Franciane Mouradian Emidio Teixeira1,2
Anna Julia Pietrobon1,2
Luana de Mendonça Oliveira1,2
Luanda Mara da Silva Oliveira1
Maria Notomi Sato1,2*- 1Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology, School of Medicine and Institute of Tropical Medicine of São Paulo, University of São Paulo, São Paulo, Brazil
- 2Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
During pregnancy, the organization of complex tolerance mechanisms occurs to assure non-rejection of the semiallogeneic fetus. Pregnancy is a period of vulnerability to some viral infections, mainly during the first and second trimesters, that may cause congenital damage to the fetus. Recently, Zika virus (ZIKV) infection has gained great notoriety due to the occurrence of congenital ZIKV syndrome, characterized by fetal microcephaly, which results from the ability of ZIKV to infect placental cells and neural precursors in the fetus. Importantly, in addition to the congenital effects, studies have shown that perinatal ZIKV infection causes a number of disorders, including maculopapular rash, conjunctivitis, and arthralgia. In this paper, we contextualize the immunological aspects involved in the maternal-fetal interface and vulnerability to ZIKV infection, especially the alterations resulting in perinatal outcomes. This highlights the need to develop protective maternal vaccine strategies or interventions that are capable of preventing fetal or even neonatal infection.
Introduction
Pregnancy represents a unique immunological condition with several regulatory mechanisms that ensure the non-rejection of the semiallogeneic fetus and its development, but it is also a time of greater vulnerability to infections (1). Associated with this, neonates also have a developing immune system with qualitative and quantitative differences from adults and poor immune memory, which increases their susceptibility to infectious agents (2, 3).
Complications during pregnancy, such as viral infections, can directly affect maternal-fetal health, since some viruses can be transmitted vertically and cause congenital infections (1, 4, 5). In addition, maternal immune activation induced by many common viruses is sufficient to cause neurological changes in the offspring (6).
In recent years, Zika virus (ZIKV) infection (Box 1) has been widely recognized because of its association with unprecedented cases of fetal microcephaly associated with congenital ZIKV syndrome (CZS) reported during the Brazilian epidemic in 2015 (5, 14). In the Americas, almost 80% of the ZIKV-associated microcephaly cases occurred in Brazil (15).
Box 1. Key points of the Zika virus (ZIKV).
ZIKV is a Flavivirus that includes other important human pathogens, such as dengue virus (DENV), West Nile virus (WNV), yellow fever (YFV), and Japanese encephalitis. Its genome contains a single open reading sequence that encodes three structural proteins (capsid [C], premembrane/membrane [prM/M], and envelope [E]) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) (7, 8). Due to genotypic differences, the African and Asian lineages have been determined (9). ZIKV is transmitted mainly by Aedes mosquitoes, highlighting the Ae. Aegypti and the Ae. Albopictus as potential vectors for worldwide expansion (10, 11). Other documented routes of transmission include sexual, intrauterine, perinatal exposure and breastfeeding (12, 13).
The main congenital infections are related to the TORCH group of pathogens, which include Toxoplasma gondii, others (Listeria monocytogenes, Treponema pallidum, human immunodeficiency virus, varicella zoster virus, enterovirus, and parvovirus), rubella, cytomegalovirus (CMV), and herpes simplex virus (HSV) (16). Due to its implication in fetal central nervous system abnormalities, the inclusion of the ZIKV to the TORCH acronym has been proposed (17).
Vertical transmission of ZIKV may occur during pregnancy (congenital transmission) or around the time of birth. Upon perinatal infection, the child may develop a maculopapular rash, conjunctivitis, arthralgia, and fever (18). While several mechanisms regarding congenital impairment and the pathogenesis of ZIKV infection in pregnant women have already been described, information on vertical transmission after delivery is still limited.
This article aims to review the immunological aspects of the maternal-fetal and neonatal interface that predispose susceptibility to infections, with an emphasis on the perinatal effects of ZIKV infection, and address maternal ZIKV vaccination studies, which offer a promising avenue.
Immune Changes During Pregnancy
Pregnancy is a complex immune phenomenon that requires several adaptations of the maternal immune system to tolerate the semiallogeneic fetus. This tolerance is associated with mechanisms involving both a reduction in presentation of fetal antigens by placental cells and suppression of the maternal immune response. In this context, several factors act to favor the generation of regulatory responses and the attenuation of inflammatory and cellular activation (19). However, the maternal immune system needs to be finely balanced during pregnancy so that, while preventing fetal and placental rejection, it does not lose its ability to fight infections.
During pregnancy, hormonal variations occur that play an active role in the modulation of immune responses, leading to a reduction in the number of dendritic cells (DCs) and monocytes, a decrease in macrophage activity, and the inhibition of natural killer (NK), T, and B cells (20). Hormones and anti-inflammatory cytokines [transforming growth factor (TGF-) β and interleukin- (IL-)10] are highly produced during this period and may further increase the tolerogenic potential of maternal DCs by favoring the generation of Th2 profile responses (21, 22).
In addition to systemic changes, many immune response regulation mechanisms are present in the placenta that represent the maternal-fetal interface, where fetal antigens are in close contact with maternal blood. These sites are largely inhibited by maternal immune cells in the decidua, which is the endometrial layer that forms in preparation for pregnancy (23). In addition, fetal placental cells that form the villi also play important immunoregulatory roles (24).
Decidual Immune Cells
The decidua is rich in leukocytes, especially uterine decidual NK (dNK) cells, macrophages, and T cells (23, 25).
dNK cells represent ~70% of the leukocytes present in the decidua during the first trimester of pregnancy and have a crucial role during placentation (23, 25), acting with trophoblastic cells (cytotrophoblasts, syncytiotrophoblast, and extravillous trophoblasts) during this process (26). The plasticity of dNK cells is crucial for successful pregnancy, and while these cells are important for orchestrating the invasion of trophoblast cells and spiral artery remodeling, they also protect the fetus from pathogens by destroying infected cells (26).
dNK cells originate from NK cell precursors, hematopoietic cells, or peripheral NK cells that migrate to the uterus during pregnancy and undergo phenotypic and functional modifications (27, 28). They are characterized by low cytotoxic capacity but high production of immunoregulatory cytokines (29), matrix metalloproteinases (30), and angiogenic factors (31) that contribute to tissue remodeling early in pregnancy. This limited cytotoxic activity may be attributed to defective immunological synapses (32) or to the expression of inhibitory variants of 2B4, NKp44/NCR2, and NKp30/NCR3 receptors (33, 34).
dNK cells have unique transcriptional profiles, in which multiple genes are expressed that are completely absent in peripheral NK cell subsets. Some genes encode proteins that are involved in maternal-fetal tolerance (29). In addition, dNK cells demonstrate differential and controlled roles of activating receptors that assure the outcome of pregnancy and in performing cytolytic functions upon viral infections (35, 36). This phenotype is even more pronounced in subsequent pregnancies and may be associated with improved placentation (37).
Decidual macrophages are also widely distributed in this niche, making up ~20–25% of local leukocytes in early pregnancy (38). These cells exhibit an immunoregulatory profile that favors angiogenesis and tissue remodeling and promotes the phagocytosis of apoptotic cells, preventing the release of proinflammatory mediators (39). These cells also prevent trophoblast lysis by dNK cells through TGF-β production (40).
DCs present in the decidua have an immature phenotype, with tolerogenic properties in both the first and third trimesters of pregnancy (41). Changes that lead to decreased immature DCs and increased mature DCs are associated with gestational pathologies (42). A peculiarity of decidual DCs is the low secretion of the Th1 proinflammatory cytokine IL-12 compared with that of circulating DCs, which favors prevalence of the Th2 response profile and fetal tolerance (43). DCs also stimulate dNK cell proliferation and activation (44), and their absence leads to impairment of the implantation process, angiogenesis, and decidual differentiation, as well as resorption of embryos (45). Together, these findings suggest that, despite being a rare population, decidual DCs are critical to gestational success.
Another population that is present in the decidua is T cells, which represent 10–20% of local leukocytes and include CD4+ and CD8+ T lymphocytes (25). Recently, it was verified that CD8+Tim-3+CTLA-4+ T cells found in the decidua play an immunosuppressive role through anti-inflammatory cytokine production, and a reduction in this population is associated with the occurrence of miscarriage (46). For CD4+ T cells, there is a prevalence of the Th2 profile response in the decidua due to the production of IL-13, IL-10, IL-4, and IL-6 by fetal placental cells, the amnion, and the decidua itself (21).
In addition, there is an increase in regulatory CD4+ T (Treg) cells, which is dependent on estradiol and exposure to paternal antigens (47, 48). These cells play a key role in maintaining tolerance by suppressing autoreactive lymphocytes and paternal antigens through TGF-β and IL-10 production. Treg cells are also found in the decidua, attracted by the production of chemokines and chorionic gonadotropin (49, 50). In humans, decidual Treg cells increase during the third trimester of healthy pregnancies, and their decrease is associated with the development of preeclampsia (51).
Immune Cells in Placental Villi
In addition to maternal tolerance mechanisms, placental fetal cells have also developed strategies to prevent rejection during pregnancy and play an immunomodulatory role. Trophoblasts do not express major histocompatibility complex (MHC) class II molecules due to a failure in the expression of the CIITA regulator (52), and the expression of these molecules by this cell type is associated with villitis, recurrent miscarriage, and gestational pemphigoid (53–55).
Trophoblasts do not express classical MHC Ia molecules (A, B, and C) even under IFN-γ stimulation, which decreases recognition and destruction by maternal immune cells (56). However, extravillous trophoblasts, which invade the decidua, express MHC Ib molecules (E, F, and G) that have tolerogenic properties and modulate T and NK cells, macrophages, and DCs (57–59). These fetal cells may also release microvesicles that carry immunomodulatory proteins, such as fibronectin, syncytin, galectin-3, human leukocyte antigen G (HLA-G), and prostaglandins (60).
The placental villi have resident macrophages, namely, Hofbauer cells (HBCs), which have an M2 regulatory phenotype and play an essential role in controlling the inflammatory response in the course of pregnancy (61). HBCs expressing DC-SIGN produce IL-10 and are decreased in preeclampsia cases (62).
Due to the remarkable tolerogenic response, pregnancy becomes a period of greater susceptibility to infections that represent a risk not only to the mother but also especially to the fetus, who may develop more severe manifestations of various diseases (63). These infectious complications can promote a tolerance break and induce an inflammatory process. In an experimental model, it was found that stimulation with Toll-like receptor (TLR) agonists and consequent induction of IFN-γ and TNF induce miscarriage (64). Inflammatory activation during pregnancy is associated with risks of fetal abnormalities, such as ventriculomegaly and hemorrhage, as well as the development of neuronal diseases, such as autism, schizophrenia, and other conditions (5, 65–67).
In general, the placenta (and its immune cells) play a protective role in inhibiting the transmission of pathogens to the fetus by separation of maternal and fetal vascular supplies, the trophoblastic barrier and HBCs. However, the placenta may also play a permissive role in the transmission of infectious agents to the fetus, as occurs with ZIKV infection (68).
Fetal and Neonatal Immunity
Infectious diseases and neonatal complications, such as prematurity and malnutrition, are responsible for most infant deaths worldwide, and it is estimated that 47% of deaths in children under 5 years old occur within the first 28 days of life (neonatal period) (69).
