|Year : 2020 | Volume
| Issue : 4 | Page : 249-256
Toll-like receptor-dependent antiviral responses at the maternal–fetal interface
Xiao-Rui Liu, Xiao-Wei Wei, Yi Lin
Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Embryo Original Diseases, School of Medicine, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
|Date of Submission||29-May-2020|
|Date of Decision||10-Jul-2020|
|Date of Acceptance||13-Oct-2020|
|Date of Web Publication||31-Dec-2020|
Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Embryo Original Diseases, School of Medicine, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University, Shanghai 200030
Source of Support: None, Conflict of Interest: None
The maternal–fetal interface is a key barrier to protect the fetus from infection. Toll-like receptors (TLRs) at the maternal–fetal interface are involved in antiviral responses. TLRs are expressed in both maternal decidua and fetal trophoblasts. Virus-induced activation of TLR signaling pathways triggers the release of interferon-related antiviral molecules and other inflammatory cytokines and/or chemokines by the host innate immune system, which may disrupt immune tolerance at the maternal–fetal interface and lead to pregnancy complications. In this review, we summarize the state of knowledge on the most common viral infections during pregnancy, antiviral TLR responses at the maternal–fetal interface, and TLR-associated pregnancy complications.
Keywords: Toll-Like Receptor; Antiviral Response; Maternal-Fetal Interface
|How to cite this article:|
Liu XR, Wei XW, Lin Y. Toll-like receptor-dependent antiviral responses at the maternal–fetal interface. Reprod Dev Med 2020;4:249-56
| Introduction|| |
Pregnant women are more susceptible to viral infection due to the development of an enhanced state of immune tolerance necessary to prevent the rejection of the semi-allogeneic fetus. Viral infection during pregnancy can lead to intrauterine infection and adverse pregnancy outcomes, such as miscarriage, preterm birth, preeclampsia, and intrauterine growth restriction.,, Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), which is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, poses a significant threat to maternal and fetal health, and, thus, an in-depth investigation into the mechanisms through which viruses affect the maternal–fetal interface is required. The maternal innate immune response constitutes a powerful defensive barrier that eliminates pathogenic infections through inflammatory responses. Toll-like receptors (TLRs) recognize many types of pathogens, including viruses, and play an essential role in the innate immune system. However, several pregnancy complications have been associated with TLR-dependent antiviral responses. Thus, understanding these responses and their role in pregnancy complications is crucial for improving clinical care provided to pregnant women. Herein, we summarize the current knowledge on antiviral TLR-dependent immune responses at the maternal–fetal interface as well as their role in pregnancy complications.
| Immune Microenvironment at the Maternal–Fetal Interface|| |
The maternal–fetal interface comprises the maternal decidua and embryonic trophoblasts. Immune cells, trophoblasts, cytokines, and chemokines constitute the immune microenvironment, which undergoes marked changes during pregnancy. Approximately, 30%–40% of decidual cells in early pregnancy are leukocytes. Natural killer (NK) cells and macrophages are the two major cell types, comprising 50%–70% and 20%–30% of all decidual immune cells, respectively. CD3+ T cells constitute 10%–20% of the leukocytes, while dendritic cells (DCs) represent approximately 1.7%.
During embryo implantation, cytotrophoblasts (CTBs), which originate from the trophectoderm, proliferate outward and differentiate into either outer syncytiotrophoblasts (STBs) or extravillous trophoblasts (EVTs). EVT invasion of the decidua and maternal spiral arteries modulates vascular remodeling and establishes the uteroplacental circulation through direct contact with the maternal blood. Furthermore, trophoblasts actively attract and educate immune cells, shaping the immune microenvironment at the maternal–fetal interface through the secretion of hormones, cytokines, and chemokines. For example, after embryo implantation, C-X-C motif chemokine ligand (CXCL) 12 (CXCL12), CXCL8, transforming growth factor-β (TGF-β), and C-C motif chemokine ligand (CCL) 2 (CCL2) are secreted constitutively by trophoblasts to recruit peripheral monocytes, neutrophils, NK cells, T cells, and regulatory T cells. After recruitment, the trophoblasts secrete interleukin 15 (IL-15) and TGF-β to induce the differentiation of decidual NK cells with decreased cytotoxic activity. Similarly, trophoblast-derived macrophage colony-stimulating factor and IL-10 promote the differentiation of peripheral blood monocytes to macrophages with an M2 phenotype.
Suppression of the maternal immune system during pregnancy promotes the transmission of viral infection. Although viruses rarely cross the placental barrier, the expression of viral entry receptors and the suppression of the maternal immune response may allow viruses to access the cells within the decidua and trophoblast layer by ascending from the lower reproductive tract or via hematogenous transmission [Figure 1].
|Figure 1: Routes of viral infection during pregnancy. Transmission may be vertical or through ascension from the vagina. TLRs involved in antiviral responses are expressed by immune cells and trophoblasts at the maternal–fetal interface. NK: Natural killer; DCs: Dendritic cells; TLRs: Toll-like receptors.|
Click here to view
| Toll-Like Receptors at the Maternal–Fetal Interface|| |
TLRs are membrane-bound proteins and major members of the pattern recognition receptor group. These receptors are expressed both externally on the cell surface (TLRs 1, 2, 4, 5, and 6) and intracellularly on endosomes and lysosomes (TLRs 3, 7, 8, and 9). They can detect a wide range of pathogen-associated molecular patterns (PAMPs) and activate signaling cascades, resulting in interferon (IFN) and pro-inflammatory cytokine production. TLRs 3, 7, 8, and 9 are involved in antiviral immunity. Among them, TLR3 recognizes double-stranded RNA (dsRNA), TLRs 7 and 8 interact with single-stranded RNA (ssRNA), and TLR9 recognizes unmethylated cytidine-phosphateguanosine DNA., Both dsRNA and ssRNA are intermediate molecules of viral replication. In addition, the expression of TLR2 and 4 is upregulated by viral glycoproteins.,
The TLRs involved in antiviral responses are widely expressed in immune and nonimmune cells at the maternal–fetal interface [Figure 1]., TLRs 1–9 are expressed dynamically in decidual NK cells, macrophages, placenta, chorioamniotic membranes, and vaginal tissues, playing important roles not only in antiviral and anti-bacterial responses but also in the regulation of the immune microenvironment during pregnancy.,,,, Upon viral recognition, TLR recruits the myeloid differentiation factor 88 (MyD88), an intracellular signaling adapter, which promotes the recruitment of immune cells as well as the activation of intracellular signaling pathways that induce IFN-mediated antiviral activity and the production of inflammatory cytokines and chemokines [Figure 2]., The innate immune responses triggered by TLRs 3, 7, 8, and 9 depend on the coordinated activation of nuclear factor-κB (NF-κB) and IFN regulatory factors (IRFs)., TLR4 activation induces tumor necrosis factor-a (TNF-a) production and potent T helper type 1 (Th1) immune response in the first trimester, which decreases subsequently. Accumulating evidence supports the notion that the TLRs expressed in trophoblasts recognize and respond to pathogens. Therefore, owing to the intrinsic antiviral defense of IFN-γ in placental STBs, CTBs are more susceptible to viral infection than STBs.
