Authors:
Simpson, Jordan, BS;1 Kashif, Muhammad, BS;2 Forbes, Alayna, BS;3 Mehkri, Yusuf, BS;4 Shalom, Moshe, BS5
1University of California Santa Barbara, CA, USA
2Midwestern University, Glendale, AZ, USA
3University of North Carolina at Wilmington, NC, USA
4University of Florida College of Medicine, Gainesville, FL, USA
5Tel Aviv University Sackler Faculty of Medicine, Tel Aviv, Israel
Author Contributions:
Jordan Simpson, Muhammad Kashif, and Alayna Forbes were involved with the drafting of and conception of the ideas presented in this manuscript. Yusuf Mehkri provided detailed feedback and revised the manuscript. Moshe Shalom provided oversight, detailed revisions and feedback.
Institution
Tel Aviv University, Sackler Faculty of Medicine, Tel Aviv, Israel
Abstract
Zika Virus is a zoonotic virus that is transmitted via the Aedes mosquito and has been known to cause congenital infection in fetuses of infected mothers. As such, women who are pregnant or who plan on becoming pregnant are advised to avoid travel to endemic areas and to properly protect themselves against infection. While Zika infection in adults can present asymptomatically or with nonspecific symptoms, such as fever and rash, there have been documented consequences of Congenital Zika Syndrome in infants, such as microcephaly. Recently, evidence has pointed towards a potential association between Congenital Zika Syndrome and heart defects. The goal of the present review is to review the current literature regarding congenital zika syndrome and its association with congenital heart defects. We also suggest a potential mechanism by which Congenital Zika Syndrome is associated with congenital heart defects.
Introduction
Zika virus (ZV) is a zoonotic virus that was first discovered in 1947 in the Rhesus macaque monkey, and not too long after, by 1953, cases began to be reported in humans.1,2 The first reported outbreak occurred in 2007 on the Yap Islands in Micronesia, in which 73% of the population was infected.3,4 Between 2013-2014, a ZV epidemic broke out in French Polynesia, infecting approximately 30,000 individuals.1,4 Prior to this outbreak, symptoms associated with ZV were minimal and consisted mostly of flu-like symptoms; however, during the outbreak in French Polynesia, an association between ZV and neurological symptoms, such as encephalitis, seizures, and encephalopathy, was discovered.1 In March 2015, ZV was reported in Brazil, and by 2016, the virus had spread to over 20 countries throughout the Americas.1,4 During the outbreak in Brazil, an increased incidence of microcephaly was noticed, from 0.5 in 10,000 to between 5 to 20 in 10,000 live births, and this was hypothesized to result from ZV infection.1,2,3 Almost a year later, in February 2016, the World Health Organization declared that ZV was a public health emergency due to of its effects on pregnant women and their newborns.3
Furthermore, the Centers for Disease Control and Prevention issued a travel alert, advising pregnant women against traveling to areas with ZV outbreaks. By this time, ZV was found in the amniotic fluid of pregnant women whose infants were born with microcephaly, highly suggesting vertical transmission of the virus from mother to fetus.4 Through the increasing number and size of ZV outbreaks, more clinical outcomes of ZV infection have been unveiled, including associations with Guillain-Barre Syndrome and microcephaly.1,4 Since the largest zika outbreak in 2016, cases in the US have decreased to only 74 reported cases in 2018.4
ZV is part of the Flaviviridae family and the Flavivirus genus.1 This family also includes Dengue virus, West Nile virus, and Yellow Fever virus.2 It is a non-segmented, positive-sense, single-stranded RNA virus that is icosahedral shaped and encased by an envelope2. ZV has a primate host, and is transmitted to humans via mosquito bites of Aedes mosquitoes, although transmission can also occur via blood transfusion, infected urine or saliva, vertically, and sexually1,3,5. Vertical transmission is possible at any point in pregnancy, regardless of the presence of symptoms in the mother; however, the risk of ZV induced birth defects increases when the mother is infected during the first trimester, and the risk of fetal neurological complications are lowest if ZV infection occurs during the third trimester4. Additionally, 20-40% of infected mothers transmit ZV to their offspring.
It is important to test infants with suspected congenital zika syndrome (CZS)3,4, defined as a collection of birth defects associated with infants of a ZV-infected mother6. These defects can range from mild to severe in presentation6, and it is recommended that the infant undergo molecular testing within 2 weeks of developing symptoms. Serological testing within 12 weeks of developing symptoms can also be done, although serological testing may be inaccurate due to possible cross-reactivity with other flaviviruses3,4,5. Infants with suspected CZS should undergo nucleic acid amplification testing of their blood and urine after birth4. For pregnant women exposed to the virus, ultrasound imaging is recommended between 18-22 weeks of gestation5. Further scans should be performed monthly to monitor for congenital infection3. Unfortunately, an effective vaccine or antiviral treatment has yet to be developed for ZV7.