Fetal and neonatal immune responses are recognized by qualitative and quantitative differences from adult immune responses in almost all aspects of immunity. Therefore, susceptibility to early-life infections is associated with fetal and neonatal immunological immaturity, which, while contributing to maintaining tolerance during pregnancy, is not fully able to combat infections (70). However, in certain situations in vitro, neonatal cells are able to respond similarly to adult cells, highlighting the plasticity of the neonatal immune system (2, 3).
Many studies have shown the onset of immune cells during fetal development. In humans, fetal macrophages come from the yolk sac (71) and migrate to target tissues such as the central nervous system, resulting in resident macrophages (72). Tissue macrophages, such as alveolar macrophages and Langerhans cells, can also be derived from fetal liver monocytes (73, 74).
During human fetal development, T cells have been found in the thymus beginning at the tenth gestational week (75). Antigen presenting cells (APCs) play an important role in the profile of generated T lymphocytes, which are much more likely to generate Treg cells. Additionally, maternal cells cross the placenta and settle in the fetal lymph nodes, stimulating the generation of Treg cells, which contribute to fetal tolerance (76). Interestingly, ~6–7% of fetal thymocytes are Treg cells (77), and these cells can still be found in high proportions (15–20% of CD4+ cells) in fetal secondary lymphoid organs during the second gestational trimester in humans (78). In addition, fetal DCs promote Treg induction and inhibit T cell tumor necrosis factor- (TNF-) α production through arginase-2 activity (79). Moreover, fetal liver NK cells inhibit Th17 cells by IFN-γ production, helping to maintain a tolerogenic environment (80).
Even after birth, several peculiarities can be observed regarding neonatal immune cells. Monocytes, DCs, and macrophages secrete reduced TNF-α, IL-12p70, and IFN-α and express reduced CD80, CD86, and MHC II after activation via TLR (81–83). There is also a reduction in secretion of IL-18 by DCs, which acts together with IL-12 and IFN-type I to activate NK cells (84). However, the secretion of IL-1β, IL-6, IL-23, and IL-10 is similar or even higher than the level in adults (81), suggesting that neonatal DCs have the ability to secrete cytokines, but their response under stimulation differs from that of adults.
Neonatal immune cells are also characterized by lower IFN-I production under viral stimulation or TLR agonists (82), possibly due to a reduced interaction of transcription interferon regulatory factor 3 (IRF3) with the co-activator CREB and DNA (85). Reduced IFN-α and IFN-β production is also associated with diminished translocation of the transcription factor IRF7 into the nucleus in neonatal plasmacytoid DCs (86). Additionally, macrophages derived from cord blood monocytes show reduced IL-6 and TNF-α production when exposed to respiratory syncytial virus (87). These cells are hyporesponsive to IFN-γ activation due to decreased signal transducer and activator of transcription- (STAT-) 1 phosphorylation (88) and produce increased levels of IL-27 cytokine to regulate IDO expression, which promotes immune tolerance by suppressing T cell responses (89).
Several factors contribute to the immaturity of the neonatal adaptive response, such as the absence of an appropriate anatomical microenvironment for T and B cell interactions in lymphoid tissues, reduced ability of T cells to regulate CD40L expression, and low expression of adhesion molecule receptors (LFA-1, LFA-3, and CD2) and MHC molecules (3). Follicular DCs in neonates are also slow to form germinal center sites in secondary lymphoid organs and to promote B cell activation and proliferation (90). Such characteristics lead to a late production of T-dependent antibodies, which have lower affinity and shorter duration responses compared to those of adults (3).
Newborns have a reduced response to T-independent antigens, such as bacterial polysaccharides, possibly due to reduced TACI expression in B cells (91). Another peculiarity is the predisposition to develop predominantly Th2 responses to live or attenuated viral immunizations (92) due to decreased secretion of Th1 cytokines (IFN-γ and IL-12) and epigenetic configurations that favor IL-4 and IL-13 production (93, 94). In the fetal/neonatal period, there is more susceptibility to infections, especially to viruses that may cause neurological impairment.
Among the main fetal complications, infections by the TORCH group are the most common, and they are associated with 2–3% of congenital abnormality manifestations (95). These pathogens are present in the maternal bloodstream and can be transmitted hematogenously to the fetus through the placenta, resulting in an intense local inflammatory process (96).
Some of these infections can be prevented or controlled, such as congenital rubella infection, which has ceased to occur in countries with immunization against the virus (97), or maternal syphilis infection, which can be easily treated during pregnancy when discovered early, diminishing the deleterious effects on the fetus (95).
In this context, congenital HSV infection has an important impact because it can be disseminated and is associated with a high degree of mortality (98). In addition to skin and mouth rashes, fever, and eye problems, neonates can develop central nervous system infections causing encephalitis in the first month of life (98).
CMV infection until the second trimester of pregnancy also causes neuronal damage to the fetus (99). Among the main neuronal symptoms, we can highlight sensorineural hearing loss in children and neurodevelopmental delay, in addition to microcephaly; however, 85–90% of infected newborns present the asymptomatic form of the disease (100, 101). Congenital rubella infection can also cause hearing loss in addition to neurological changes, such as meningoencephalitis and microcephaly (102), when it occurs during the first trimester of pregnancy. However, other infections do not have an effective treatment or diagnosis and, despite presenting mild manifestations in the pregnant woman, can generate fatal manifestations in the fetus.
Neonatal infection occurs mainly during childbirth (85%) but can occur during the intrauterine (5%) and postnatal (10%) periods (98). Perinatal infections can occur through vertical transmission from a viremic mother to her newborn during pregnancy, delivery, breastfeeding, and close contact between the mother and her baby, as evidenced for ZIKV (103).
Perinatal transmission has already been reported for other arboviruses, such as DENV (104, 105), WNV (106), Chikungunya virus (CHIKV) (107), and YFV (108). The evidence for perinatal transmission of ZIKV was described in 2013 (109), prior to the recent epidemiological outbreak in Brazil.
The contemporary strain of ZIKV has a single serine to asparagine substitution (S139N) in its prM polyprotein that makes it more neurotropic because of an increase in its infectivity to neuronal progenitors and consequent microcephaly, which was confirmed in mice (110). It is also worth mentioning that this mutation emerged before the 2013 outbreak in French Polynesia.
Maternal ZIKV infection during pregnancy is usually asymptomatic for the mothers and can induce severe damage to the fetus similar to that found in the TORCH infections, such as fetal microcephaly, which was reported during the Brazilian epidemic in 2015 (111). Additional damage may include eye injuries, fetal growth restriction, and congenital contractures (112).
Altogether, this makes it vital to develop research for a better understanding of the pathology of ZIKV infection and to design vaccines and treatments that are appropriate for pregnancy.
Brief Overview of ZIKV Infection
ZIKV infection is an emergent aggravating factor of public health issue worldwide, representing a high morbidity rate that is mainly associated with congenital infection. Most cases of ZIKV infection occur by the vector route through the bite of the Aedes mosquito (Box 1). However, confirmed cases of non-vector infection, including sexual transmission, blood transfusion, and vertical transmission, have been reported (12). Sexual transmission has been confirmed in more than 13 countries in which sex partners have coincidentally traveled to epidemic regions, and in most cases, transmission occurs from male to female (113).
In this context, in ZIKV-infected women, viral particles disappear from the vaginal tract 3 weeks after symptoms, although the virus persists in the bloodstream (114). In men, it was verified that ZIKV persists in the semen for ~120 days and for 34 days in urine, whereas only 5% of patients had the virus in their saliva (115). Another study showed that virus persists for up to 100 days in blood and 168 days in semen, and it was associated with major production of soluble factors, including proinflammatory cytokines at early stages of infection (116). ZIKV infection has also been shown to modify semen characteristics, with late sperm motility and the presence of the replication-competent virus (117). This fact reflects public health implications because it may contribute to sexual transmission, especially in couples who wish to have children (117).
Male genital tract cells are highly permissive to the ZIKV; this fact still remains underexplored but could lead to male infertility, as a “break” in the immune privilege of the testes could compromise spermatogenesis (118). Although the long-term effect on male fertility remains unclear, men who were tested 12 months after the symptoms of infection, were negative for ZIKV by RT-PCR, but the sperm count was abnormal in 80% of the cases, including low sperm concentration and impaired motility (119).
The possibility of sexual transmission of ZIKV made headlines following the recent outbreak in the Americas, where most cases occurred in people who had symptoms but were asymptomatic at the time of intercourse (120). The growing number of cases of sexual transmission led the Centers for Disease Control (CDC) to recommend that people who had traveled to endemic areas abstain or have sex using a condom for at least 8 weeks for women and 6 months for men to prevent sexual transmission (121).
In adults, the infection is usually asymptomatic, and the symptoms are non-specific and last between 2 and 7 days, which makes diagnosis difficult. The main symptoms include fever, headache, vomiting, lymphadenopathy, a maculopapular rash, and conjunctivitis (122). One of the most alarming consequences of infection is the ability of the virus to attack mature or developing neuronal cells (123).
In rare cases, it can cause Guillain-Barre Syndrome (GBS), which is characterized by an acute inflammatory polyradiculoneuropathy resulting in weakness in the limbs and cranial nerves, with consequent physical limitations (124). People with GBS usually have more significant weakness within 2–4 weeks after symptoms begin, and as the disease progresses, the weakness may develop into paralysis. In some cases, the disease may result in neuromuscular respiratory failure (125).
Although ZIKV infection is asymptomatic or mild in most cases, infection during pregnancy can cause fetal developmental defects, such as microcephaly and other severe brain abnormalities.
Infection in Pregnant Women and Congenital Effects
ZIKV infection causes microcephaly and other neurological malformations that characterize CZS. In the beginning of the epidemic in 2015, ZIKV triggered a microcephaly outbreak in northeastern Brazil, where the incidence was 20 times higher than during other periods, and viral RNA was found in the fetal brain tissue of newborns with microcephaly, as well as in the amniotic fluid and placenta of mothers (126). It was estimated that 10% of babies of infected mothers had some birth defect (127).
At the peak of the epidemic in 2016, 216,207 probable cases of acute ZIKV disease were reported in Brazil, and it is estimated that 8,604 babies were born with malformations (128). In 2019, 1649 probable cases of ZIKV infections were reported in pregnant women, 447 of which were confirmed by laboratory tests (129).
Microcephaly is defined by the World Health Organization (WHO) as a reduction in head circumference (occipitofrontal diameter) in infants born at 37 or more weeks of gestation, with a measurement for boys equal to or <31.9 cm and for girls equal to or <31.5 cm (130). CZS is characterized by severe microcephaly and others neurological lesions, ocular findings, and congenital contractures. Additionally, other abnormalities described include craniosynostosis, fetal growth restriction, craniofacial malformations, pulmonary hypoplasia, and arthrogryposis (112).
For other arboviruses, severe consequences of maternal-fetal transmission have been reported, notably for CHIKV (encephalopathy and hemorrhagic fever) (107) and DENV (preterm birth, fetal death, low birthweight, and fetal abnormalities) (131). In a murine experimental model, it was reported that intrauterine ZIKV infection led to placental dysfunction and perinatal effects (132).
Manifestations due to mother-to-child transmission can be detected early, denoting the clinical and laboratory aspects of anomalies prior to birth, at the moment of delivery, or later, indicating that diseases may appear months or even years after the birth of congenitally infected babies (102) (Figure 1).