|Figure 2: TLR signaling in innate immune defense. TLRs 2, 4, and 6 localize on cellular membranes and recognize viral ligands. TLRs 3, 7, 8, and 9 localize on endosomal membranes and recognize viral dsRNA, ssRNA, and CpG DNA. MyD88 and TRIF are two signaling adaptors. TLR signaling upregulates IFN, pro-inflammatory cytokine, and chemokine expression. CCL: C-C motif chemokine ligand; CpG: Cytidine-phosphateguanosine; CXCL: C-X-C motif chemokine ligand; dsRNA: Double-stranded RNA; IFNs: Interferons; IL: Interleukin; MyD88: Myeloid differentiation factor 88; ssRNA: Single-stranded RNA; TNF: Tumor necrosis factor; TRIF: Toll/IL-1R domain-containing adaptor-inducing IFN-β; TLR: Toll-like receptor.|
Click here to view
| Viral Infections during Pregnancy|| |
Viral infections during pregnancy may have adverse effects on pregnancy outcomes and cause birth defects. Apart from direct fetal infection by vertical transmission, viruses can infect the decidua and placenta by ascending from the lower reproductive tract or via hematogenous transmission. Furthermore, soluble immune factors produced by infected decidua and/or placenta may reach the fetus. Currently, some of the most concerning viral infections to occur during pregnancy are those caused by the human cytomegalovirus (CMV), Zika virus (ZIKV), human immunodeficiency virus (HIV), hepatitis B virus (HBV), human papillomavirus (HPV), influenza virus (IV), herpes simplex virus (HSV), and SARS-CoV-2.
CMV, a double-stranded DNA (dsDNA) virus that can be transmitted vertically, is the most common virus identified at the maternal–fetal interface. CMV infection is associated with preterm birth, preeclampsia, fetal/neonatal death, and intrauterine growth restriction. The transmission rate in the first trimester is only 30% but rises up to 70% in the third trimester. The presence of intronic single-nucleotide polymorphisms in certain alleles increases the odds of contracting a viral infection, and the adverse effects caused by the infection may vary among populations expressing different polymorphisms. Polymorphisms of immune response genes, such as TLR2, TLR7, TLR9, and IL-6, are associated with CMV infection in late gestation. CMV entry receptors are expressed in trophoblasts and monocytes/macrophages at the maternal–fetal interface.
Upon CMV exposure, TLR2 recognizes viral glycoproteins B and H, leading to the activation of NF-κB and increased TNF-a and IL-12 production. In addition, it has been observed that TLR3 mediates IFN-β production; TLR4 induces IL-6, IL-8, and IFN-β production; and TLR9 mediates IL-8 and TNF-a responses., The expression of IFN-γ by immune cells is also significantly upregulated. During pregnancy, CMV virions are more often detected in the decidua than in placental trophoblasts. A pro-inflammatory bias is induced in the placenta and amniotic fluid through an increase in the levels of pro-inflammatory cytokines such as TNF-a, IL-1β, IL-12, and IL-17 and monocyte chemoattractant protein-1 (MCP-1/CCL2), CCL4, and CXCL10 chemokines, while reducing anti-inflammatory IL-4 levels., TNF-a released from CMV-infected trophoblasts can induce the apoptosis of neighboring uninfected cells. CMV infection may also inhibit the release of CXCL2 in the EVT and increase the expression of receptors for CXCL2, such as CXCR4 and CXCR7, resulting in impaired trophoblast invasion and migration. Inadequate trophoblast invasion may damage vascular remodeling and decrease the blood flow from mother to fetus, causing growth abnormalities.
A wide range of CMV-encoded gene products may modulate host defenses. Infected cells, such as CD14+ monocytes, macrophages, and DCs, produce CMV-encoded homologs of human IL-10, which polarize uninfected cells toward an anti-inflammatory M2 phenotype, restricting the production of pro-inflammatory cytokines (TNF-a and IL-1β) and CD4+ T cell responses to limit viral clearance., Decidual NK cells provide an ideal microenvironment for healthy placentation and play a positive role in the control of viral spread. NK cells possess traits of adaptive immunity and can acquire immunological memory in a manner similar to that of T and B cells. CMV infection results in the expansion of NK cells harboring CMV-specific receptors, and after encountering CMV-infected decidual fibroblasts, decidual NK cells become more cytotoxic than before, increasing the antiviral immune responses. Subsequently, upon re-exposure to CMV, the “adaptive” NK cells can expand rapidly to resist infection.
