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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 4  |  Page : 249-256

Toll-like receptor-dependent antiviral responses at the maternal–fetal interface


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 Submission29-May-2020
Date of Decision10-Jul-2020
Date of Acceptance13-Oct-2020
Date of Web Publication31-Dec-2020

Correspondence Address:
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
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.305928

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  Abstract 


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

How to cite this URL:
Liu XR, Wei XW, Lin Y. Toll-like receptor-dependent antiviral responses at the maternal–fetal interface. Reprod Dev Med [serial online] 2020 [cited 2021 Apr 14];4:249-56. Available from: https://www.repdevmed.org/text.asp?2020/4/4/249/305928




  Introduction Top


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.[1] Viral infection during pregnancy can lead to intrauterine infection and adverse pregnancy outcomes, such as miscarriage, preterm birth, preeclampsia, and intrauterine growth restriction.[2],[3],[4] 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.[5] Toll-like receptors (TLRs) recognize many types of pathogens, including viruses, and play an essential role in the innate immune system.[6] However, several pregnancy complications have been associated with TLR-dependent antiviral responses.[7] 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 Top


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.[8] Approximately, 30%–40% of decidual cells in early pregnancy are leukocytes.[9] Natural killer (NK) cells and macrophages are the two major cell types, comprising 50%–70% and 20%–30% of all decidual immune cells, respectively.[10] CD3+ T cells constitute 10%–20% of the leukocytes,[11] while dendritic cells (DCs) represent approximately 1.7%.[12]

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[13] and establishes the uteroplacental circulation through direct contact with the maternal blood.[14] 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.[15] 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.[16] After recruitment, the trophoblasts secrete interleukin 15 (IL-15) and TGF-β to induce the differentiation of decidual NK cells with decreased cytotoxic activity.[17] Similarly, trophoblast-derived macrophage colony-stimulating factor and IL-10 promote the differentiation of peripheral blood monocytes to macrophages with an M2 phenotype.[18]

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].[19]
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.

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  Toll-Like Receptors at the Maternal–Fetal Interface Top


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.[6] TLRs 3, 7, 8, and 9 are involved in antiviral immunity.[6] 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.[20],[21] Both dsRNA and ssRNA are intermediate molecules of viral replication. In addition, the expression of TLR2 and 4 is upregulated by viral glycoproteins.[20],[22]

The TLRs involved in antiviral responses are widely expressed in immune and nonimmune cells at the maternal–fetal interface [Figure 1].[23],[24] 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.[15],[25],[26],[27],[28] 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].[6],[29] 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).[6],[30] 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.[25] 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.[7]
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.

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  Viral Infections during Pregnancy Top


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.[7] Furthermore, soluble immune factors produced by infected decidua and/or placenta may reach the fetus.[31] 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.

Cytomegalovirus

CMV, a double-stranded DNA (dsDNA) virus that can be transmitted vertically, is the most common virus identified at the maternal–fetal interface.[32] CMV infection is associated with preterm birth, preeclampsia, fetal/neonatal death, and intrauterine growth restriction.[33] The transmission rate in the first trimester is only 30% but rises up to 70% in the third trimester.[34] 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.[28] Polymorphisms of immune response genes, such as TLR2, TLR7, TLR9, and IL-6, are associated with CMV infection in late gestation.[28] CMV entry receptors are expressed in trophoblasts and monocytes/macrophages at the maternal–fetal interface.[35]

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.[36] 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.[37],[38] The expression of IFN-γ by immune cells is also significantly upregulated.[39] During pregnancy, CMV virions are more often detected in the decidua than in placental trophoblasts.[35] 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.[40],[41] TNF-a released from CMV-infected trophoblasts can induce the apoptosis of neighboring uninfected cells.[42] 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.[33] Inadequate trophoblast invasion may damage vascular remodeling and decrease the blood flow from mother to fetus, causing growth abnormalities.[43]

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.[44],[45] 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.[46] 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.[47] Subsequently, upon re-exposure to CMV, the “adaptive” NK cells can expand rapidly to resist infection.[46]

Zika virus

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.[4] Moreover, ZIKV-specific IgM antibodies have been found in the cerebral fluid of newborns.[48] 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.[49] Infection in early pregnancy leads to microcephaly, miscarriage, stillbirth, and intrauterine growth restriction, while infection in late pregnancy can cause fetal abnormalities.[50],[51]

During pregnancy, ZIKV targets the maternal decidual tissues, CTBs, monocytes, endothelial cells, and Hofbauer cells in the chorionic villi at the maternal–fetal interface.[39],[49],[52] 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.[39] 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.[53],[54] 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.[55] 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.[54] 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.[39]

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.[56] 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).[57] After in utero exposure to HIV, infants present increased susceptibility to bacterial infection due to TLR4 anergy.[58]

Hepatitis B virus

HBV infection affects about 3.87%–9.98% of women at reproductive age and pregnant women in China.[59] A recent population-based cohort study reported that maternal prepregnancy infection with HBV increases the risk of preterm birth.[59] The expression of TLR7, TLR8, IFN-a, IFN-β, and IL-8 is significantly induced in trophoblastic cells exposed to HBV.[60] Reportedly, the TLR7 agonist GS-9620 (Vesatolimod) can increase T and NK cell responses and induce immunity to HBV infection.[61] 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.[62]

Human papillomavirus

HPV is a double-stranded DNA virus that has been detected in placenta.[63] Large cohort studies have shown that HPV infection induces the apoptosis of trophoblasts and can be associated with spontaneous abortion and delivery.[64],[65] TLR7 expression is increased in HPV-positive cells, whereas TLR9 expression is decreased.[66]

Influenza virus

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).[67] 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.[68] 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.[69],[70]

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.[71] HSV-2 is present in the placenta of asymptomatic women,[71] and TLR9 is known to recognize HSV-2 DNA and trigger IFN-a secretion by plasmacytoid DCs.[21]

Coronavirus

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.[72] 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.[73],[74] However, Dong et al.[75] 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.[76],[77],[78] 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.[79],[80] 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.[79] 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.[81] 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.[81]


  Toll-Like Receptors and Pregnancy Complications Top


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.[82] 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.[2],[3],[4]

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.[83],[84],[85] 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.[83] 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.[86],[87],[88] 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.[89],[90],[91] In contrast, dsRNA induced no embryo resorption in the NOD/SCID mouse model, which is deficient in T, B, and NK cell activity.[92]

Preterm birth

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.[93] 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.[93] 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.[94]

Preeclampsia

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.[95] 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.[96],[97],[98] Treatment of mice with TLRs 3 and 7, or TLR7/8 agonists, causes pregnancy-dependent hypertension and placental inflammation.[98] 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.[99],[100]


  Conclusions Top


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.



 
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