Figure 1. ZIKV vertical transmission and a possible maternal reservoir. ZIKV infection in pregnant women may occur by mosquito bite or sexual contact with an infected partner. Mother-to-child transmission can either occur in utero (infection in the first trimester of pregnancy is related to congenital ZIKV syndrome [CZS]) or in the perinatal period via breastfeeding. ZIKV presents tropism for multiple tissues and is present in several body fluids, which contribute to its transmission by different routes. However, after gestational infection with the congenital involvement of the child, it is still unknown whether the ZIKV establishes a reservoir in the mother that may influence the course of a second pregnancy.
In CZS, most of the abnormalities reported in the first cases were calcifications at the cortical–subcortical junction of the white matter and malformations in cortical development associated with other abnormalities (133, 134). Other authors have described changes such as parenchymal atrophy (and secondary ventriculomegaly), subependymal pseudocysts, agenesis/hypoplasia of the corpus callosum, parenchymal calcification, cerebellar and brainstem hypoplasia, lissencephaly–pachygyria, and cortical laminar necrosis (112, 135).
Eye injuries were also detected in CZS newborns; most cases occurred in babies with a small cephalic diameter at birth and in mothers who reported symptoms in the first trimester of pregnancy (136). In different regions where the viral outbreaks occurred, similar lesions were found, such as macular lesions, optical nerve abnormalities, chorioretinal atrophy/scarring, focal pigment mottling of retina, microphthalmia, glaucoma, cataract, iris coloboma, and subluxation (112, 137).
In a prospective cohort study involving 216 infants, 31.5% of children between 7 and 32 months of age had below-average neurodevelopment (cognitive, language, and motor domain) and/or abnormal ocular or auditory assessments. There was also resolution of the microcephaly with normal neurodevelopment in two of eight children, the development of secondary microcephaly (children born with normal head circumference that develop microcephaly in the first year of life) in two other children, and autism spectrum disorder in three previously healthy children in the second year of life (138).
Other parameters were also evaluated, such as the eruption of primary teeth in 74 children with CZS for a period of 2 years, where 94.4% simultaneously exhibited two or more related signs and symptoms. Increased salivation, irritability, and gingival itching were the most commonly reported signs and symptoms (139).
A prospective study in progress aims to evaluate ~10,000 pregnant women from six endemic countries from the beginning of pregnancy up to 6 weeks after delivery and their children until they are 1 year old (140). This study will contribute to understanding the critical questions about the impact of intrauterine exposure to ZIKV, even without congenital abnormalities.
Finding a correlation between ophthalmological and neurological findings, as well as the attempt to standardize the syndrome and its correlation with other congenital infections, has become difficult due to the lack of a more accurate description of neuroimaging and ophthalmic results. Furthermore, the prospective study of children who have been exposed to ZIKV to assess other later effects has become indispensable.
Mechanisms Involved in Congenital Infection
It is well-established that ZIKV infection during pregnancy can cause harm to the fetus (95). However, the mechanisms involved in congenital infection are still being studied in cohorts of children with or without microcephaly. Some data suggest that neonatal infection may be persistent and may occur at different stages of pregnancy.
More severe damage to fetal development, such as microcephaly, has been shown when maternal ZIKV infection occurs in the first trimester of pregnancy (141). Histopathological findings in the placenta at this time were similar to those found in TORCH infections, including chronic villitis, edema, trophoblastic lesion, and an increase in HBCs (142). However, third semester placentas showed only delayed villous maturation without any pathological changes. In addition, ZIKV RNA was also detected in the placentas of infected patients in the second and third trimesters (142). Studies in mice have also shown greater congenital damage when infection occurs in the early stages of pregnancy (143, 144).
Additionally, inflammatory and necrotic lesions of the placenta that are typical of other TORCH infections do not occur in placentas from the second and third trimesters with intrauterine ZIKV infection (96). On the other hand, these placentas do present proliferation and hyperplasia of HBCs.
Regarding the transplacental passage of ZIKV, some studies suggest that the autophagy pathway participates in the formation of microvesicles carrying the virus (145). In a primary culture of murine neurons, an increase in exosome production was observed following ZIKV infection through the expression of neutral sphingomyelinase (nSMase)-2 or SMPD3, which regulate the production and release of exosomes (146). SMPD3 silencing reduced the viral load, showing the important role for exosomes in ZIKV infection.
Another vertical transmission mechanism is placental translocation of infected cells or free virions (147). ZIKV is capable of infecting several primary cells and explants of the human placenta (cytotrophoblasts, endothelial cells, fibroblasts, HBCs, amniotic epithelial cells, and trophoblast progenitors), which have high expression of AXL, Tyro3, and TIM1—input receptors of ZIKV—in their membranes. These cells, especially HBCs, migrate to the placental–fetal interface and infect the fetus (148). In addition, the use of Duramycin, a peptide capable of binding to enveloped virions, prevents virion binding to the TIM1 receptor, resulting in reduced ZIKV infection in placental cells and explants. In addition, ZIKV has a greater tropism to the placenta and the most prominent cytopathic effects during the first trimester of pregnancy (68).
However, trophoblasts isolated from term placentas were found to be resistant to infection due to the constitutive production of type III IFN (IFN-λ1), which also ensured the protection of other cells because IFN-λ1 prevents infection in paracrine and autocrine manners (149).
In humans, the ZIKV NS5 protein antagonizes IFN signaling by binding to STAT2 and promoting its proteosomal degradation (150). STAT2 signaling appears to be relevant in the response against ZIKV, as STAT2-deficient mice are also susceptible to infections (151), as well as mice that are deficient in type I IFN receptors.
Once infected cells or virions come into contact with the fetal interface, ZIKV infects fetal cells and may cause teratogenic effects, such as microcephaly. Viral RNA was detected in the placentas of 9 out of 12 ZIKV-infected mothers who had miscarriages at up to 19 weeks of gestation (152). ZIKV RNA was also detected in the brain of 7 out of 8 fetuses with microcephaly, showing that early pregnancy infection may favor a replicative niche of the virus in the placenta, contributing to teratogenic effects.
ZIKV has the potential to cross the blood–brain barrier, as evidenced in vitro (153), due to AXL expression in endothelial cells. In addition, ZIKV has tropism to neuronal progenitor cells (154), astrocytes, oligodendrocytes, mature neurons, reproductive organ tissue cells (uterus, vagina, and testis), eye tissue (ganglion cells, optic nerve, and cornea), fluids (tears, saliva, semen, and urine), hepatocytes, epithelial cells, fibroblasts, renal cells, peripheral blood mononuclear cells, and neutrophils (155).
ZIKV tropism to neuronal progenitor cells leads to the manifestations observed in CZS (microcephaly, cerebellar malformation, brainstem, thalamus, and ocular impairment) (156), which are related to the cellular damage caused by ZIKV infection. Following in vitro ZIKV infection, cortical neuronal progenitors show unregulated cell replication cycles, decreased cell division rate, and increased apoptosis (157). ZIKV is capable of breaking double-stranded DNA and inhibiting DNA repair pathways during the cell replication cycle (158). In addition, permanence in phase S increases viral replication in neuronal progenitors, favoring increased neuronal damage in CZS.
Another mechanism associated with neuronal progenitor cell death is TLR3 activation by ZIKV, which promotes dysregulation of genes involved in neurogenesis and apoptotic pathways (159). Curiously, the remaining infected neuronal cells appear to behave as reservoirs for the virus without significant immunological activation, suggesting that there may be repercussions even several months after infection (160).
It is noteworthy that although ZIKV is able to infect a wide variety of cell types, and some cells are more permissive than others. In this context, ZIKV most effectively infects the most differentiated neuronal progenitor cells (161) and modulates Notch pathway gene expression, which is involved in cell proliferation, apoptosis, and differentiation during neurogenesis.
Moreover, cases of dizygotic twin pregnancies in which only one of the neonates had CZS show that intrinsic factors, such as oligogenic and epigenetic mechanisms, also influence infection, since serodiscordance was not observed in monozygotic twins (162).
Postnatal ZIKV Infection
The neonatal phase is characterized by a high susceptibility of neonates to infections due to their developing immune systems (163). During this period, neonates depend on maternal immunity via passive antibody transfer through breastfeeding. However, breast milk can be a potent vehicle for viral transmission, as has already been shown for flaviviruses such as DENV (164, 165) and WNV (165). Postnatal infection in children through breastfeeding has also been observed in ZIKV infection (Figure 1) (13, 166, 167).
ZIKV has been detected in breast milk and the mammary tissue of mice but there has not been transmission to the offspring via this route (168). Human case reports have confirmed the presence of ZIKV in breast milk and its transmission to newborns (13, 167). In addition, the presence of ZIKV was also evidenced in breast milk, as well as in the serum and urine of a newborn with congenital defects whose mother was infected early during pregnancy (169).
In one of the reported cases, an infected Brazilian woman at the end of pregnancy presented persistent virus in breast milk, with a high viral load and cytopathic effects, suggesting a high infectious capacity to her newborn (170). Breastfeeding was suspended, transmission to the child was not evidenced, and no abnormalities were associated with fetal development.
The persistence of the ZIKV viral load was also reported in cerebrospinal fluid and serum at 6 and 17 months of age in a case of severe microcephaly (171). However, the viral presence in breast milk was not evaluated. In addition, the clinical development of the infant consisted mainly of recurrent episodes of seizures, delayed neuropsychomotor development, dysphagia, visual impairment, and double spastic hemiplegia.
Although knowledge about the pathogenesis of ZIKV infection has expanded after the epidemiological outbreak in pregnant women in the Americas, there is still little information available on the clinical manifestations of ZIKV infection in the pediatric population.
A cohort study of 351 children under 18 years of age with confirmed ZIKV infection showed that in addition to fever, other frequent symptoms were rash (79.8%), facial or neck erythema (69.2%), fatigue (66.7%), headache (63.5%), chills (60.4%), pruritus (58.7%), and conjunctival hyperemia (58.1%) (172).
Most case studies of symptomatic pediatric ZIKV infection have shown a typically mild disease (172–174), similar to that observed in adult infection. However, complications associated with infection in newborns have rarely been reported (18), as well as ZIKV-related Guillain-Barré syndrome in adolescents (175).
Despite the impact of CZS, the consequences of congenital ZIKV infection in non-microcephalic newborns have received considerable attention (Figure 2). Among the babies that appear healthy at birth, there are increasing reports of postnatal developmental defects (176). In the United States, it has been described that 9% of 1-year-old babies from ZIKV-infected mothers had at least one neurodevelopmental abnormality, possibly associated with CZS infection (177).
Figure 2. Adverse effects of congenital and postnatal ZIKV infections. Intrauterine exposure to ZIKV may lead to congenital infection causing fetal microcephaly, among other CZS-related effects. Even in infants who have not had microcephaly, congenital ZIKV infection can cause delays in locomotor and cognitive development. Pediatric ZIKV infection is self-limiting and typically causes mild and even asymptomatic disease similar to adult infection. *Rare cases of ZIKV-associated Guillain-Barré.
In immunocompetent mice, mild congenital ZIKV infection in pups did not display apparent defects at birth, whereas manifestations of postnatal growth impediments and neurobehavioral deficits (locomotor and cognitive) persisted to adulthood (178). Postnatal effects of infection appear to be associated with the gestational period during which the infection occurred (179).