ZIKV is a mosquito-borne ssRNA virus that can be transmitted vertically from mother to fetus because ZIKV RNA has been identified in fetal brain tissue, amniotic fluid, and placenta. Moreover, ZIKV-specific IgM antibodies have been found in the cerebral fluid of newborns. Several receptors, including the type I receptor-tyrosine kinases (AXL and TYRO3), are expressed in various cell types throughout the placenta, including the amniotic epithelia, CTBs, Hofbauer cells, and placental fibroblasts. Infection in early pregnancy leads to microcephaly, miscarriage, stillbirth, and intrauterine growth restriction, while infection in late pregnancy can cause fetal abnormalities.,
During pregnancy, ZIKV targets the maternal decidual tissues, CTBs, monocytes, endothelial cells, and Hofbauer cells in the chorionic villi at the maternal–fetal interface.,, Maternal decidual tissues show similar susceptibility to ZIKV from the first trimester to mid-gestation, while significantly reduced susceptibility to ZIKV has been reported in chorionic villus tissues with increasing gestational age. Different IFN responses are induced in different cell types. Accordingly, both mouse and in vitro studies have shown that placenta and the human choriocarcinoma cell line, JEG-3, present increased levels of IFN-β and IFN-stimulated genes, such as CXCL10, IFIT1, and MX1, when infected with ZIKV., Furthermore, TLRs 3 and 8 are activated in ZIKV-infected human trophoblast-derived HTR-8 cells and induce high levels of IFN-a, IL-6, IL-8, TNF-a, CCL2, and CCL5. In addition, mock-infected decidual tissue with ZIKV upregulates the expression of IFN-a, IFN-β, IFN-γ, CXCL6, migration inhibition factor, and leukemia inhibitory factor. Moreover, TLR7/8 agonists can inhibit ZIKV replication in placental cells. Unlike CMV-infection, which elicits the upregulation of leukocyte migration, mobilization, and homing functions, ZIKV does not activate decidual tissue immune cell responses. The impact of ZIKV on chorionic villus tissue is distinctively characterized by increased apoptotic gene expression, cell death, and necrosis molecular functions.
Human immunodeficiency virus
Peripheral blood mononuclear cells incubated with TLR9 agonist MGN1703 show increased secretion of IFN-a and CXCL10 and higher proportion of IFN-γ-producing NK cells, which inhibits the spread of HIV. A recent study reported that HIV-1 is endocytosed and degraded by CD4+ T cells that express TLR8 and secrete IL-6. Next, active CD4+ T cells differentiate into either Th1 or Th17 cells, depending on the cytokine environment (Th1-cytokine, IFN-γ; Th17-cytokine, IL-17). After in utero exposure to HIV, infants present increased susceptibility to bacterial infection due to TLR4 anergy.
Hepatitis B virus
HBV infection affects about 3.87%–9.98% of women at reproductive age and pregnant women in China. A recent population-based cohort study reported that maternal prepregnancy infection with HBV increases the risk of preterm birth. The expression of TLR7, TLR8, IFN-a, IFN-β, and IL-8 is significantly induced in trophoblastic cells exposed to HBV. Reportedly, the TLR7 agonist GS-9620 (Vesatolimod) can increase T and NK cell responses and induce immunity to HBV infection. In addition, the IL-1R/TLR signaling pathway augments HBV-specific CD8+ T cell responses to produce IFN-γ, TNF-a, and IL-2, which contributes to HBV clearance.
HPV is a double-stranded DNA virus that has been detected in placenta. Large cohort studies have shown that HPV infection induces the apoptosis of trophoblasts and can be associated with spontaneous abortion and delivery., TLR7 expression is increased in HPV-positive cells, whereas TLR9 expression is decreased.
In naturally occurring influenza, the expression of TLRs 3, 7, 8, and 9 is increased, while that of TLRs 2 and 4 is suppressed; moreover, the infection presents increased levels of inflammatory cytokines (IL-6, MCP-1/CCL2, CXCL10/IP-10, and IFN-γ). It has been reported that TLR3 expression is markedly upregulated in mice infected with influenza A virus, which induces the production of inflammatory mediators, such as IL-6 and IL-12p40/p70, and increases the number of CD8+ T cells. In patients with H1N1 infection, the expression of TLRs 2, 3, and 9 and IL-2, IL-6, IFN-γ, and TNF-a increases, whereas that of IL-10 decreases. However, only TLR9, IFN-β, TGF-β, IL-2, IL-8, and TNF-a expression has been shown to increase in H1N1-infected pregnant and postpartum women.,
Herpes simplex virus
HSV is a DNA virus that infects the decidua and/or placenta in 6%–14% of pregnancies. It can be transmitted from an infected mother to her fetus and increases the risk of miscarriage and fetal death. HSV-2 is present in the placenta of asymptomatic women, and TLR9 is known to recognize HSV-2 DNA and trigger IFN-a secretion by plasmacytoid DCs.
The ongoing COVID-19 pandemic has raised concerns regarding the possible vertical transmission of SARS-CoV-2 from mother to fetus. To date, this issue is under considerable debate. Chen et al. did not detect SARS-CoV-2 in samples of amniotic fluid, breastmilk, cord blood, or neonatal throat swabs collected from COVID-19 patients. Several other studies support the notion that SARS-CoV-2-dominated intrauterine infection involves a low risk of vertical transmission., However, Dong et al. have recently reported that a newborn from an infected mother presented elevated IgM antibodies to SARS-CoV-2, suggesting that the newborn was infected in utero.
Coronaviruses are enveloped, ssRNA viruses. SARS-CoV-2 shares approximately 79% and 50% sequence identity with SARS-CoV-1 and Middle East respiratory syndrome-CoV, respectively. This suggests that SARS-CoV-2 infection may have a similar pathogenesis to that of SARS-CoV-1.,, Because SARS-CoV-2 is a novel virus and its exact mechanism of viral infection has not been completely elucidated, herein, we describe the pathogenesis of SARS-CoV-1 infection.
TLR3 is a key regulator against SARS-CoV-1 infection, while TLR4 signaling provides modest protection., Knockout TLR3-/-, TLR4-/-, MyD88-/-, and TIR domain-containing adaptor-inducing IFN-β (TRIF)-/- mice, the latter of which is a TLR3/TLR 4 adaptor, show higher viral titers and mortality than wild-type mice, suggesting that the recognition of viral PAMPs by TLRs through the TRIF adaptor protein is suitable to control viral replication during SARS-CoV-1 infection. When BALB/c mice are infected with SARS-CoV-1, cytokines (IL-6 and TNF-a) and chemokines (CCL2, CCL3, CCL5, and CXCL10) are released to recruit NK cells, macrophages, and DCs to the site of infection. Next, a second enhanced production of chemokines (CCL2, CCL3, CCL5, CXCL10, and CXCL9) and cytokines (IL-2, IL-6, IFN-γ, and TNF-a) occurs when viral clearance begins and is associated with an influx of CD4+ T cells.
