Enhanced expression of IFI16 and RIG-I in human third-trimester placentas following HSV-1 infection

Abstract

The innate immune response in the placenta depends on the ability of maternal immune cells and fetal trophoblast cells to detect and eliminate invading pathogens through germline-encoded pattern recognition receptors (PRRs). In the present study, we analysed the transcripts and protein expression of interferon (IFN)-inducible protein (IFI)16, melanoma differentiation-associated protein 5 (MDA5), RIG-I-like receptor (RIG-I) and Toll-like receptor (TLR)-3 in third-trimester human placentas and investigated cytokine profiles generated during herpes simplex type 1 (HSV-1) infection. Decidual and chorionic villous biopsies (38-42 weeks of gestation) were obtained from healthy women immediately after a caesarean section. The expression of the DDX58 (RIG-I), IFIH1 (MDA5), IFI16 and TLR3 transcripts was measured using quantitative real-time polymerase chain reaction (qRT-PCR). Extracellular cytokine and PRRs levels were then quantified by enzyme-linked immunosorbent assays (ELISAs). All examined PRRs genes, including DDX58, IFIH1, IFI16 and TLR3, were expressed constitutively at the mRNA and protein levels in the placental biopsies. The concentration of the IFI16 protein was increased in HSV-1-infected decidual and chorionic villous explants compared to those of mock-infected tissues (P = 0·029). Higher protein expression levels of RIG-I in both the maternal and fetal parts of the placenta were found (P = 0·009 and P = 0·004, respectively). In addition, increased production of IFN-β by HSV-1-infected tissues was noticed (P = 0·004 for decidua, P = 0·032 for chorionic villi). No significant differences in the IFN-α, interleukin (IL)-6 and IL-8 levels were found. These results showed that HSV-1 infection can enhance the expression of IFI16 and RIG-I proteins in the human term placenta.

STING-Mediated IFI16 Degradation Negatively Controls Type I Interferon Production

“…IFI16 shuttles between the cytoplasm and the nucleus and recognizes both dsDNA and ssDNA (Ansari et al, 2015;Monroe et al, 2014). Although it was known that IFI16 is inducible in cells stimulated with IFN-I or IFN-II or infected with HSV-1 (Dawson and Trapani, 1995;Jab1o nska et al, 2018), it is still unclear whether there is an intrinsic pathway that negatively controls IFI16 levels to maintain normal immunity against infection. The IFI16 protein level is (A) HEK293T cells in 24-well plates were cotransfected with a firefly IFN-b-luciferase reporter (150 ng), renilla luciferase transfection control (20 ng), and the indicated dose of FLAG-IFI16/HA-STING expressing plasmids for 24 h. Relative firefly luciferase activity was quantified 24 h post-transfection.…”

Congenital Herpes Simplex Virus: A Histopathological View of the Placenta

“…The teratogenic effect of HSV on an embryo may provoke a variety of clinical outcomes, namely, ventriculomegaly, microcephaly, intracerebral calcifications, limb dysplasia [1], eye defects [4], and fetal loss [11,14]. As previously reported, primary infection in late pregnancy increases the risk of vertical transmission [13].…”

“…HSV is a double-stranded DNA virus and a member of the Herpesviridae family [4], responsible for oral and genital herpes [5]. As a neurotropic virus, it is detected in the dorsal root ganglion, following primary infection [1,6].…”

Gestational Viral Infections: Role of Host Immune System

“…Moreover, HSV is capable of increasing the expression of TLR3, RIG-I, IFI6 and IFN-β proteins as well as decreasing TNFα production in terms of human placental explant cultures [ 124 ] ( Figure 2 ), affecting maternal innate immune system antiviral responses.…”