy may result in placental pathology without overt fetal harm. Our results suggest that flaviviruses in the Spondweni serocomplex, which includes ZIKV and SPOV, may vary in their pathogenic potential during pregnancy. Author SummaryZika virus (ZIKV) can cause fetal harm. Does this risk extend to its closest known relative, Spondweni virus (SPOV)? Should SPOV circulate in humans, what risks would it pose in pregnancy? SPOV can injure fetuses in immunocompromised mice, but the physiology of pregnancy in mice differs greatly from that of humans. We therefore infected pregnant rhesus macaques with SPOV during early gestation and compared maternal viremia, placental pathology, and fetal outcomes with macaques infected with African- or Asian-lineage ZIKVs at the same gestational age. All fetuses survived to near-term pregnancy, fetal tissues were negative for SPOV RNA, and fetal growth tracked within expected ranges. Nonetheless, all SPOV-exposed pregnancies showed placental injury, including mononuclear/lymphohistiocytic villitis and maternal vascular malperfusion. Despite the absence of detectable SPOV RNA in fetal tissues, SPOV RNA persisted at term in maternal-fetal interface tissues in two of four animals. These data indicate placental injury without detectable vertical transmission in this translational model. Our results suggest that SPOV and ZIKV display a wide range of risks to the developing fetus. Identifying viral and host factors that increase the potential for fetal harm will be important for assessing risks posed by emerging viruses in this family.