Prospective studies related to congenital ZIKV infection, as well as the long-term effects in children with or without CZS, are still under development. The few existing data show that microcephalic infants have important overall developmental delays, while in normocephalic infants other developmental complications have been observed, although neuroimaging findings have been normal (176). These complications include adaptive, fine motor, language, and personal–social delays.
Maternal Immunization as a Protection Tool
Despite the reduction in the number of new ZIKV infections, the development of a safe protective vaccine is a public health priority. In the face of the recent ZIKV infection epidemic, several groups have developed different vaccine strategies (Box 2) that are capable of inducing high levels of neutralizing antibodies (nAbs), as well as generating protection against the challenge of infection in non-pregnant mouse and non-human primate models (184–186). However, in these studies, it has not been demonstrated whether this protection prevents congenital changes or has a long-term protective effect. Although several vaccine strategies have progressed into Phase I clinical trials in humans (187), gestational protection vaccine studies are still limited.
Box 2. ZIKV vaccine approaches.
Candidate vaccines include those based on inactivated or live-attenuated virus, viral vectors, DNA or RNA, virus-like particles, subunit vaccines, and viral proteins (180). Viral surface or envelope proteins are the most antigenic and often considered as the best candidates for immunization (181). In addition, E protein, composed of three domains (ED I/II/III), is the major inducer of neutralizing antibodies (nAbs) against ZIKV (182, 183).
Great progress has been made in the development of a ZIKV vaccine since the outbreak in 2015. Studies show that over 45 ZIKV candidate vaccines are in preclinical development (188). Currently, according to the WHO, 15 vaccine candidates are in Phase 1 clinical trials, two of which have now progressed to Phase 2 (189). Both of the Phase 2 vaccines are directed at the ZIKV prME immunogen. One is mRNA-based and indicated for adults and is sponsored by Moderna Therapeutics, while the other corresponds to a DNA model developed by National Institute of Allergy and Infectious Diseases (NIAID) and is for adults and children.
In neonates, active immunization tends to be less effective due to the immaturity of the adaptive immune system (3, 190). At this stage, children mainly depend on passive immunity by maternal antibody transfer. Thus, active maternal immunizations are a way to provide infants with passive immunity to specific diseases, with the potential to protect the mother, her fetus, and the infant during vulnerable periods in their lives (191).
Due to the immunological conditions present during pregnancy, vaccination in this period has evoked discussion. However, in recent decades, this approach has been increasingly used (191) and even proposed in ZIKV vaccination clinical trials (192). These vaccine strategies aim to induce a strong neutralizing humoral response that is able to prevent offspring from developing congenital and perinatal infections. Some candidate vaccines targeting females before ZIKV infection during pregnancy or in their offspring have shown satisfactory results (Table 1).
Table 1. Maternal vaccine strategies for ZIKV infection.
One of the first studies in this area used two different vaccine strategies and showed that maternal immunization of mice protected the fetus from vertical transmission of ZIKV when challenged during pregnancy, with the induction of high levels of nAbs that prevented placental damage and fetal demise (193). In addition, the vaccination of pregnant mice prevented the development of microcephaly in their offspring and generated a long-term protective response. This was evidenced in both in utero and neonatal challenges, with a reduction in ZIKV-infected cells in the brain (196).
In another model, maternal immunization of mice also prevented postnatal ZIKV infection and inhibited the growth delay of their offspring by increasing nAbs titers in the colostrum and offspring serum (194). It has also been reported that the immunization of female mice before pregnancy protected offspring from lethal challenge with two epidemic human ZIKV strains (195).
Recently, an adenovirus vector-based ZIKV vaccine provided robust maternal-fetal and postnatal protection against fetal ZIKV transmission in utero as well as in infants against ZIKV infection after birth (197).
In addition to prophylactic vaccine studies, the development of other therapeutic interventions is also necessary, especially for use in infected pregnant women. In this area, some groups have a neutralizing antibody therapy approach.
In mice, a study demonstrated that the passive transfer of serum from immunized females to offspring born to naive females and immunocompromised adults was able to protect against lethal ZIKV infection due to the cross-neutralizing activity of the serum (195).
Human monoclonal antibody studies have shown therapeutic efficacy in experimental models. A highly effective nAbs from a ZIKV-infected patient that was evaluated in pregnant and non-pregnant mice was able to prevent maternal-fetal transmission (182). Similarly, prior administration of a cocktail containing three potent ZIKV-neutralizing monoclonal antibodies to rhesus monkeys on the eve of the ZIKV challenge also completely inhibited viremia (198).
The current scenario highlights the importance of offering protection to women of childbearing age and their children by developing prophylactic maternal vaccines or interventions that are able to prevent pregnant women from developing ZIKV infection and, consequently, to prevent fetal/perinatal transmission.
Conclusions and Future Perspectives
Prospective studies of children born to ZIKV-infected women are important for understanding the long-term effects of the disease. Follow-ups of children who are victims of intrauterine exposure will be critical in assessing the effects that may be influenced by the subtle immune responses triggered by ZIKV and in providing support for the early interventions that will improve the neurodevelopment of the children. In parallel, future studies of vaccine strategies that generate an optimal neutralizing antibody response are essential, considering that passive mother-to-child immunity against ZIKV during pregnancy could prevent congenital infection.
Author Contributions
For the preparation of this review, FT, AP, LMO, LMSO and MS wrote, read and approved the final manuscript. FT drew the figures. FT and MS created the study concept and edited the manuscript.
Funding
This work was supported by the Laboratório de Investigação Médica, Unidade 56, Department of Dermatology, School of Medicine, University of São Paulo, Brazil; Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP/ n° 2018/18230-6 and n° 2017/18199-9).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1. Mor G, Cardenas I. The immune system in pregnancy: a unique complexity. Am J Reprod Immunol. (2010) 63:425–33. doi: 10.1111/j.1600-0897.2010.00836.x
2. de Brito CA, Goldoni AL, Sato MN. Immune adjuvants in early life: targeting the innate immune system to overcome impaired adaptive response. Immunotherapy. (2009) 1:883–95. doi: 10.2217/imt.09.38
3. Adkins B, Leclerc C, Marshall-Clarke S. Neonatal adaptive immunity comes of age. Nat Rev Immunol. (2004) 4:553–64. doi: 10.1038/nri1394
4. Ohkawara T, Katsuyama T, Ida-Eto M, Narita N, Narita M. Maternal viral infection during pregnancy impairs development of fetal serotonergic neurons. Brain Dev. (2015) 37:88–93. doi: 10.1016/j.braindev.2014.03.007
5. Cugola FR, Fernandes IR, Russo FB, Freitas BC, Dias JL, Guimarães KP, et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature. (2016) 534:267–71. doi: 10.1038/nature18296
6. Knuesel I, Chicha L, Britschgi M, Schobel SA, Bodmer M, Hellings JA, et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat Rev Neurol. (2014) 10:643–60. doi: 10.1038/nrneurol.2014.187
7. Kuno G, Chang GJ. Full-length sequencing and genomic characterization of Bagaza, Kedougou, and Zika viruses. Arch Virol. (2007) 152:687–96. doi: 10.1007/s00705-006-0903-z
8. Medin CL, Rothman AL. Zika virus: the agent and its biology, with relevance to pathology. Arch Pathol Lab Med. (2017) 141:33–42. doi: 10.5858/arpa.2016-0409-RA
9. Haddow AD, Schuh AJ, Yasuda CY, Kasper MR, Heang V, Huy R, et al. Genetic characterization of Zika virus strains: geographic expansion of the Asian lineage. PLoS Negl Trop Dis. (2012) 6:e1477. doi: 10.1371/journal.pntd.0001477
10. Wong PS, Li MZ, Chong CS, Ng LC, Tan CH. Aedes (Stegomyia) albopictus (Skuse): a potential vector of Zika virus in Singapore. PLoS Negl Trop Dis. (2013) 7:e2348. doi: 10.1371/journal.pntd.0002348
11. Chouin-Carneiro T, Vega-Rua A, Vazeille M, Yebakima A, Girod R, Goindin D, et al. Differential susceptibilities of aedes aegypti and aedes albopictus from the americas to zika virus. PLoS Negl Trop Dis. (2016) 10:e0004543. doi: 10.1371/journal.pntd.0004543
12. Grischott F, Puhan M, Hatz C, Schlagenhauf P. Non-vector-borne transmission of Zika virus: a systematic review. Travel Med Infect Dis. (2016) 14:313–30. doi: 10.1016/j.tmaid.2016.07.002
13. Blohm GM, Lednicky JA, Márquez M, White SK, Loeb JC, Pacheco CA, et al. Evidence for mother-to-child transmission of Zika virus through breast milk. Clin Infect Dis. (2018) 66:1120–1. doi: 10.1093/cid/cix968
14. Teixeira MG, Costa MC, de Oliveira WK, Nunes ML, Rodrigues LC. The epidemic of zika virus-related microcephaly in Brazil: detection, control, etiology, and future scenarios. Am J Public Health. (2016) 106:601–5. doi: 10.2105/AJPH.2016.303113
15. PAHO/WHO, Pan American Health Organization/World Health Organization. Zika-epidemiological Report Brazil. (2017). Washington, DC. Available online at: http://www.paho.org/hq/index.php?option=com_docman&task=doc_view&gid=35221&&Itemid=270<=en
16. Neu N, Duchon J, Zachariah P. TORCH infections. Clin Perinatol. (2015) 42:77–103. doi: 10.1016/j.clp.2014.11.001
17. Coyne CB, Lazear HM. Zika virus - reigniting the TORCH. Nat Rev Microbiol. (2016) 14:707–15. doi: 10.1038/nrmicro.2016.125
18. Karwowski MP, Nelson JM, Staples JE, Fischer M, Fleming-Dutra KE, Villanueva J, et al. Zika virus disease: a CDC update for pediatric health care providers. Pediatrics. (2016) 137:e20160621. doi: 10.1542/peds.2016-0621