| Toll-Like Receptors and Pregnancy Complications|| |
Innate immune responses at the maternal–fetal interface must tolerate the semi-allogeneic fetus while maintaining host defense against possible pathogens. An insufficient immune response may lead to infection, whereas an excessive response can disturb the immune tolerance. In addition to serious outcomes, such as increased maternal morbidity and mortality, viral activation of the TLR signaling pathways, and changes in the cytokine microenvironment, an exaggerated immune response can damage the decidua, placenta, and fetus, resulting in fetal abnormalities and several pregnancy complications, such as miscarriage, preterm birth, and preeclampsia.,,
Recurrent spontaneous abortion
Recurrent spontaneous abortion (RSA) is defined as two or more consecutive pregnancy failures that occur prior 20–28 weeks of human pregnancy. Compared to women with normal pregnancies, patients with RSA have a significantly higher expression of TLRs 2, 3, 4, 6 and 9 in decidual tissues and higher levels of pro-inflammatory cytokines, such as IL-2, IFN-γ, and TNF-a.,, High expression of TLR3 in decidual NK cells is critical for cytotoxicity enhancement and, thus, for the modulation of immune tolerance at the maternal–fetal interface. In addition, the relationship between TLRs and embryo resorption has been studied in several murine models. A synthetic dsRNA poly(I:C) has been shown to induce TLR3 responses, activate NK cells, increase TNF-a and IFN-γ levels, and boost embryo resorption in pregnant BALB/c mice obtained through mating combinations of C57BL/6 and abortion-prone CBA/J × DBA/2 mice, and the effect was completely abrogated following pretreatment with anti-TLR3.,, NK cell-deficient nonobese diabetic (NOD) mice are more susceptible to TLR-induced embryo loss than wild-type mice after administration of agonists of TLRs 3, 7, and 9 and show increased levels of TNF-a and M1 macrophages.,, In contrast, dsRNA induced no embryo resorption in the NOD/SCID mouse model, which is deficient in T, B, and NK cell activity.
Maternal inflammation induced by infection is associated with an increased risk of preterm birth. Notably, an increased activity of TLRs 2, 3, and 4 is observed within the placenta in infection-associated preterm birth. It has been observed that a challenge with a high dose of poly(I:C) alone or a low dose of poly(I:C) plus lipopolysaccharide induces preterm birth in WT mice, which is associated with robust uterine IL-6 and TNF production. IFN-β, specifically when it interacts with Type I IFN/IFN receptor, plays a critical role in facilitating the susceptibility to a secondary inflammatory challenge, promoting chemokine (CCL2 and CCL4) and cytokine (IL-6 and TNF-a) production and finally inducing preterm birth. TLR2 activation significantly induces NF-κB-driven cytokine production and high IFN-β and IL-6 expression, which leads to preterm birth. An antibody against IL-6 or disruption of type I IFN receptor can reduce excessive inflammation and the effect of TLR2-induced preterm birth.
Preeclampsia affects approximately 3%–8% of pregnancies and is associated with insufficient EVT infiltration, deficient spiral artery remodeling, and dysregulated immune responses to intrauterine infection. There is growing evidence showing that the expression of TLRs 2, 3, 4, 7, 8, and 9 is significantly increased in the placenta and immune cells from preeclampsia patients compared with that of normal pregnant women.,, Treatment of mice with TLRs 3 and 7, or TLR7/8 agonists, causes pregnancy-dependent hypertension and placental inflammation. After a pathogenic challenge, the trophoblasts in the placenta overexpress specific TLRs that can induce chemokines and cytokines, resulting in a large recruitment of macrophages, DCs, and NK cells to the maternal–fetal interface, which leads to excessive inflammation, trophoblast apoptosis, and damage to the vascular endothelial cells in the placenta.,
| Conclusions|| |
The immune microenvironment at the maternal–fetal interface must protect the fetus from infections while maintaining an adequate immune tolerance. Overall, viral infection during pregnancy may cause fetal injury and adverse pregnancy outcomes, not only by vertical transmission but also through infection and dysfunction of the decidua and placenta. Recognition of viral DNA, RNA, or glycoproteins by TLRs 2, 3, 4, 7, 8, and 9 induces different IFNs, inflammatory cytokines, and chemokines that may disrupt the fine balance between immune protection and tolerance. Furthermore, viral infection can also induce apoptosis and impair the invasiveness of trophoblasts, resulting in pregnancy complications, such as preeclampsia, recurrent pregnancy loss, and preterm birth. Understanding how viruses affect the maternal–fetal interface through TLR activation is crucial to reveal the mechanisms underlying vertical transmission and improve the clinical care provided to pregnant women.
Financial support and sponsorship
This work was supported by the grants from the Anti-COVID-19 Fund from International Peace Maternity and Child Health Hospital (GFY2020-COVID-19-01), the National Natural Science Foundation of China (81401274), and the Interdisciplinary Program of Shanghai Jiao Tong University (YG2017ZD09 and YG2017MS40).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Silasi M, Cardenas I, Kwon JY, Racicot K, Aldo P, Mor G. Viral infections during pregnancy. Am J Reprod Immunol 2015;73:199-213. doi: 10.1111/aji.12355.
Wylie KM, Wylie TN, Cahill AG, Macones GA, Tuuli MG, Stout MJ. The vaginal eukaryotic DNA virome and preterm birth. Am J Obstet Gynecol 2018;219:189.e1-12. doi: 10.1016/j.ajog.2018.04.048.
Sansone M, Sarno L, Saccone G, Berghella V, Maruotti GM, Migliucci A, et al
. Risk of preeclampsia in human immunodeficiency virus-infected pregnant women. Obstet Gynecol 2016;127:1027-32. doi: 10.1097/Aog. 0000000000001424.
Bhatnagar J, Rabeneck DB, Martines RB, Reagan-Steiner S, Ermias Y, Estetter LB, et al
. Zika virus RNA replication and persistence in brain and placental tissue. Emerg Infect Dis 2017;23:405-14. doi: 10.3201/eid2303.161499.
Medzhitov R, Janeway CA Jr. Decoding the patterns of self and nonself by the innate immune system. Science 2002;296:298-300. doi: 10.1126/science.1068883.
