TGF-β1 Promotes Zika Virus Infection in Immortalized Human First-Trimester Trophoblasts via the Smad Pathway

Abstract

The Zika virus (ZIKV) is well known for causing congenital Zika syndrome if the infection occurs during pregnancy; however, the mechanism by which the virus infects and crosses the placenta barrier has not been completely understood. In pregnancy, TGF-β1 is abundant at the maternal–fetal interface. TGF-β1 has been reported to enhance rubella virus binding and infection in human lung epithelial cells. Therefore, in this study, we investigate the role of TGF-β1 in ZIKV infection in the immortalized human first-trimester trophoblasts, i.e., Swan.71. The cells were treated with TGF-β1 (10 ng/mL) for two days before being inoculated with the virus (American strain PRVABC59) at a multiplicity of infection of five. The results showed an enhancement of ZIKV infection, as demonstrated by the immunofluorescent assay and flow cytometry analysis. Such enhanced infection effects were abolished using SB431542 or SB525334, inhibitors of the TGF-β/Smad signaling pathway. An approximately 2-fold increase in the virus binding to the studied trophoblasts was found. In the presence of the Smad inhibitors, virus replication was significantly suppressed. An enhancement in Tyro3 and AXL (receptors for ZIKV) expression induced by TGF-β1 was also noted. The results suggest that TGF-β1 promotes the virus infection via the Smad pathway. Further studies should be carried out to clarify the underlying mechanisms of these findings.

TGF-β signaling in health, disease and therapeutics

“…[718][719][720][721][722] TGF-β-mediated immunosuppression can also contribute to viral infection, as elevated TGF-β expression during viral infection not only impairs early innate immunity such as IFN responses, NK functions, and macrophage activity but also suppresses the adaptive immune responses of T cells and B cells. 428,[723][724][725][726][727][728][729][730][731] Notably, TGF-β can also enhance viral infection through certain pathogen-specific mechanisms as in the cases of human immunodeficiency virus type 1 (HIV-1) infection, [732][733][734] human T-cell leukemia virus type I (HTLV-I) infection, 735 hepatitis C virus (HCV) infection, 736 Zika virus (ZIKV) infection, 737 as well as rubella virus (RuV) infection. 738 Furthermore, TGF-β can promote the survival and growth of parasites in hosts through downregulation of NO, IFN-γ, TNF-α, IL-6, IL-17, and Th17 cells as well as upregulation of IL-4, IL-10, and Treg cells, contributing to the infection of Fasciola hepatica, 739 Echinococcus multilocularis, 740 Toxoplasma gondii, 741 Leishmania, 742 and Plasmodium.…”

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

“…The results showed an enhancement in ZIKV binding and replication in these trophoblast cells. In addition, such enhancement effects were abolished using an inhibitor of the Smad pathway, SB431542 or SB525334 [ 34 ].…”

“…One of the reported studies addressing the role of TGF-β1 in viral infection in pregnancy is our recent work on Zika virus infection in trophoblast cells with the predominant role of the Smad pathway. The enhancement effect of ZIKV induced by TGF-β1 might be attributed to an increase in cellular receptors of ZIKV, AXL and Tyro3 [ 34 ]. In addition, increasing extracellular matrix synthesis resulting from the Smad pathway leading to an enhancement of non-specific binding of ZIKV to the trophoblast cells may not be excluded.…”

“… Trophoblasts, microvillous structure and the published effects of TGF-β1 on viral infection in trophoblasts at the maternal–fetal interface. ❶, TGF-β1 increases the infection and replication of HCMV in STBs through macrophage contact [ 26 ]; ❷, enhancement of ZIKV infection and replication in trophoblasts by TGF-β1 [ 34 ]; ❸, no effect on HIV construct replication in trophoblasts under TGF-β1 treatment [ 257 ]; ❹, increases HBx-transfected trophoblast proliferation and invasion [ 258 ]. Abbreviations: HCMV, human cytomegalovirus; HBV, hepatitis B virus; HIV, human immunodeficiency virus; ZIKV, Zika virus; CBT, cytotrophoblast; STB, syncytiotrophoblast; EVT, extravillous trophoblast; T reg, regulatory T cells.…”

“…TGF-β1 also plays some roles in viral infection [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. It is worthy of note that it can promote ZIKV infection in the immortalized first-trimester trophoblast cells via the Smad pathway [ 34 ]. This finding provides a potential approach to studying the mechanisms of transplacental viral infections and congenital viral syndromes.…”