Hepatitis C Virus Sensing by Human Trophoblasts Induces Innate Immune Responses and Recruitment of Maternal NK Cells: Potential Implications for Limiting Vertical Transmission

Abstract

Hepatitis C virus (HCV) is the world’s most common blood-borne viral infection for which there is no vaccine. The rates of vertical transmission range between 3–6% with odds 90% higher in the presence of HIV co-infection. Prevention of vertical transmission is not possible due to lack of an approved therapy for use in pregnancy or an effective vaccine. Recently, HCV has been identified as an independent risk factor for pre-term delivery, perinatal mortality and other complications. In this study, we characterized the immune responses that contribute to the control of viral infection at the maternal-fetal interface (MFI) in the early gestational stages. Here we show that primary human trophoblast cells and an extravillous trophoblast cell line (HTR8), from first and second trimester of pregnancy, express receptors relevant for HCV binding/entry and are permissive for HCV-uptake. We found that HCV-RNA sensing by human trophoblast cells induces robust up-regulation of Type I/III IFNs and secretion of multiple chemokines that elicit recruitment and activation of decidual NK cells. Furthermore, we observed that HCV-RNA transfection induces a pro-apoptotic response within HTR8 that could affect the morphology of the placenta. For the first time, we demonstrate that HCV-RNA sensing by human trophoblast cells elicits a strong antiviral response that alters the recruitment and activation of innate immune cells at the MFI. This work provides a paradigm shift in our understanding of HCV-specific immunity at the MFI, as well as novel insights into mechanisms that limit vertical transmission, but may paradoxically lead to virus-related pregnancy complications.

Mechanisms and Prevention of Vertical Transmission in Chronic Viral Hepatitis

“…4 and 5). The authors further demonstrated the presence of HCV NS5A protein, a nonstructural HCV protein, within human trophoblast cells, suggesting endocytosis and uptake of HCV 2. This was a meticulously designed study, which effectively demonstrated this mechanism of transmission.…”

Human embryonic stem cell–derived hepatoblasts are an optimal lineage stage for hepatitis C virus infection

“…Finally, the host animals were F/R mice that lacked mature T and B cells but retained both natural killer cells and macrophages. The natural killer cells were regarded as first‐line effectors of the innate immune response and played a distinct role against HCV infection . The loss of HCV from engrafted hHBs could be due partially to the existing innate immune cells.…”

“…The natural killer cells were regarded as first-line effectors of the innate immune response and played a distinct role against HCV infection. (15,44) The loss of HCV from engrafted hHBs could be due partially to the existing innate immune cells. In future, we will improve the hESC-derived HBs engrafted mouse model through removing natural killer cells by antibody treatments along with other forms of immunosuppression for susceptibility or enhanced HCV replication.…”

Inflammation and preterm birth

“…Furthermore, the interaction of dNK cells with HLA-E and HLA-G molecules expressed by extravillous trophoblast has been shown to be critically involved in the inhibition of dNK cell cytolytic functions during normal pregnancy [119,136]. Notably, the recent findings that human trophoblast cells promote the activation and cyotoxicity of dNK cells upon hepatitis C virus sensing [138] clearly indicate that NK cells at the feto-maternal interface can switch their phenotype in case of infection and suggest a possible involvement of these cells in the pathogenesis of PTB.…”