Lester SN, Li K. Toll-like receptors in antiviral innate immunity. J Mol Biol 2014;426:1246-64. doi: 10.1016/j.jmb.2013.11.024.
Racicot K, Mor G. Risks associated with viral infections during pregnancy. J Clin Invest 2017;127:1591-9. doi: 10.1172/JCI87490.
Mor G, Cardenas I, Abrahams V, Guller S. Inflammation and pregnancy: The role of the immune system at the implantation site. Ann N Y Acad Sci 2011;1221:80-7. doi: 10.1111/j.1749-6632.2010.05938.x.
Trundley A, Moffett A. Human uterine leukocytes and pregnancy. Tissue Antigens 2004;63:1-2. doi: 10.1111/j. 1399-0039.2004.00170.x.
Moffett-King A. Natural killer cells and pregnancy. Nat Rev Immunol 2002;2:656-63. doi: 10.1038/nri886.
Nancy P, Erlebacher A. T cell behavior at the maternal-fetal interface. Int J Dev Biol 2014;58:189-98. doi: 10.1387/ijdb.140054ae.
Gardner L, Moffett A. Dendritic cells in the human decidua. Biol Reprod 2003;69:1438-46. doi: 10.1095/biolreprod.103.017574.
Ji L, Brkic J, Liu M, Fu G, Peng C, Wang YL. Placental trophoblast cell differentiation: Physiological regulation and pathological relevance to preeclampsia. Mol Aspects Med 2013;34:981-1023. doi: 10.1016/j.mam.2012.12.008.
Staun-Ram E, Shalev E. Human trophoblast function during the implantation process. Reprod Biol Endocrinol 2005;3:56. doi: 10.1186/1477-7827-3-56.
Mor G, Aldo P, Alvero AB. The unique immunological and microbial aspects of pregnancy. Nat Rev Immunol 2017;17:469-82. doi: 10.1038/nri.2017.64.
Ramhorst R, Fraccaroli L, Aldo P, Alvero AB, Cardenas I, Leirós CP, et al
. Modulation and recruitment of inducible regulatory T cells by first trimester trophoblast cells. Am J Reprod Immunol 2012;67:17-27. doi: 10.1111/j.1600-0897.2011.01056.x.
Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C, Natanson-Yaron S, et al
. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med 2006;12:1065-74. doi: 10.1038/nm1452.
Svensson-Arvelund J, Mehta RB, Lindau R, Mirrasekhian E, Rodriguez-Martinez H, Berg G, et al
. The human fetal placenta promotes tolerance against the semiallogeneic fetus by inducing regulatory T cells and homeostatic M2 macrophages. J Immunol 2015;194:1534-44. doi: 10.4049/jimmunol.1401536.
Fisher S, Genbacev O, Maidji E, Pereira L. Human cytomegalovirus infection of placental cytotrophoblasts in vitro
and in utero
: Implications for transmission and pathogenesis. J Virol 2000;74:6808-20. doi: 10.1128/jvi.74.15.6808-6820.2000.
Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 2011;34:637-50. doi: 10.1016/j.immuni.2011.05.006.
Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med 2003;198:513-20. doi: 10.1084/jem. 20030162.
Farhat K, Riekenberg S, Heine H, Debarry J, Lang R, Mages J, et al
. Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling. J Leukoc Biol 2008;83:692-701. doi: 10.1189/jlb.0807586.
Koga K, Izumi G, Mor G, Fujii T, Osuga Y. Toll-like receptors at the maternal-fetal interface in normal pregnancy and pregnancy complications. Am J Reprod Immunol 2014;72:192-205. doi: 10.1111/aji.12258.
Zarember KA, Godowski PJ. Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol 2002;168:554-61. doi: 10.4049/jimmunol.168.2.554.
Ziegler SM, Feldmann CN, Hagen SH, Richert L, Barkhausen T, Goletzke J, et al
. Innate immune responses to toll-like receptor stimulation are altered during the course of pregnancy. J Reprod Immunol 2018;128:30-7. doi: 10.1016/j.jri.2018.05.009.
Patni S, Wynen LP, Seager AL, Morgan G, White JO, Thornton CA. Expression and activity of Toll-like receptors 1-9 in the human term placenta and changes associated with labor at term. Biol Reprod 2009;80:243-8. doi: 10.1095/biolreprod.108.069252.
Duriez M, Quillay H, Madec Y, El Costa H, Cannou C, Marlin R, et al
. Human decidual macrophages and NK cells differentially express Toll-like receptors and display distinct cytokine profiles upon TLR stimulation. Front Microbiol 2014;5:316. doi: 10.3389/fmicb. 2014.00316.
Mhandire DZ, Mhandire K, Magadze M, Wonkam A, Kengne AP, Dandara C. Genetic variation in toll like receptors 2, 7, 9 and interleukin-6 is associated with cytomegalovirus infection in late pregnancy. BMC Med Genet 2020;21:113. doi: 10.1186/s12881-020-01044-8.
Mogensen TH, Paludan SR. Molecular pathways in virus-induced cytokine production. Microbiol Mol Biol Rev 2001;65:131-50. doi: 10.1128/MMBR.65.1.131-150.2001.
McCartney SA, Colonna M. Viral sensors: Diversity in pathogen recognition. Immunol Rev 2009;227:87-94. doi: 10.1111/j. 1600-065X.2008.00726.x.
Cardenas I, Means RE, Aldo P, Koga K, Lang SM, Booth CJ, et al
. Viral infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor. J Immunol 2010;185:1248-57. doi: 10.4049/jimmunol.1000289.
Leruez-Ville M, Ville Y. Fetal cytomegalovirus infection. Best Pract Res Clin Obstet Gynaecol 2017;38:97-107. doi: 10.1016/j.bpobgyn. 2016.10.005.
van Zuylen WJ, Ford CE, Wong DD, Rawlinson WD. Human cytomegalovirus modulates expression of noncanonical Wnt receptor ROR2 to alter trophoblast migration. J Virol 2016;90:1108-15. doi: 10.1128/JVI.02588-15.
