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

Abstract

Although Zika virus (ZIKV) infection in pregnant women can cause placental damage, intrauterine growth restriction, microcephaly, and fetal demise, these disease manifestations only became apparent in the context of a large epidemic in the Americas. We hypothesized that ZIKV is not unique among arboviruses in its ability to cause congenital infection. To evaluate this, we tested the capacity of four emerging arboviruses (West Nile virus, WNV; Powassan virus, POWV; chikungunya virus, CHIKV; and Mayaro virus, MAYV) from related (flavivirus) and unrelated (alphavirus) genera to infect the placenta and fetus in immunocompetent, wild-type mice. Whereas all four viruses caused placental infection, only infection with the neurotropic flaviviruses (WNV and POWV) resulted in fetal demise. WNV and POWV also replicated efficiently in second-trimester human maternal (decidua) and fetal (chorionic villi and fetal membrane) explants whereas CHIKV and MAYV replicated less efficiently. In mice, RNA in situ hybridization and histopathological analysis revealed that WNV infected the placenta and fetal central nervous system, causing injury to the developing brain. In comparison, CHIKV and MAYV did not cause substantive placental or fetal damage despite evidence of vertical transmission. Based on the susceptibility of human maternal and fetal tissue explants and pathogenesis experiments in immunocompetent mice, other emerging neurotropic flaviviruses may share with ZIKV the capacity for transplacental transmission, and subsequent infection and injury to the developing fetus.

Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis

“…ZIKV is not unique among flaviviruses in its ability to cause microcephaly and other developmental defects (O’Leary et al, 2006; Platt et al, 2018), but the scale of the ZIKV epidemic has increased the urgency to understand the mechanisms behind this neuropathogenesis. Moreover, while ZIKV can cause microcephaly, there is currently no evidence that DENV can.…”

Zika virus and the nonmicrocephalic fetus: why we should still worry

“…(98, 99) A recent study suggests that several other emerging and ZIKV-related viruses may also infect the placenta and cause fetal demise. (100) Human maternal and fetal tissue explants were highly susceptible to West Nile virus (WNV) and Powassan virus infections, with less efficient infection by the alphaviruses, Mayaro virus and Chikungunya virus (CHIKV); WNV could also infect the fetal brain and cause stillbirth or abortion in an immunocompetent mouse model. (100) Further, a case series of WNV infections in human pregnancies reported neurologic injuries similar to the CZS including meningitis, lissencephaly, and microcephaly.…”

“…(100) Human maternal and fetal tissue explants were highly susceptible to West Nile virus (WNV) and Powassan virus infections, with less efficient infection by the alphaviruses, Mayaro virus and Chikungunya virus (CHIKV); WNV could also infect the fetal brain and cause stillbirth or abortion in an immunocompetent mouse model. (100) Further, a case series of WNV infections in human pregnancies reported neurologic injuries similar to the CZS including meningitis, lissencephaly, and microcephaly. (101) Vertical transmission of CHIKV has been reported with documented neonatal encephalitis and long-term adverse outcomes on child neurocognitive function.…”

“…(104) These studies suggest that emerging flaviviruses may share ZIKV’s teratogenic capacity and that pregnancy outcomes in regions at risk for viral infections with unknown risk to the fetus should be monitored for birth defects. (100)…”

Recognizing the Global Impact of Zika Virus Infection during Pregnancy

“…There are other known and emerging threats to pregnant women and infants, including the possible teratogenicity of some related flaviviruses that might not be apparent in the absence of surveillance systems that monitor pregnancies, infants, and birth defects and in the absence of a major outbreak of disease from these flaviviruses. 10 The approaches and lessons learned from the ZIKV outbreak in the Americas show the necessity of improved and integrated ongoing systems for surveillance of pregnancies, infectious diseases, and birth defects to rapidly address the next emerging health threat affecting pregnant women and infants. 11 Sustained commitment to better monitoring systems for these medically vulnerable populations will more promptly identify serious health threats and will provide an opportunity for the public health field to have a positive effect on infant health and prevent birth defects.…”