19. Leber A, Teles A, Zenclussen AC. Regulatory T cells and their role in pregnancy. Am J Reprod Immunol. (2010) 63:445–59. doi: 10.1111/j.1600-0897.2010.00821.x
20. Schumacher A, Costa SD, Zenclussen AC. Endocrine factors modulating immune responses in pregnancy. Front Immunol. (2014) 5:196. doi: 10.3389/fimmu.2014.00196
21. Sykes L, MacIntyre DA, Yap XJ, Teoh TG, Bennett PR. The Th1:th2 dichotomy of pregnancy and preterm labour. Mediators Inflamm. (2012) 2012:967629. doi: 10.1155/2012/967629
22. Holmes VA, Wallace JM, Gilmore WS, McFaul P, Alexander HD. Plasma levels of the immunomodulatory cytokine interleukin-10 during normal human pregnancy: a longitudinal study. Cytokine. (2003) 21:265–9. doi: 10.1016/S1043-4666(03)00097-8
23. King A. Uterine leukocytes and decidualization. Hum Reprod Update. (2000) 6:28–36. doi: 10.1093/humupd/6.1.28
24. PrabhuDas M, Bonney E, Caron K, Dey S, Erlebacher A, Fazleabas A, et al. Immune mechanisms at the maternal-fetal interface: perspectives and challenges. Nat Immunol. (2015) 16:328–34. doi: 10.1038/ni.3131
25. Bulmer JN, Morrison L, Longfellow M, Ritson A, Pace D. Granulated lymphocytes in human endometrium: histochemical and immunohistochemical studies. Hum Reprod. (1991) 6:791–8. doi: 10.1093/oxfordjournals.humrep.a137430
26. Jabrane-Ferrat N. Features of human decidual NK cells in healthy pregnancy and during viral infection. Front Immunol. (2019) 10:1397 doi: 10.3389/fimmu.2019.01397
27. Chiossone L, Vacca P, Orecchia P, Croxatto D, Damonte P, Astigiano S, et al. In vivo generation of decidual natural killer cells from resident hematopoietic progenitors. Haematologica. (2014) 99:448–57. doi: 10.3324/haematol.2013.091421
28. Cerdeira AS, Rajakumar A, Royle CM, Lo A, Husain Z, Thadhani RI, et al. Conversion of peripheral blood NK cells to a decidual NK-like phenotype by a cocktail of defined factors. J Immunol. (2013) 190:3939–48. doi: 10.4049/jimmunol.1202582
29. Koopman LA, Kopcow HD, Rybalov B, Boyson JE, Orange JS, Schatz F, et al. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med. (2003) 198:1201–12. doi: 10.1084/jem.20030305
30. Naruse K, Lash GE, Innes BA, Otun HA, Searle RF, Robson SC, et al. Localization of matrix metalloproteinase (MMP)-2, MMP-9 and tissue inhibitors for MMPs (TIMPs) in uterine natural killer cells in early human pregnancy. Hum Reprod. (2009) 24:553–61. doi: 10.1093/humrep/den408
31. Lash GE, Schiessl B, Kirkley M, Innes BA, Cooper A, Searle RF, et al. Expression of angiogenic growth factors by uterine natural killer cells during early pregnancy. J Leukoc Biol. (2006) 80:572–80. doi: 10.1189/jlb.0406250
32. Kopcow HD, Allan DS, Chen X, Rybalov B, Andzelm MM, Ge B, et al. Human decidual NK cells form immature activating synapses and are not cytotoxic. Proc Natl Acad Sci USA. (2005) 102:15563–8. doi: 10.1073/pnas.0507835102
33. Vacca P, Pietra G, Falco M, Romeo E, Bottino C, Bellora F, et al. Analysis of natural killer cells isolated from human decidua: evidence that 2B4 (CD244) functions as an inhibitory receptor and blocks NK-cell function. Blood. (2006) 108:4078–85. doi: 10.1182/blood-2006-04-017343
34. Siewiera J, Gouilly J, Hocine HR, Cartron G, Levy C, Al-Daccak R, et al. Natural cytotoxicity receptor splice variants orchestrate the distinct functions of human natural killer cell subtypes. Nat Commun. (2015) 6:10183 doi: 10.1038/ncomms10183
35. 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
36. El Costa H, Casemayou A, Aguerre-Girr M, Rabot M, Berrebi A, Parant O, et al. Critical and differential roles of NKp46- and NKp30-activating receptors expressed by uterine NK cells in early pregnancy. J Immunol. (2008) 181:3009–17. doi: 10.4049/jimmunol.181.5.3009
37. Gamliel M, Goldman-Wohl D, Isaacson B, Gur C, Stein N, Yamin R, et al. Trained memory of human uterine NK cells enhances their function in subsequent pregnancies. Immunity. (2018) 48:951–62.e5. doi: 10.1016/j.immuni.2018.03.030
38. Faas MM, Spaans F, De Vos P. Monocytes and macrophages in pregnancy and pre-eclampsia. Front Immunol. (2014) 5:298. doi: 10.3389/fimmu.2014.00298
39. Ning F, Liu H, Lash GE. The role of decidual macrophages during normal and pathological pregnancy. Am J Reprod Immunol. (2016) 75:298–309. doi: 10.1111/aji.12477
40. Co EC, Gormley M, Kapidzic M, Rosen DB, Scott MA, Stolp HA, et al. Maternal decidual macrophages inhibit NK cell killing of invasive cytotrophoblasts during human pregnancy. Biol Reprod. (2013) 88:155. doi: 10.1095/biolreprod.112.099465
41. Gardner L, Moffett A. Dendritic cells in the human decidua. Biol Reprod. (2003) 69:1438–46. doi: 10.1095/biolreprod.103.017574
42. Askelund K, Liddell HS, Zanderigo AM, Fernando NS, Khong TY, Stone PR, et al. CD83(+)dendritic cells in the decidua of women with recurrent miscarriage and normal pregnancy. Placenta. (2004) 25:140–5. doi: 10.1016/S0143-4004(03)00182-6
43. Miyazaki S, Tsuda H, Sakai M, Hori S, Sasaki Y, Futatani T, et al. Predominance of Th2-promoting dendritic cells in early human pregnancy decidua. J Leukoc Biol. (2003) 74:514–22. doi: 10.1189/jlb.1102566
44. Laskarin G, Redzović A, Rubesa Z, Mantovani A, Allavena P, Haller H, et al. Decidual natural killer cell tuning by autologous dendritic cells. Am J Reprod Immunol. (2008) 59:433–45. doi: 10.1111/j.1600-0897.2008.00599.x
45. Plaks V, Birnberg T, Berkutzki T, Sela S, BenYashar A, Kalchenko V, et al. Uterine DCs are crucial for decidua formation during embryo implantation in mice. J Clin Invest. (2008) 118:3954–65. doi: 10.1172/JCI36682
46. Wang S, Sun F, Li M, Qian J, Chen C, Wang M, et al. The appropriate frequency and function of decidual Tim-3. Cell Death Dis. (2019) 10:407. doi: 10.1038/s41419-019-1642-x
47. Zhao JX, Zeng YY, Liu Y. Fetal alloantigen is responsible for the expansion of the CD4(+)CD25(+) regulatory T cell pool during pregnancy. J Reprod Immunol. (2007) 75:71–81. doi: 10.1016/j.jri.2007.06.052
48. Tai P, Wang J, Jin H, Song X, Yan J, Kang Y, et al. Induction of regulatory T cells by physiological level estrogen. J Cell Physiol. (2008) 214:456–64. doi: 10.1002/jcp.21221
49. Tilburgs T, Roelen DL, van der Mast BJ, de Groot-Swings GM, Kleijburg C, Scherjon SA, et al. Evidence for a selective migration of fetus-specific CD4+CD25bright regulatory T cells from the peripheral blood to the decidua in human pregnancy. J Immunol. (2008) 180:5737–45. doi: 10.4049/jimmunol.180.8.5737
50. Schumacher A, Brachwitz N, Sohr S, Engeland K, Langwisch S, Dolaptchieva M, et al. Human chorionic gonadotropin attracts regulatory T cells into the fetal-maternal interface during early human pregnancy. J Immunol. (2009) 182:5488–97. doi: 10.4049/jimmunol.0803177
51. Tsuda S, Zhang X, Hamana H, Shima T, Ushijima A, Tsuda K, et al. Clonally expanded decidual effector regulatory T cells increase in late gestation of normal pregnancy, but not in preeclampsia, in humans. Front Immunol. (2018) 9:1934. doi: 10.3389/fimmu.2018.01934
52. Murphy SP, Tomasi TB. Absence of MHC class II antigen expression in trophoblast cells results from a lack of class II transactivator (CIITA) gene expression. Mol Reprod Dev. (1998) 51:1–12. doi: 10.1002/(SICI)1098-2795(199809)51:1<1::AID-MRD1>3.0.CO;2-L
53. Borthwick GM, Holmes RC, Stirrat GM. Abnormal expression of class II MHC antigens in placentae from patients with pemphigoid gestationis: analysis of class II MHC subregion product expression. Placenta. (1988) 9:81–94. doi: 10.1016/0143-4004(88)90075-6
54. Labarrere CA, Faulk WP. MHC class II reactivity of human villous trophoblast in chronic inflammation of unestablished etiology. Transplantation. (1990) 50:812–6. doi: 10.1097/00007890-199011000-00014
55. Athanassakis I, Aifantis Y, Makrygiannakis A, Koumantakis E, Vassiliadis S. Placental tissue from human miscarriages expresses class II HLA-DR antigens. Am J Reprod Immunol. (1995) 34:281–7. doi: 10.1111/j.1600-0897.1995.tb00954.x
56. Hunt JS, Andrews GK, Wood GW. Normal trophoblasts resist induction of class I HLA. J Immunol. (1987) 138:2481–7.
57. Ishitani A, Sageshima N, Hatake K. The involvement of HLA-E and -F in pregnancy. J Reprod Immunol. (2006) 69:101–13. doi: 10.1016/j.jri.2005.10.004
58. Hunt JS, Langat DK, McIntire RH, Morales PJ. The role of HLA-G in human pregnancy. Reprod Biol Endocrinol. (2006) 4 (Suppl. 1):S10. doi: 10.1186/1477-7827-4-S1-S10
59. Juch H, Blaschitz A, Dohr G, Hutter H. HLA class I expression in the human placenta. Wien Med Wochenschr. (2012) 162:196–200. doi: 10.1007/s10354-012-0070-7
60. Record M. Intercellular communication by exosomes in placenta: a possible role in cell fusion? Placenta. (2014) 35:297–302. doi: 10.1016/j.placenta.2014.02.009
61. Selkov SA, Selutin AV, Pavlova OM, Khromov-Borisov NN, Pavlov OV. Comparative phenotypic characterization of human cord blood monocytes and placental macrophages at term. Placenta. (2013) 34:836–9. doi: 10.1016/j.placenta.2013.05.007
62. Yang SW, Cho EH, Choi SY, Lee YK, Park JH, Kim MK, et al. DC-SIGN expression in Hofbauer cells may play an important role in immune tolerance in fetal chorionic villi during the development of preeclampsia. J Reprod Immunol. (2017) 124:30–7. doi: 10.1016/j.jri.2017.09.012
63. Kourtis AP, Read JS, Jamieson DJ. Pregnancy and infection. N Engl J Med. (2014) 371:1077. doi: 10.1056/NEJMc1408436
64. Chaouat G, Assal Meliani A, Martal J, Raghupathy R, Elliott JF, Elliot J, et al. IL-10 prevents naturally occurring fetal loss in the CBA x DBA/2 mating combination, and local defect in IL-10 production in this abortion-prone combination is corrected by in vivo injection of IFN-tau. J Immunol. (1995) 154:4261–8.
65. Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry. (2010) 167:261–80. doi: 10.1176/appi.ajp.2009.09030361
66. Patterson PH. Maternal infection and immune involvement in autism. Trends Mol Med. (2011) 17:389–94. doi: 10.1016/j.molmed.2011.03.001
67. Rudolph MD, Graham AM, Feczko E, Miranda-Dominguez O, Rasmussen JM, Nardos R, et al. Maternal IL-6 during pregnancy can be estimated from newborn brain connectivity and predicts future working memory in offspring. Nat Neurosci. (2018) 21:765–72. doi: 10.1038/s41593-018-0128-y
68. El Costa H, Gouilly J, Mansuy JM, Chen Q, Levy C, Cartron G, et al. ZIKA virus reveals broad tissue and cell tropism during the first trimester of pregnancy. Sci Rep. (2016) 6:35296. doi: 10.1038/srep35296
69. United Nations Inter-agency Group for Child Mortality Estimation (UN IGME). Levels & Trends in Child Mortality: Report 2019, Estimates developed by the United Nations Inter-agency Group for Child Mortality Estimation. New York, NY: United Nations Children's Fund (2019).