Enders G, Daiminger A, Bäder U, Exler S, Enders M. Intrauterine transmission and clinical outcome of 248 pregnancies with primary cytomegalovirus infection in relation to gestational age. J Clin Virol 2011;52:244-6. doi: 10.1016/j.jcv.2011.07.005.
Pereira L, Maidji E, McDonagh S, Genbacev O, Fisher S. Human cytomegalovirus transmission from the uterus to the placenta correlates with the presence of pathogenic bacteria and maternal immunity. J Virol 2003;77:13301-14. doi: 10.1128/jvi.77.24.13301-13314.2003.
Yew KH, Carsten B, Harrison C. Scavenger receptor A1 is required for sensing HCMV by endosomal TLR-3/-9 in monocytic THP-1 cells. Mol Immunol 2010;47:883-93. doi: 10.1016/j.molimm.2009.10.009.
Compton T, Kurt-Jones EA, Boehme KW, Belko J, Latz E, Golenbock DT, et al
. Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2. J Virol 2003;77:4588-96. doi: 10.1128/jvi.77.8.4588-4596.2003.
Yew KH, Carpenter C, Duncan RS, Harrison CJ. Human cytomegalovirus induces TLR4 signaling components in monocytes altering TIRAP, TRAM and downstream interferon-beta and TNF-alpha expression. PLoS One 2012;7:e44500. doi: 10.1371/journal.pone.0044500.
Weisblum Y, Oiknine-Djian E, Vorontsov OM, Haimov-Kochman R, Zakay-Rones Z, Meir K, et al
. Zika virus infects early – And midgestation human maternal decidual tissues, inducing distinct innate tissue responses in the maternal-fetal interface. J Virol 2017;91:e01905-16. doi: 10.1128/JVI.01905-16.
Scott GM, Chow SS, Craig ME, Pang CN, Hall B, Wilkins MR, et al
. Cytomegalovirus infection during pregnancy with maternofetal transmission induces a proinflammatory cytokine bias in placenta and amniotic fluid. J Infect Dis 2012;205:1305-10. doi: 10.1093/infdis/jis186.
Hamilton ST, Scott G, Naing Z, Iwasenko J, Hall B, Graf N, et al
. Human cytomegalovirus-induces cytokine changes in the placenta with implications for adverse pregnancy outcomes. PLoS One 2012;7:e52899. doi: 10.1371/journal.pone.0052899.
Chan G, Hemmings DG, Yurochko AD, Guilbert LJ. Human cytomegalovirus-caused damage to placental trophoblasts mediated by immediate-early gene-induced tumor necrosis factor-alpha. Am J Pathol 2002;161:1371-81. doi: 10.1016/s0002-9440(10)64413-6.
Longo S, Borghesi A, Tzialla C, Stronati M. IUGR and infections. Early Hum Dev 2014;90:S42-4. doi: 10.1016/S0378-3782(14)70014-3.
Avdic S, Cao JZ, McSharry BP, Clancy LE, Brown R, Steain M, et al
. Human cytomegalovirus interleukin-10 polarizes monocytes toward a deactivated M2c phenotype to repress host immune responses. J Virol 2013;87:10273-82. doi: 10.1128/JVI.00912-13.
Avdic S, McSharry BP, Steain M, Poole E, Sinclair J, Abendroth A, et al
. Human cytomegalovirus-encoded human interleukin-10 (IL-10) homolog amplifies its immunomodulatory potential by upregulating human IL-10 in monocytes. J Virol 2016;90:3819-27. doi: 10.1128/JVI.03066-15.
O'Sullivan TE, Sun JC, Lanier LL. Natural killer cell memory. Immunity 2015;43:634-45. doi: 10.1016/j.immuni.2015.09.013.
Siewiera J, El Costa H, Tabiasco J, Berrebi A, Cartron G, Le Bouteiller P, et al
. Human cytomegalovirus infection elicits new decidual natural killer cell effector functions. PLoS Pathog 2013;9:e1003257. doi: 10.1371/journal.ppat.1003257.
Cordeiro MT, Pena LJ, Brito CA, Gil LH, Marques ET. Positive IgM for Zika virus in the cerebrospinal fluid of 30 neonates with microcephaly in Brazil. Lancet 2016;387:1811-2. doi: 10.1016/S0140-6736(16)30253-7.
Tabata T, Petitt M, Puerta-Guardo H, Michlmayr D, Wang C, Fang-Hoover J, et al
. Zika virus targets different primary human placental cells, suggesting two routes for vertical transmission. Cell Host Microbe 2016;20:155-66. doi: 10.1016/j.chom.2016.07.002.
Driggers RW, Ho CY, Korhonen EM, Kuivanen S, Jääskeläinen AJ, Smura T, et al
. Zika virus infection with prolonged maternal viremia and fetal brain abnormalities. N Engl J Med 2016;374:2142-51. doi: 10.1056/NEJMoa1601824.
Brasil P, Pereira JP, Moreira ME, Ribeiro Nogueira RM, Damasceno L, Wakimoto M, et al
. Zika virus infection in pregnant women in Rio de Janeiro. N Engl J Med 2016;375:2321-34. doi: 10.1056/NEJMoa1602412.
Quicke KM, Bowen JR, Johnson EL, McDonald CE, Ma H, O'Neal JT, et al
. Zika virus infects human placental macrophages. Cell Host Microbe 2016;20:83-90. doi: 10.1016/j.chom.2016.05.015.
Vermillion MS, Lei J, Shabi Y, Baxter VK, Crilly NP, McLane M, et al
. Intrauterine Zika virus infection of pregnant immunocompetent mice models transplacental transmission and adverse perinatal outcomes. Nat Commun 2017;8:14575. doi: 10.1038/ncomms14575.
Martinez Viedma MD, Pickett BE. Characterizing the different effects of zika virus infection in placenta and microglia cells. Viruses 2018;10:649. doi: 10.3390/v10110649.
Luo H, Winkelmann ER, Fernandez-Salas I, Li L, Mayer SV, Danis-Lozano R, et al
. Zika, dengue and yellow fever viruses induce differential anti-viral immune responses in human monocytic and first trimester trophoblast cells. Antiviral Res 2018;151:55-62. doi: 10.1016/j.antiviral.2018.01.003.
