For the first time, scientists have demonstrated that Rift Valley fever virus — an emerging mosquito-borne infectious disease that leads to severe illness in humans — can be transmitted from mother to fetus in rats.
The study, published in the December 5 issue of Science Advances, lays the groundwork for testing the efficacy of potential vaccines and therapies and for understanding the potential risk of RVFV infection to pregnant women.
The virus was first discovered in 1931 during an epidemic in farm sheep in the Rift Valley of Kenya, and since then outbreaks have been reported in sub-Saharan Africa, North Africa, and more recently in Saudi Arabia and Yemen, raising concerns that RVFV may spread to Asia and Europe. Ongoing outbreaks of RVFV in Uganda, Kenya and Rwanda have prompted the World Health Organization to classify the virus as a "priority disease," highlighting the urgent need for more data to identify the effect of RVFV infection in pregnant women.
RVFV infections in pregnant livestock cause high rates of fetal death. In humans, the disease spreads by exposure to infected animals (specifically by coming in contact with blood or drinking raw milk) or through infected mosquito bites — causing body aches, joint pain, dizziness and headaches with occasional progression to hemorrhagic fever. Data from human outbreaks, while limited, hint that transmission of RVFV from the mother to the developing human fetus can occur, potentially leading to miscarriage.
Cynthia McMillen, a postdoctoral associate at the University of Pittsburgh Center for Vaccine Research and her colleagues observed that pregnant rats were more susceptible to RVFV-induced death than their non-pregnant counterparts. The researchers also found that RVFV infection resulted in fetal death and severe birth defects that develop later in gestation when the placenta is fully formed (rather than earlier, as happens with other viruses including Zika), even in pups from infected pregnant rats with no symptoms.
"Vaccination of livestock is one way that natural outbreaks [of RVFV] are controlled. Unfortunately, several live forms of vaccines used in livestock during outbreaks can themselves be passed from mother to fetus and lead to death, therefore they cannot be used in pregnant livestock," said Amy Hartman, an assistant professor at the University of Pittsburgh Center for Vaccine Research.
"Our rat model will be useful for screening initial vaccine candidates to determine whether the vaccine itself can cause fetal infection or death. The rat model can also be used to test vaccines and therapeutic drugs to determine whether the vaccine or treatment can protect fetuses after infection with natural RVFV," said Hartman. "This model will allow us to understand the immune response necessary to protect fetuses from virulent virus."
While the liver is considered the primary target organ of RVFV, the authors showed that reproductive tissues, especially the placenta, were major sites of virus replication. McMillen and her colleagues infected human placental tissue isolated within the second trimester with RVFV growing in the lab. This led to active replication of the virus in the syncytial layer, a region of the placenta typically resistant to viral infections.
The researchers say this is the first analysis to pinpoint the degree to which RVFV targets reproductive tissues. The ovaries, uterus and placenta are previously unrecognized sites of virus replication in both pregnant and non-pregnant animals.
"A more comprehensive study of pregnant women during natural outbreaks is required. We do not know the incidence of RVFV during pregnancy, and epidemiological study of the effect of the virus in pregnant women is sorely needed," said Hartman.