70. Holt PG, Jones CA. The development of the immune system during pregnancy and early life. Allergy. (2000) 55:688–97. doi: 10.1034/j.1398-9995.2000.00118.x
71. Ginhoux F, Jung S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol. (2014) 14:392–404. doi: 10.1038/nri3671
72. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. (2010) 330:841–5. doi: 10.1126/science.1194637
73. Hoeffel G, Wang Y, Greter M, See P, Teo P, Malleret B, et al. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J Exp Med. (2012) 209:1167–81. doi: 10.1084/jem.20120340
74. Schneider C, Nobs SP, Kurrer M, Rehrauer H, Thiele C, Kopf M. Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages. Nat Immunol. (2014) 15:1026–37. doi: 10.1038/ni.3005
75. Haynes BF, Hale LP. The human thymus. A chimeric organ comprised of central and peripheral lymphoid components. Immunol Res. (1998) 18:175–92. doi: 10.1007/BF02788778
76. Mold JE, Michaëlsson J, Burt TD, Muench MO, Beckerman KP, Busch MP, et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science. (2008) 322:1562–5. doi: 10.1126/science.1164511
77. Darrasse-Jèze G, Marodon G, Salomon BL, Catala M, Klatzmann D. Ontogeny of CD4+CD25+ regulatory/suppressor T cells in human fetuses. Blood. (2005) 105:4715–21. doi: 10.1182/blood-2004-10-4051
78. Cupedo T, Nagasawa M, Weijer K, Blom B, Spits H. Development and activation of regulatory T cells in the human fetus. Eur J Immunol. (2005) 35:383–90. doi: 10.1002/eji.200425763
79. McGovern N, Shin A, Low G, Low D, Duan K, Yao LJ, et al. Human fetal dendritic cells promote prenatal T-cell immune suppression through arginase-2. Nature. (2017) 546:662–6. doi: 10.1038/nature22795
80. Fu B, Li X, Sun R, Tong X, Ling B, Tian Z, et al. Natural killer cells promote immune tolerance by regulating inflammatory TH17 cells at the human maternal-fetal interface. Proc Natl Acad Sci USA. (2013) 110:E231–40. doi: 10.1073/pnas.1206322110
81. Kollmann TR, Crabtree J, Rein-Weston A, Blimkie D, Thommai F, Wang XY, et al. Neonatal innate TLR-mediated responses are distinct from those of adults. J Immunol. (2009) 183:7150–60. doi: 10.4049/jimmunol.0901481
82. Renneson J, Dutta B, Goriely S, Danis B, Lecomte S, Laes JF, et al. IL-12 and type I IFN response of neonatal myeloid DC to human CMV infection. Eur J Immunol. (2009) 39:2789–99. doi: 10.1002/eji.200939414
83. Winterberg T, Vieten G, Meier T, Yu Y, Busse M, Hennig C, et al. Distinct phenotypic features of neonatal murine macrophages. Eur J Immunol. (2015) 45:214–24. doi: 10.1002/eji.201444468
84. La Pine TR, Joyner JL, Augustine NH, Kwak SD, Hill HR. Defective production of IL-18 and IL-12 by cord blood mononuclear cells influences the T helper-1 interferon gamma response to group B Streptococci. Pediatr Res. (2003) 54:276–81. doi: 10.1203/01.PDR.0000072515.10652.87
85. Aksoy E, Albarani V, Nguyen M, Laes JF, Ruelle JL, De Wit D, et al. Interferon regulatory factor 3-dependent responses to lipopolysaccharide are selectively blunted in cord blood cells. Blood. (2007) 109:2887–93. doi: 10.1182/blood-2006-06-027862
86. Danis B, George TC, Goriely S, Dutta B, Renneson J, Gatto L, et al. Interferon regulatory factor 7-mediated responses are defective in cord blood plasmacytoid dendritic cells. Eur J Immunol. (2008) 38:507–17. doi: 10.1002/eji.200737760
87. Matsuda K, Tsutsumi H, Sone S, Yoto Y, Oya K, Okamoto Y, et al. Characteristics of IL-6 and TNF-alpha production by respiratory syncytial virus-infected macrophages in the neonate. J Med Virol. (1996) 48:199–203. doi: 10.1002/(SICI)1096-9071(199602)48:2<199::AID-JMV13>3.0.CO;2-A
88. Maródi L, Goda K, Palicz A, Szabó G. Cytokine receptor signalling in neonatal macrophages: defective STAT-1 phosphorylation in response to stimulation with IFN-gamma. Clin Exp Immunol. (2001) 126:456–60. doi: 10.1046/j.1365-2249.2001.01693.x
89. Jung JY, Gleave Parson M, Kraft JD, Lyda L, Kobe B, Davis C, et al. Elevated interleukin-27 levels in human neonatal macrophages regulate indoleamine dioxygenase in a STAT-1 and STAT-3-dependent manner. Immunology. (2016) 149:35–47. doi: 10.1111/imm.12625
90. Pihlgren M, Tougne C, Bozzotti P, Fulurija A, Duchosal MA, Lambert PH, et al. Unresponsiveness to lymphoid-mediated signals at the neonatal follicular dendritic cell precursor level contributes to delayed germinal center induction and limitations of neonatal antibody responses to T-dependent antigens. J Immunol. (2003) 170:2824–32. doi: 10.4049/jimmunol.170.6.2824
91. Kanswal S, Katsenelson N, Selvapandiyan A, Bram RJ, Akkoyunlu M. Deficient TACI expression on B lymphocytes of newborn mice leads to defective Ig secretion in response to BAFF or APRIL. J Immunol. (2008) 181:976–90. doi: 10.4049/jimmunol.181.2.976
92. Bot A, Antohi S, Bot S, Garcia-Sastre A, Bona C. Induction of humoral and cellular immunity against influenza virus by immunization of newborn mice with a plasmid bearing a hemagglutinin gene. Int Immunol. (1997) 9:1641–50. doi: 10.1093/intimm/9.11.1641
93. Rose S, Lichtenheld M, Foote MR, Adkins B. Murine neonatal CD4+ cells are poised for rapid Th2 effector-like function. J Immunol. (2007) 178:2667–78. doi: 10.4049/jimmunol.178.5.2667
94. Webster RB, Rodriguez Y, Klimecki WT, Vercelli D. The human IL-13 locus in neonatal CD4+ T cells is refractory to the acquisition of a repressive chromatin architecture. J Biol Chem. (2007) 282:700–9. doi: 10.1074/jbc.M609501200
95. Zorrilla CD, García García I, García Fragoso L, De La Vega A. Zika virus infection in pregnancy: maternal, fetal, and neonatal considerations. J Infect Dis. (2017) 216(Suppl_10):S891–6. doi: 10.1093/infdis/jix448
96. Schwartz DA. Viral infection, proliferation, and hyperplasia of Hofbauer cells and absence of inflammation characterize the placental pathology of fetuses with congenital Zika virus infection. Arch Gynecol Obstet. (2017) 295:1361–8. doi: 10.1007/s00404-017-4361-5
97. Castillo-Solórzano C, Marsigli C, Bravo-Alcántara P, Flannery B, Ruiz Matus C, Tambini G, et al. Elimination of rubella and congenital rubella syndrome in the Americas. J Infect Dis. (2011) 204(Suppl 2):S571–8. doi: 10.1093/infdis/jir472
98. Pinninti SG, Kimberlin DW. Neonatal herpes simplex virus infections. Semin Perinatol. (2018) 42:168–75. doi: 10.1053/j.semperi.2018.02.004
99. Barkovich AJ, Lindan CE. Congenital cytomegalovirus infection of the brain: imaging analysis and embryologic considerations. AJNR Am J Neuroradiol. (1994) 15:703–15.
100. Dollard SC, Grosse SD, Ross DS. New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection. Rev Med Virol. (2007) 17:355–63. doi: 10.1002/rmv.544
101. Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. (2007) 17:253–76. doi: 10.1002/rmv.535
102. Ostrander B, Bale JF. Congenital and perinatal infections. Handb Clin Neurol. (2019) 162:133–53. doi: 10.1016/B978-0-444-64029-1.00006-0
103. Song BH, Yun SI, Woolley M, Lee YM. Zika virus: history, epidemiology, transmission, and clinical presentation. J Neuroimmunol. (2017) 308:50–64. doi: 10.1016/j.jneuroim.2017.03.001
104. Basurko C, Carles G, Youssef M, Guindi WE. Maternal and fetal consequences of dengue fever during pregnancy. Eur J Obstet Gynecol Reprod Biol. (2009) 147:29–32. doi: 10.1016/j.ejogrb.2009.06.028
105. Tan PC, Rajasingam G, Devi S, Omar SZ. Dengue infection in pregnancy: prevalence, vertical transmission, and pregnancy outcome. Obstet Gynecol. (2008) 111:1111–7. doi: 10.1097/AOG.0b013e31816a49fc
106. Pridjian G, Sirois PA, McRae S, Hinckley AF, Rasmussen SA, Kissinger P, et al. Prospective study of pregnancy and newborn outcomes in mothers with West nile illness during pregnancy. Birth Defects Res A Clin Mol Teratol. (2016) 106:716–23. doi: 10.1002/bdra.23523
107. Gérardin P, Barau G, Michault A, Bintner M, Randrianaivo H, Choker G, et al. Multidisciplinary prospective study of mother-to-child chikungunya virus infections on the island of La Réunion. PLoS Med. (2008) 5:e60. doi: 10.1371/journal.pmed.0050060
108. Bentlin MR, de Barros Almeida RA, Coelho KI, Ribeiro AF, Siciliano MM, Suzuki A, et al. Perinatal transmission of yellow fever, Brazil, 2009. Emerg Infect Dis. (2011) 17:1779–80. doi: 10.3201/eid1709.110242
109. Besnard M, Lastere S, Teissier A, Cao-Lormeau V, Musso D. Evidence of perinatal transmission of Zika virus, French Polynesia, December 2013 and February 2014. Euro Surveill. (2014) 19. doi: 10.2807/1560-7917.ES2014.19.13.20751
110. Yuan L, Huang XY, Liu ZY, Zhang F, Zhu XL, Yu JY, et al. A single mutation in the prM protein of Zika virus contributes to fetal microcephaly. Science. (2017) 358:933–6. doi: 10.1126/science.aam7120
111. Vesnaver TV, Tul N, Mehrabi S, Parissone F, Štrafela P, Mlakar J, et al. Zika virus associated microcephaly/micrencephaly-fetal brain imaging in comparison with neuropathology. BJOG. (2017) 124:521–5. doi: 10.1111/1471-0528.14423
112. Marques VM, Santos CS, Santiago IG, Marques SM, Nunes Brasil MDG, Lima TT, et al. Neurological complications of congenital zika virus infection. Pediatr Neurol. (2019) 91:3–10. doi: 10.1016/j.pediatrneurol.2018.11.003
113. Hills SL, Russell K, Hennessey M, Williams C, Oster AM, Fischer M, et al. Transmission of Zika virus through sexual contact with travelers to areas of ongoing transmission - continental United States, 2016. MMWR Morb Mortal Wkly Rep. (2016) 65:215–6. doi: 10.15585/mmwr.mm6508e2
114. Prisant N, Breurec S, Moriniere C, Bujan L, Joguet G. Zika virus genital tract shedding in infected women of childbearing age. Clin Infect Dis. (2017) 64:107–9. doi: 10.1093/cid/ciw669
115. Paz-Bailey G, Rosenberg ES, Doyle K, Munoz-Jordan J, Santiago GA, Klein L, et al. Persistence of Zika virus in body fluids - final report. N Engl J Med. (2018) 379:1234–43. doi: 10.1056/NEJMoa1613108
116. Mansuy JM, El Costa H, Gouilly J, Mengelle C, Pasquier C, Martin-Blondel G, et al. Peripheral plasma and semen cytokine response to Zika virus in humans. Emerg Infect Dis. (2019) 25:823–5. doi: 10.3201/eid2504.171886
117. Joguet G, Mansuy JM, Matusali G, Hamdi S, Walschaerts M, Pavili L, et al. Effect of acute Zika virus infection on sperm and virus clearance in body fluids: a prospective observational study. Lancet Infect Dis. (2017) 17:1200–8. doi: 10.1016/S1473-3099(17)30444-9
118. Matusali G, Houzet L, Satie AP, Mahé D, Aubry F, Couderc T, et al. Zika virus infects human testicular tissue and germ cells. J Clin Invest. (2018) 128:4697–710. doi: 10.1172/JCI121735
119. Avelino-Silva VI, Alvarenga C, Abreu C, Tozetto-Mendoza TR, Canto CLMD, Manuli ER, et al. Potential effect of Zika virus infection on human male fertility? Rev Inst Med Trop São Paulo. (2018) 60:e64. doi: 10.1590/s1678-9946201860064
120. Fréour T, Mirallié S, Hubert B, Splingart C, Barrière P, Maquart M, et al. Sexual transmission of Zika virus in an entirely asymptomatic couple returning from a Zika epidemic area, France, April 2016. Euro Surveill. (2016) 21. doi: 10.2807/1560-7917.ES.2016.21.23.30254
121. Hastings AK, Fikrig E. Zika virus and sexual transmission: a new route of transmission for mosquito-borne flaviviruses. Yale J Biol Med. (2017) 90:325–30.