Offersen R, Nissen SK, Rasmussen TA, Østergaard L, Denton PW, Søgaard OS, et al
. A novel Toll-like receptor 9 agonist, MGN1703, enhances HIV-1 transcription and NK cell-mediated inhibition of HIV-1-infected autologous CD4+ T cells. J Virol 2016;90:4441-53. doi: 10.1128/JVI.00222-16.
Meås HZ, Haug M, Beckwith MS, Louet C, Ryan L, Hu Z, et al
. Sensing of HIV-1 by TLR8 activates human T cells and reverses latency. Nat Commun 2020;11:147. doi: 10.1038/s41467-019-13837-4.
Maloupazoa Siawaya AC, Mvoundza Ndjindji O, Kuissi Kamgaing E, Mveang-Nzoghe A, Mbani Mpega CN, Leboueny M, et al
. Altered toll-like receptor-4 response to lipopolysaccharides in infants exposed to HIV-1 and its preventive therapy. Front Immunol 2018;9:222. doi: 10.3389/fimmu.2018.00222.
Liu J, Zhang S, Liu M, Wang Q, Shen H, Zhang Y. Maternal pre-pregnancy infection with hepatitis B virus and the risk of preterm birth: A population-based cohort study. Lancet Glob Health 2017;5:e624-32. doi: 10.1016/S2214-109X(17)30142-0.
Tian T, Sun D, Wang P, Wang H, Bai X, Yang X, et al
. Roles of toll-like receptor 7 and 8 in prevention of intrauterine transmission of hepatitis B virus. Cell Physiol Biochem 2015;37:445-53. doi: 10.1159/000430367.
Boni C, Vecchi A, Rossi M, Laccabue D, Giuberti T, Alfieri A, et al
. TLR7 agonist increases responses of hepatitis B virus-specific T cells and natural killer cells in patients with chronic hepatitis B treated with nucleos(t)Ide. Ide analogues. Gastroenterology 2018;154:1764-77.e7. doi: 10.1053/j.gastro.2018.01.030.
Ma Z, Liu J, Wu W, Zhang E, Zhang X, Li Q, et al
. The IL-1R/TLR signaling pathway is essential for efficient CD8 T-cell responses against hepatitis B virus in the hydrodynamic injection mouse model. Cell Mol Immunol 2017;14:997-1008. doi: 10.1038/cmi.2017.43.
Weyn C, Thomas D, Jani J, Guizani M, Donner C, Van Rysselberge M, et al
. Evidence of human papillomavirus in the placenta. J Infect Dis 2011;203:341-3. doi: 10.1093/infdis/jiq056.
Gomez LM, Ma Y, Ho C, McGrath CM, Nelson DB, Parry S. Placental infection with human papillomavirus is associated with spontaneous preterm delivery. Hum Reprod 2008;23:709-15. doi: 10.1093/humrep/dem404.
Ambühl LM, Baandrup U, Dybkǣr K, Blaakǣr J, Uldbjerg N, Sørensen S. Human papillomavirus infection as a possible cause of spontaneous abortion and spontaneous preterm delivery. Infect Dis Obstet Gynecol 2016;2016:3086036. doi: 10.1155/2016/3086036.
Jouhi L, Datta N, Renkonen S, Atula T, Mäkitie A, Haglund C, et al
. Expression of Toll-like receptors in HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma – An in vivo
and in vitro
study. Tumour Biol 2015;36:7755-64. doi: 10.1007/s13277-015-3494-z.
Lee N, Wong CK, Hui DS, Lee SK, Wong RY, Ngai KL, et al
. Role of human Toll-like receptors in naturally occurring influenza A infections. Influenza Other Respir Viruses 2013;7:666-75. doi: 10.1111/irv.12109.
Le Goffic R, Balloy V, Lagranderie M, Alexopoulou L, Escriou N, Flavell R, et al
. Detrimental contribution of the Toll-like receptor (TLR) 3 to influenza A virus-induced acute pneumonia. PLoS Pathog 2006;2:e53. doi: 10.1371/journal.ppat.0020053.
Liu Y, Chen H, Sun Y, Chen F. Antiviral role of Toll-like receptors and cytokines against the new 2009 H1N1 virus infection. Mol Biol Rep 2012;39:1163-72. doi: 10.1007/s11033-011-0846-7.
Periolo N, Avaro M, Czech A, Russo M, Benedetti E, Pontoriero A, et al
. Pregnant women infected with pandemic influenza influenza A (H1N1)pdm09 virus showed differential immune response correlated with disease severity. J Clin Virol 2015;64:52-8. doi: 10.1016/j.jcv.2015.01.009.
Finger-Jardim F, Teixeira LO, de Oliveira GR, Barral MF, da Hora VP, Gonçalves CV, et al
. Herpes simplex virus: Prevalence in placental tissue and incidence in neonatal cord blood samples. J Med Virol 2014;86:519-24. doi: 10.1002/jmv.23817.
Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, et al
. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: A retrospective review of medical records. Lancet 2020;395:809-15. doi: 10.1016/S0140-6736(20)30360-3.
Fan C, Lei D, Fang C, Li C, Wang M, Liu Y, et al
. Perinatal transmission of COVID-19 associated SARS-CoV-2: Should we worry? Clin Infect Dis 2020. doi: 10.1093/cid/ciaa226.
Schwartz DA. An analysis of 38 pregnant women with COVID-19, their newborn infants, and maternal-fetal transmission of SARS-CoV-2: Maternal coronavirus infections and pregnancy outcomes. Arch Pathol Lab Med 2020;144:799-805. doi: 10.5858/arpa.2020-0901-SA.
Dong L, Tian J, He S, Zhu C, Wang J, Liu C, et al
. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA 2020;323:1846-8. doi: 10.1001/jama.2020.4621.
Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004;203:631-7. doi: 10.1002/path.1570.
To KF, Lo AW. Exploring the pathogenesis of severe acute respiratory syndrome (SARS): The tissue distribution of the coronavirus (SARS-CoV) and its putative receptor, angiotensin-converting enzyme 2 (ACE2). J Pathol 2004;203:740-3. doi: 10.1002/path.1597.
Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al
. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020;395:565-74. doi: 10.1016/S0140-6736(20)30251-8.
