Rift Valley fever virus targets the maternal-foetal interface in ovine and human placentas

Abstract

Background Rift Valley fever virus (RVFV) is an arbovirus of the order Bunyavirales that causes severe disease in ruminants and humans. Outbreaks in sheep herds are characterised by newborn fatalities and abortion storms. The association of RVFV infections with abortions of ovines and other ruminants is well recognized, whereas the pathology resulting in abortion has remained undescribed. Accumulating evidence suggests that RVFV is abortogenic in humans as well, warranting more research on the interaction of RVFV with the ruminant and human placenta. Methodology/Principal findings Pregnant ewes were inoculated with a highly virulent strain of RVFV and necropsied at different days post infection. Tissues were collected and analysed by PCR, virus isolation, and immunohistochemistry. The results show that RVFV replicates efficiently in maternal placental epithelial cells before the virus infects foetal trophoblasts. Moreover, the virus was shown to bypass the maternal epithelial cell layer by directly targeting foetal trophoblasts in the haemophagous zone, a region of the ovine placenta where maternal blood is in direct contact with foetal cells. Abortion was associated with widespread necrosis of placental tissues accompanied with severe haemorrhages. Experiments with human placental explants revealed that the same virus strain replicates efficiently in both cyto-and syncytiotrophoblasts. Conclusions/Significance This study demonstrates that RVFV targets the foetal-maternal interface in both ovine and human placentas. The virus was shown to cross the ovine placental barrier via two distinct routes, ultimately resulting in placental and foetal demise followed by abortion. Our finding that RVFV replicates efficiently in human trophoblasts underscores the risk of RVFV infection for human pregnancy.

Safety and immunogenicity of the Rift Valley fever arMP-12 ΔNSm21/384 candidate vaccine in pregnant ewes

“…RVFV virus replicates efficiently in maternal placental epithelial cells before the virus infects foetal trophoblasts. The virus has also been shown to bypass the maternal epithelial cell layer by directly targeting foetal trophoblasts in the haemophagous zone, a region of the ovine placenta where maternal blood is in direct contact with foetal cells [26] . Thus, the two lambs with fore limb malformations and one lamb with a deformed tail born during the first trimester of pregnancy in this study were consistent with transplacental virus infection, suggesting that the malformation could be attributed to infection by the RVFV arMP-12ΔNSm21/384 vaccine virus.…”

“…However, one report claimed that the MP-12 vaccine caused abortions in sheep and foetal malformation, but this alleged observation has not been confirmed [15] . The MP-12 parent vaccine virus was used to develop a recombinant arMP-12ΔNSm21/384 vaccine candidate with nucleotides deleted from the genes that encoded for the non-structural M protein [26] . Experimental studies including pregnant sheep and calves demonstrated that this recombinant vaccine was safe, efficacious and non-teratogenic [16] , [17] , [18] .…”

Reverse Genetics System for Shuni Virus, an Emerging Orthobunyavirus with Zoonotic Potential

“…All dilutions and suspensions were prepared in complete medium. After 48 h, an immunoperoxidase monolayer assay (IPMA) was performed as described previously using the rabbit antisera as primary antibodies and anti-goat-HRP (Dako, Agilent, Santa Clara, CA, USA) as a secondary antibody [37]. A well was scored positive for neutralization if less than 50% of the cells were stained, the negative control (without serum) was used as 100% cell staining.…”

“…All growth curves were performed in triplicate and each sample was titrated in triplicate using end-point dilution assay as described previously [38]. An immunoperoxidase monolayer assay (IPMA) was performed as described using the rabbit antisera as primary antibodies and anti-rabbit-HRP (Dako, Agilent, Santa Clara, CA, USA) as a secondary antibody [37]. Titres were determined using the Spearman-Kärber algorithm and were expressed as TCID 50 /mL.…”

Early Pathogenesis of Wesselsbron Disease in Pregnant Ewes

“…Each placentome contains maternal and foetal tissues, which are separated by several cell layers. The maternal epithelium and foetal trophoblasts form the actual barrier between mother and foetus in the synepitheliochorial part of the placenta, whereas in the so-called haemophagous zones, foetal trophoblasts are in direct contact with stagnant pools of maternal blood [19].…”