122. 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
123. Hu B, Huo Y, Yang L, Chen G, Luo M, Yang J, et al. ZIKV infection effects changes in gene splicing, isoform composition and lncRNA expression in human neural progenitor cells. Virol J. (2017) 14:217. doi: 10.1186/s12985-017-0882-6
124. Hughes RA, Hadden RD, Gregson NA, Smith KJ. Pathogenesis of Guillain-Barré syndrome. J Neuroimmunol. (1999) 100:74–97. doi: 10.1016/S0165-5728(99)00195-2
125. Walteros DM, Soares J, Styczynski AR, Abrams JY, Galindo-Buitrago JI, Acosta-Reyes J, et al. Long-term outcomes of Guillain-Barré syndrome possibly associated with Zika virus infection. PLoS ONE. (2019) 14:e0220049. doi: 10.1371/journal.pone.0220049
126. Carod-Artal FJ. Neurological complications of Zika virus infection. Expert Rev Anti Infect Ther. (2018) 16:399–410. doi: 10.1080/14787210.2018.1466702
127. Reynolds MR, Jones AM, Petersen EE, Lee EH, Rice ME, Bingham A, et al. Vital signs: update on zika virus-associated birth defects and evaluation of all U.S. infants with congenital zika virus exposure - u.S. Zika Pregnancy registry, 2016. MMWR Morb Mortal Wkly Rep. (2017) 66:366–73. doi: 10.15585/mmwr.mm6613e1
128. WHO, World Health Organization. Zika: The Continuing Threat. Bull World Health Organ. (2019) 97:6–7. doi: 10.2471/BLT.19.020119
129. Ministério da Saúde B. Secretaria de Vigilância em Saúde. Boletim Epidemiológico 22. Monitoramento dos Casos de Arboviroses Urbanas Transmitidas Pelo Aedes (dengue, chikungunya e Zika). Semanas Epidemiológicas 1 a 34. (2019).
130. Ashwal S, Michelson D, Plawner L, Dobyns WB; Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Practice parameter: evaluation of the child with microcephaly (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. (2009) 73:887–97. doi: 10.1212/WNL.0b013e3181b783f7
131. Leite RC, Souza AI, Castanha PM, Cordeiro MT, Martelli CT, Ferreira AL, et al. Dengue infection in pregnancy and transplacental transfer of anti-dengue antibodies in Northeast, Brazil. J Clin Virol. (2014) 60:16–21. doi: 10.1016/j.jcv.2014.02.009
132. 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
133. de Fatima Vasco Aragao M. Zika virus study in The BMJ was different from the one reported in the New England Journal of Medicine. BMJ. (2016) 353:i2444. doi: 10.1136/bmj.i2444
134. Hazin AN, Poretti A, Di Cavalcanti Souza Cruz D, Tenorio M, van der Linden A, Pena LJ, et al. Computed tomographic findings in microcephaly associated with zika virus. N Engl J Med. (2016) 374:2193–5. doi: 10.1056/NEJMc1603617
135. Zare Mehrjardi M, Carteaux G, Poretti A, Sanei Taheri M, Bermudez S, Werner H, et al. Neuroimaging findings of postnatally acquired Zika virus infection: a pictorial essay. JPN J Radiol. (2017) 35:341–9. doi: 10.1007/s11604-017-0641-z
136. Oliveira Melo AS, Malinger G, Ximenes R, Szejnfeld PO, Alves Sampaio S, Bispo de Filippis AM. Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg? Ultrasound Obstet Gynecol. (2016) 47:6–7. doi: 10.1002/uog.15831
137. de Paula Freitas B, de Oliveira Dias JR, Prazeres J, Sacramento GA, Ko AI, Maia M, et al. Ocular findings in infants with microcephaly associated with presumed zika virus congenital infection in Salvador, Brazil. JAMA Ophthalmol. (2016) 134:529–35. doi: 10.1001/jamaophthalmol.2016.0267
138. Nielsen-Saines K, Brasil P, Kerin T, Vasconcelos Z, Gabaglia CR, Damasceno L, et al. Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children. Nat Med. (2019) 25:1213–7. doi: 10.1038/s41591-019-0496-1
139. Cavalcanti AFC, Aguiar YPC, de Oliveira Melo AS, de Freitas Leal JIB, Cavalcanti AL, Cavalcanti SDLB. Teething symptoms in children with congenital Zika syndrome, A 2-year follow-up. Int J Paediatr Dent. (2019) 29:74–8. doi: 10.1111/ipd.12431
140. Lebov JF, Arias JF, Balmaseda A, Britt W, Cordero JF, Galvão LA, et al. International prospective observational cohort study of Zika in infants and pregnancy (ZIP study): study protocol. BMC Pregnancy Childbirth. (2019) 19:282. doi: 10.1186/s12884-019-2589-8
141. Mlakar J, Korva M, Tul N, Popović M, Poljšak-Prijatelj M, Mraz J, et al. Zika virus associated with microcephaly. N Engl J Med. (2016) 374:951–8. doi: 10.1056/NEJMoa1600651
142. de Noronha L, Zanluca C, Burger M, Suzukawa AA, Azevedo M, Rebutini PZ, et al. Zika virus infection at different pregnancy stages, anatomopathological findings, target cells and viral persistence in placental tissues. Front Microbiol. (2018) 9:2266. doi: 10.3389/fmicb.2018.02266
143. Miner JJ, Cao B, Govero J, Smith AM, Fernandez E, Cabrera OH, et al. Zika virus infection during pregnancy in mice causes placental damage and fetal demise. Cell. (2016) 165:1081–91. doi: 10.1016/j.cell.2016.05.008
144. Yockey LJ, Varela L, Rakib T, Khoury-Hanold W, Fink SL, Stutz B, et al. Vaginal exposure to Zika virus during pregnancy leads to fetal brain infection. Cell. (2016) 166:1247–56.e4. doi: 10.1016/j.cell.2016.08.004
145. Zhang ZW, Li ZL, Yuan S. The role of secretory autophagy in Zika virus transfer through the placental barrier. Front Cell Infect Microbiol. (2016) 6:206. doi: 10.3389/fcimb.2016.00206
146. Zhou W, Woodson M, Sherman MB, Neelakanta G, Sultana H. Exosomes mediate Zika virus transmission through SMPD3 neutral Sphingomyelinase in cortical neurons. Emerg Microbes Infect. (2019) 8:307–26. doi: 10.1080/22221751.2019.1578188
147. 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
148. 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
149. Bayer A, Lennemann NJ, Ouyang Y, Bramley JC, Morosky S, Marques ET, et al. Type III interferons produced by human placental trophoblasts confer protection against zika virus infection. Cell Host Microbe. (2016) 19:705–12. doi: 10.1016/j.chom.2016.03.008
150. Grant A, Ponia SS, Tripathi S, Balasubramaniam V, Miorin L, Sourisseau M, et al. Zika virus targets human STAT2 to inhibit type i interferon signaling. Cell Host Microbe. (2016) 19:882–90. doi: 10.1016/j.chom.2016.05.009
151. Tripathi S, Balasubramaniam VR, Brown JA, Mena I, Grant A, Bardina SV, et al. A novel Zika virus mouse model reveals strain specific differences in virus pathogenesis and host inflammatory immune responses. PLoS Pathog. (2017) 13:e1006258. doi: 10.1371/journal.ppat.1006258
152. 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
153. Alimonti JB, Ribecco-Lutkiewicz M, Sodja C, Jezierski A, Stanimirovic DB, Liu Q, et al. Zika virus crosses an in vitro human blood brain barrier model. Fluids Barriers CNS. (2018) 15:15. doi: 10.1186/s12987-018-0100-y
154. Miner JJ, Diamond MS. Zika virus pathogenesis and tissue tropism. Cell Host Microbe. (2017) 21:134–42. doi: 10.1016/j.chom.2017.01.004
155. Ngono AE, Shresta S. Immune response to dengue and Zika. Annu Rev Immunol. (2018) 36:279–308. doi: 10.1146/annurev-immunol-042617-053142
156. Adamski A, Bertolli J, Castañeda-Orjuela C, Devine OJ, Johansson MA, Duarte MAG, et al. Estimating the numbers of pregnant women infected with Zika virus and infants with congenital microcephaly in Colombia, 2015–2017. J Infect. (2018) 76:529–35. doi: 10.1016/j.jinf.2018.02.010
157. Tang H, Hammack C, Ogden SC, Wen Z, Qian X, Li Y, et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell. (2016) 18:587–90. doi: 10.1016/j.stem.2016.02.016
158. Hammack C, Ogden SC, Madden JC, Medina A, Xu C, Phillips E, et al. Zika virus infection induces DNA damage response in human neural progenitors that enhances viral replication. J Virol. (2019) 93. doi: 10.1128/JVI.00638-19
159. Dang J, Tiwari SK, Lichinchi G, Qin Y, Patil VS, Eroshkin AM, et al. Zika virus depletes neural progenitors in human cerebral organoids through activation of the innate immune receptor TLR3. Cell Stem Cell. (2016) 19:258–65. doi: 10.1016/j.stem.2016.04.014
160. Hanners NW, Eitson JL, Usui N, Richardson RB, Wexler EM, Konopka G, et al. Western Zika virus in human fetal neural progenitors persists long term with partial cytopathic and limited immunogenic effects. Cell Rep. (2016) 15:2315–22. doi: 10.1016/j.celrep.2016.05.075
161. Ferraris P, Cochet M, Hamel R, Gladwyn-Ng I, Alfano C, Diop F, et al. Zika virus differentially infects human neural progenitor cells according to their state of differentiation and dysregulates neurogenesis through the Notch pathway. Emerg Microbes Infect. (2019) 8:1003–16. doi: 10.1080/22221751.2019.1637283
162. Caires-Júnior LC, Goulart E, Melo US, Araujo BHS, Alvizi L, Soares-Schanoski A, et al. Discordant congenital Zika syndrome twins show differential in vitro viral susceptibility of neural progenitor cells. Nat Commun. (2018) 9:475. doi: 10.1038/s41467-017-02790-9
163. Zhang X, Zhivaki D, Lo-Man R. Unique aspects of the perinatal immune system. Nat Rev Immunol. (2017) 17:495–507. doi: 10.1038/nri.2017.54
164. Barthel A, Gourinat AC, Cazorla C, Joubert C, Dupont-Rouzeyrol M, Descloux E. Breast milk as a possible route of vertical transmission of dengue virus? Clin Infect Dis. (2013) 57:415–7. doi: 10.1093/cid/cit227
165. Centers for Disease Control and Prevention (CDC). Intrauterine West Nile virus infection–New York, 2002. MMWR Morb Mortal Wkly Rep. (2002) 51:1135–6.
