Rift Valley Fever Virus Propagates in Human Villous Trophoblast Cell Lines and Induces Cytokine mRNA Responses Known to Provoke Miscarriage

Abstract

The mosquito-borne Rift Valley fever (RVF) is a prioritised disease that has been listed by the World Health Organization for urgent research and development of counteraction. Rift Valley fever virus (RVFV) can cause a cytopathogenic effect in the infected cell and induce hyperimmune responses that contribute to pathogenesis. In livestock, the consequences of RVFV infection vary from mild symptoms to abortion. In humans, 1–3% of patients with RVFV infection develop severe disease, manifested as, for example, haemorrhagic fever, encephalitis or blindness. RVFV infection has also been associated with miscarriage in humans. During pregnancy, there should be a balance between pro-inflammatory and anti-inflammatory mediators to create a protective environment for the placenta and foetus. Many viruses are capable of penetrating that protective environment and infecting the foetal–maternal unit, possibly via the trophoblasts in the placenta, with potentially severe consequences. Whether it is the viral infection per se, the immune response, or both that contribute to the pathogenesis of miscarriage remains unknown. To investigate how RVFV could contribute to pathogenesis during pregnancy, we infected two human trophoblast cell lines, A3 and Jar, representing normal and transformed human villous trophoblasts, respectively. They were infected with two RVFV variants (wild-type RVFV and RVFV with a deleted NSs protein), and the infection kinetics and 15 different cytokines were analysed. The trophoblast cell lines were infected by both RVFV variants and infection caused upregulation of messenger RNA (mRNA) expression for interferon (IFN) types I–III and inflammatory cytokines, combined with cell line-specific mRNA expression of transforming growth factor (TGF)-β1 and interleukin (IL)-10. When comparing the two RVFV variants, we found that infection with RVFV lacking NSs function caused a hyper-IFN response and inflammatory response, while the wild-type RVFV suppressed the IFN I and inflammatory response. The induction of certain cytokines by RVFV infection could potentially lead to teratogenic effects that disrupt foetal and placental developmental pathways, leading to birth defects and other pregnancy complications, such as miscarriage.

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

“…The intertwined structure of the labyrinth zone provides the primary means of nutrient, oxygen, and waste exchange between the mother and fetus. The basal zone (also called junctional zone) is also a fetal derived tissue that helps to maintain pregnancy through production of steroids and hormones [ 23 , 24 ]. This section of placenta contains spongiotrophoblasts, trophoblast giant cells, and trophoblast glycogen cells.…”

“…For instance, ex vivo infection of second trimester [ 21 ] and full-term human placentas [ 12 ] showed infection of cytotrophoblasts and syncytiotrophoblasts of chorionic villi, which correlates with infection of similar cells in the labyrinth zone (cytotrophoblasts and syncytiotrophoblasts) and basal zone (giant cells) of rats. Immortalized human trophoblast cell lines (A3 and Jar), are also permissive to RVFV infection [ 24 ]. Despite general similarities in cellular constituents, there are distinct differences in the structure of placentas in rats and humans which should be considered when using rats as a model to study human disease.…”

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

“…For instance, ex vivo infection of second trimester (McMillen et al, 2018) and full-term human placentas (Oymans et al, 2020) showed infection of cytotrophoblasts and syncytiotrophoblasts of chorionic villi, which correlates with infection of similar cells in the labyrinth zone (cytotrophoblasts and syncytiotrophoblasts) and basal zone (giant cells) of rats. Immortalized human trophoblast cell lines (A3 and Jar), are also permissive to RVFV infection (Gwon et al, 2021).…”

Roles of TGF-β1 in Viral Infection during Pregnancy: Research Update and Perspectives

“…Enhanced expression or association with an elevated concentration of TGF-β1 in different viral infections have been thought or reported as a result of system or local immune response to protect against viral pathogens such as IAV, HIV, SARS-CoV-2, hepatitis E virus, chikungunya virus, Rift Valley Fever Virus, etc. [ 217 , 218 , 219 , 220 , 221 , 222 , 223 ]. However, its functions related to the viral infection and the viral life cycle have not always been well addressed, including the viruses of the typical ToRCH pathogens and other known potentially transplacental transmissions, or recently emerging viruses such as ZIKV and SARS-CoV-2.…”