Totura AL, Whitmore A, Agnihothram S, Schäfer A, Katze MG, Heise MT, et al
. Toll-like receptor 3 signaling via TRIF contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus infection. mBio 2015;6:e00638-15. doi: 10.1128/mBio. 00638-15.
Sheahan T, Morrison TE, Funkhouser W, Uematsu S, Akira S, Baric RS, et al
. MyD88 is required for protection from lethal infection with a mouse-adapted SARS-CoV. PLoS Pathog 2008;4:e1000240. doi: 10.1371/journal.ppat.1000240.
Chen J, Lau YF, Lamirande EW, Paddock CD, Bartlett JH, Zaki SR, et al
. Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4+T cells are important in control of SARS-CoV infection. J Virol 2010;84:1289-301. doi: 10.1128/JVI.01281-09.
King AE, Kelly RW, Sallenave JM, Bocking AD, Challis JR. Innate immune defences in the human uterus during pregnancy. Placenta 2007;28:1099-106. doi: 10.1016/j.placenta.2007.06.002.
Bao SH, Shuai W, Tong J, Wang L, Chen P, Sun J. Increased expression of Toll-like receptor 3 in decidual natural killer cells of patients with unexplained recurrent spontaneous miscarriage. Eur J Obstet Gynecol Reprod Biol 2012;165:326-30. doi: 10.1016/j.ejogrb.2012.08.005.
Triantafilou M, De Glanville B, Aboklaish AF, Spiller OB, Kotecha S, Triantafilou K. Synergic activation of toll-like receptor (TLR) 2/6 and 9 in response to Ureaplasma parvum & urealyticum in human amniotic epithelial cells. PLoS One 2013;8:e61199. doi: 10.1371/journal.pone.0061199.
Xu L, Qiu T, Wang Y, Chen Y, Cheng W. Expression of C-type lectin receptors and Toll-like receptors in decidua of patients with unexplained recurrent spontaneous abortion. Reprod Fertil Dev 2017;29:1613-24. doi: 10.1071/RD15489.
Lin Y, Zeng Y, Zeng S, Wang T. Potential role of toll-like receptor 3 in a murine model of polyinosinic-polycytidylic acid-induced embryo resorption. Fertil Steril 2006;85:1125-9. doi: 10.1016/j.fertnstert.2005.08.056.
Shimada S, Iwabuchi K, Watano K, Shimizu H, Yamada H, Minakami H, et al
. Expression of allograft inflammatory factor-1 in mouse uterus and poly (I: C)-induced fetal resorption. Am J Reprod Immunol 2003;50:104-12. doi: 10.1034/j.1600-0897.2003.00060.x.
Lin Y, Zeng Y, Di J, Zeng S. Murine CD200+ CK7+ trophoblasts in a poly(I:C)-induced embryo resorption model. Reproduction 2005;130:529-37. doi: 10.1530/rep.1.00575.
Wang J, Wu F, Xie Q, Liu X, Tian F, Xu W, et al
. Anakinra and etanercept prevent embryo loss in pregnant nonobese diabetic mice. Reproduction 2015;149:377-84. doi: 10.1530/REP-14-0614.
Sun Y, Qin X, Shan B, Wang W, Zhu Q, Sharma S, et al
. Differential effects of the CpG-Toll-like receptor 9 axis on pregnancy outcome in nonobese diabetic mice and wild-type controls. Fertil Steril 2013;99:1759-67. doi: 10.1016/j.fertnstert.2013.01.121.
Liu XR, Guo YN, Qin CM, Qin XL, Tao F, Su F, et al
. Transcriptomic insights into the response of placenta and decidua basalis to the CpG oligodeoxynucleotide stimulation in non-obese diabetic mice and wild-type controls. Int J Mol Sci 2016;17:1281. doi: 10.3390/ijms17081281.
Lin Y, Liang Z, Chen Y, Zeng Y. TLR3-involved modulation of pregnancy tolerance in double-stranded RNA-stimulated NOD/SCID mice. J Immunol 2006;176:4147-54. doi: 10.4049/jimmunol. 176.7.4147.
Cappelletti M, Presicce P, Lawson MJ, Chaturvedi V, Stankiewicz TE, Vanoni S, et al
. Type I interferons regulate susceptibility to inflammation-induced preterm birth. JCI Insight 2017;2:e91288. doi: 10.1172/jci.insight.91288.
Cappelletti M, Lawson MJ, Chan CC, Wilburn AN, Divanovic S. Differential outcomes of TLR2 engagement in inflammation-induced preterm birth. J Leukoc Biol 2018;103:535-43. doi: 10.1002/JLB.3MA0717-274RR.
Yang F, Zheng Q, Jin L. Dynamic function and composition changes of immune cells during normal and pathological pregnancy at the maternal-fetal interface. Front Immunol 2019;10:2317. doi: 10.3389/fimmu.2019.02317.
Bouças AP, de Souza BM, Bauer AC, Crispim D. Role of innate immunity in preeclampsia: A systematic review. Reprod Sci 2017;24:1362-70. doi: 10.1177/1933719117691144.
Pineda A, Verdin-Terán SL, Camacho A, Moreno-Fierros L. Expression of toll-like receptor TLR-2, TLR-3, TLR-4 and TLR-9 is increased in placentas from patients with preeclampsia. Arch Med Res 2011;42:382-91. doi: 10.1016/j.arcmed.2011.08.003.
Chatterjee P, Weaver LE, Doersch KM, Kopriva SE, Chiasson VL, Allen SJ, et al
. Placental Toll-like receptor 3 and Toll-like receptor 7/8 activation contributes to preeclampsia in humans and mice. PLoS One 2012;7:e41884. doi: 10.1371/journal.pone.0041884.
Abrahams VM, Mor G. Toll-like receptors and their role in the trophoblast. Placenta 2005;26:540-7. doi: 10.1016/j.placenta.2004.08.010.
Afkham A, Eghbal-Fard S, Heydarlou H, Azizi R, Aghebati-Maleki L, Yousefi M. Toll-like receptors signaling network in pre-eclampsia: An updated review. J Cell Physiol 2019;234:2229-40. doi: 10.1002/jcp.27189.
[Figure 1], [Figure 2]