166. Dupont-Rouzeyrol M, Biron A, O'Connor O, Huguon E, Descloux E. Infectious Zika viral particles in breastmilk. Lancet. (2016) 387:1051. doi: 10.1016/S0140-6736(16)00624-3
167. Colt S, Garcia-Casal MN, Peña-Rosas JP, Finkelstein JL, Rayco-Solon P, Weise Prinzo ZC, et al. Transmission of Zika virus through breast milk and other breastfeeding-related bodily-fluids: a systematic review. PLoS Negl Trop Dis. (2017) 11:e0005528. doi: 10.1371/journal.pntd.0005528
168. Regla-Nava JA, Viramontes KM, Vozdolska T, Huynh AT, Villani T, Gardner G, et al. Detection of Zika virus in mouse mammary gland and breast milk. PLoS Negl Trop Dis. (2019) 13:e0007080. doi: 10.1371/journal.pntd.0007080
169. Giovanetti M, Goes de Jesus J, Lima de Maia M, Junior JX, Castro Amarante MF, Viana P, et al. Genetic evidence of Zika virus in mother's breast milk and body fluids of a newborn with severe congenital defects. Clin Microbiol Infect. (2018) 24:1111–2. doi: 10.1016/j.cmi.2018.06.008
170. Sotelo JR, Sotelo AB, Sotelo FJB, Doi AM, Pinho JRR, Oliveira RC, et al. Persistence of Zika virus in breast milk after infection in late stage of pregnancy. Emerg Infect Dis. (2017) 23:856–7. doi: 10.3201/eid2305.161538
171. Brito CAA, Henriques-Souza A, Soares CRP, Castanha PMS, Machado LC, Pereira MR, et al. Persistent detection of Zika virus RNA from an infant with severe microcephaly—a case report. BMC Infect Dis. (2018) 18:388. doi: 10.1186/s12879-018-3313-4
172. Read JS, Torres-Velasquez B, Lorenzi O, Rivera Sanchez A, Torres-Torres S, Rivera LV, et al. Symptomatic Zika virus infection in infants, children, adolescents living in puerto rico. JAMA Pediatr. (2018) 172:686–93. doi: 10.1001/jamapediatrics.2018.0870
173. Goodman AB, Dziuban EJ, Powell K, Bitsko RH, Langley G, Lindsey N, et al. Characteristics of children aged <18 years with Zika virus disease acquired postnatally - states US, January 2015–July 2016. MMWR Morb Mortal Wkly Rep. (2016) 65:1082–5. doi: 10.15585/mmwr.mm6539e2
174. Griffin I, Zhang G, Fernandez D, Cordero C, Logue T, White SL, et al. Epidemiology of pediatric zika virus infections. Pediatrics. (2017) 140:e20172044. doi: 10.1542/peds.2017-2044
175. Salinas JL, Walteros DM, Styczynski A, Garzón F, Quijada H, Bravo E, et al. Zika virus disease-associated Guillain-Barré syndrome-Barranquilla, Colombia 2015–2016. J Neurol Sci. (2017) 381:272–7. doi: 10.1016/j.jns.2017.09.001
176. Prata-Barbosa A, Martins MM, Guastavino AB, Cunha AJLA. Effects of Zika infection on growth. J Pediatr. (2019) 95 (Suppl. 1):30–41. doi: 10.1016/j.jpedp.2018.10.005
177. Rice ME, Galang RR, Roth NM, Ellington SR, Moore CA, Valencia-Prado M, et al. Vital signs: Zika-associated birth defects and neurodevelopmental abnormalities possibly associated with congenital zika virus infection - territories US, and freely associated States, 2018. MMWR Morb Mortal Wkly Rep. (2018) 67:858–67. doi: 10.15585/mmwr.mm6731e1
178. Paul AM, Acharya D, Neupane B, Thompson EA, Gonzalez-Fernandez G, Copeland KM, et al. Congenital Zika virus infection in immunocompetent mice causes postnatal growth impediment and neurobehavioral deficits. Front Microbiol. (2018) 9:2028. doi: 10.3389/fmicb.2018.02028
179. Valentine GC, Seferovic MD, Fowler SW, Major AM, Gorchakov R, Berry R, et al. Timing of gestational exposure to Zika virus is associated with postnatal growth restriction in a murine model. Am J Obstet Gynecol. (2018) 219:403.e1–403.e9. doi: 10.1016/j.ajog.2018.06.005
180. Tripp RA, Ross TM. Development of a Zika vaccine. Expert Rev Vaccines. (2016) 15:1083–5. doi: 10.1080/14760584.2016.1192474
181. Alam A, Ali S, Ahamad S, Malik MZ, Ishrat R. From ZikV genome to vaccine: in silico approach for the epitope-based peptide vaccine against Zika virus envelope glycoprotein. Immunology. (2016) 149:386–99. doi: 10.1111/imm.12656
182. Sapparapu G, Fernandez E, Kose N, Bin Cao, Fox JM, Bombardi RG, et al. Neutralizing human antibodies prevent Zika virus replication and fetal disease in mice. Nature. (2016) 540:443–7. doi: 10.1038/nature20564
183. Hasan SS, Miller A, Sapparapu G, Fernandez E, Klose T, Long F, et al. A human antibody against Zika virus crosslinks the E protein to prevent infection. Nat Commun. (2017) 8:14722. doi: 10.1038/ncomms14722
184. Larocca RA, Abbink P, Peron JP, Zanotto PM, Iampietro MJ, Badamchi-Zadeh A, et al. Vaccine protection against Zika virus from Brazil. Nature. (2016) 536:474–8. doi: 10.1038/nature18952
185. Abbink P, Larocca RA, De La Barrera RA, Bricault CA, Moseley ET, Boyd M, et al. Protective efficacy of multiple vaccine platforms against Zika virus challenge in rhesus monkeys. Science. (2016) 353:1129–32. doi: 10.1126/science.aah6157
186. Pardi N, Hogan MJ, Pelc RS, Muramatsu H, Andersen H, DeMaso CR, et al. Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination. Nature. (2017) 543:248–51. doi: 10.1038/nature21428
187. Poland GA, Kennedy RB, Ovsyannikova IG, Palacios R, Ho PL, Kalil J. Development of vaccines against Zika virus. Lancet Infect Dis. (2018) 18:211–9. doi: 10.1016/S1473-3099(18)30063-X
188. Barrett ADT. Current status of Zika vaccine development: Zika vaccines advance into clinical evaluation. NPJ Vaccines. (2018) 3:24. doi: 10.1038/s41541-018-0061-9
189. WHO, World Health Organization. WHO Vaccine Pipeline Tracker. (2019). Available online at: https://www.who.int/immunization/research/vaccine__pipeline__tracker__spreadsheet/en/
190. Siegrist CA. Neonatal and early life vaccinology. Vaccine. (2001) 19:3331–46. doi: 10.1016/S0264-410X(01)00028-7
191. Kachikis A, Englund JA. Maternal immunization: optimizing protection for the mother and infant. J Infect. (2016) 72 (Suppl):S83–90. doi: 10.1016/j.jinf.2016.04.027
192. Cohen J. Zika rewrites maternal immunization ethics. Science. (2017) 357:241. doi: 10.1126/science.357.6348.241
193. Richner JM, Jagger BW, Shan C, Fontes CR, Dowd KA, Cao B, et al. Vaccine mediated protection against Zika virus-induced congenital disease. Cell. (2017) 170:273–83.e12. doi: 10.1016/j.cell.2017.06.040
194. Wang R, Liao X, Fan D, Wang L, Song J, Feng K, et al. Maternal immunization with a DNA vaccine candidate elicits specific passive protection against post-natal Zika virus infection in immunocompetent BALB/c mice. Vaccine. (2018) 36:3522–32. doi: 10.1016/j.vaccine.2018.04.051
195. Tai W, He L, Wang Y, Sun S, Zhao G, Luo C, et al. Critical neutralizing fragment of Zika virus EDIII elicits cross-neutralization and protection against divergent Zika viruses. Emerg Microbes Infect. (2018) 7:7. doi: 10.1038/s41426-017-0007-8
196. Zhu X, Li C, Afridi SK, Zu S, Xu JW, Quanquin N, et al. E90 subunit vaccine protects mice from Zika virus infection and microcephaly. Acta Neuropathol Commun. (2018) 6:77. doi: 10.1186/s40478-018-0572-7
197. Larocca RA, Mendes EA, Abbink P, Peterson RL, Martinot AJ, Iampietro MJ, et al. Adenovirus vector-based vaccines confer maternal-fetal protection against zika virus challenge in pregnant IFN-αβR. Cell Host Microbe. (2019) 26:591–600.e4. doi: 10.1016/j.chom.2019.10.001
Keywords: maternal-fetal, neonatal, Zika virus, adverse effects, congenital infections
Citation: Teixeira FME, Pietrobon AJ, Oliveira LM, Oliveira LMS and Sato MN (2020) Maternal-Fetal Interplay in Zika Virus Infection and Adverse Perinatal Outcomes. Front. Immunol. 11:175. doi: 10.3389/fimmu.2020.00175
Received: 20 September 2019; Accepted: 22 January 2020;
Published: 14 February 2020.
Edited by:
Ana Claudia Zenclussen, University Hospital Magdeburg, GermanyReviewed by:
Nabila Jabrane-Ferrat, INSERM U1043 Centre de Physiopathologie de Toulouse Purpan, FranceAmilcar Tanuri, Federal University of Rio de Janeiro, Brazil
Copyright © 2020 Teixeira, Pietrobon, Oliveira, Oliveira and Sato. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Maria Notomi Sato, marisato@usp.br