Clinical presentation of ZV usually includes a non-specific fever, making ZV infection easily misdiagnosable1. Other symptoms may also include a pruritic skin rash, myalgia, arthralgia, fatigue, headache, and conjunctivitis2,4,7. Rarer symptoms include emesis, diarrhea, ocular erythema, weakness, and fluid retention7. Only 20-25% of infected individuals are symptomatic, and symptoms generally resolve without treatment within 2 weeks2,4,7. In rarer cases, development of Guillain-Barre Syndrome and peripheral nerve involvement have been reported2,3. ZV symptoms in pregnant women resemble those in other adults, including skin rash, conjunctivitis, myalgia, headaches, and lymphadenopathy4. Additionally, when an infected individual is pregnant, newborns may present with neurological complications and congenital defects2,3,7. It is also important to note that signs and symptoms can develop later in childhood3. While microcephaly is the most common sign of CZS, cases of congenital heart defects (CHDs) have been reported as well. The aim of the present review is to discuss what is currently known regarding CZS that presents with CHD, and to recommend that clinicians should look out for CHD when caring for infants exposed to ZV prenatally.
Zika Pathophysiology
The interaction between ZV and the immune system begins immediately, as the virus invades various cells in the initial stages of infection 14. The virus replicates in epithelial, endothelial, astrocytic, microglial, peripheral blood mononuclear, and placental cells. ZV has a broad cell tropism, and can infect human myeloid, skin, and progenitor cells of testicular, neuronal, and placental origin.18,26
The genome of ZV codes for viral proteins that can be divided into structural and non-structural groups. Structural proteins are components of the viral capsid and envelope, and include the core, pre-membrane, and envelope.38 The non-structural proteins are crucial in the replication, immunomodulation, and transactivation processes. The pre-membrane and envelope proteins help the virus in attaching to the AXL receptor, a transmembrane receptor tyrosine kinase protein, of the host cell membrane 8. Following attachment, endocytic uptake of the virus occurs followed by the uncoating of the nucleocapsid, releasing the viral RNA into the cytoplasm. The intracellular viral positive sense RNA is replicated to form a negative sense template, and then non-structural proteins form a replication complex that synthesizes positive sense RNA from the negative-sense RNA9. The endoplasmic reticulum then produces and modifies a viral polyprotein, and immature virions accumulate in the secretory vesicles and endoplasmic reticulum before they are released from the cell. The non-structural proteins, together with C-protein, cause cell cycle arrest, apoptosis, and death10. Cell culture studies demonstrated that ZV induces apoptosis in a non-cell-autonomous way through the release of cytotoxic factors, such as tumor necrosis factor α, interleukin 1β, and glutamate16.
ZV has adapted to endure in different hosts, including arthropods, particularly mosquitoes of the genus Aedes, and vertebrates, predominantly primates. The virus can infect neural stem, blood, skin, retinal, placenta, neuro-progenitor, and testicular cells11. Furthermore, the virus can also infect monocytes, enabling passage across the placental and blood-brain barriers. ZV-infected cells undergo apoptosis and necrosis, and, therefore, a prenatal infection can result in placental insufficiency and fetal brain abnormalities that may even lead to fetal loss12.
Zika virus has been associated with severe infection and adverse pregnancy outcomes13. To track pathology in brain development after exposure to in-utero ZV, Chimelli et al.13 examined central nervous system lesions in stillbirths and newborns that died no later than 48 hours after birth due to congenital ZV infection13. Pathological analysis showed that infection in the early stages of gestation directly affected neuroglial components. Despite the varying degree of histopathology, all samples showed some extent of destructive lesions and calcification. According to Mavigner et al.14, postnatal brain developmental complications that result from ZV infection include functional and structural changes in the brain, transient seizures, and delayed brain atrophy15,16.
It has also been argued that ZV shows tropism for elements of the optical system17. Miner et al.18 established that ZV caused conjunctivitis in mice, and that viral RNA could be observed in intraocular fluids. Additionally, Zhao et al.19 suggested that retinopathy may occur when retinal cells are exposed to ZV in-utero, and that Muller cells in the retina were permissive to ZV and underwent pro-inflammatory reactions when infected. Similarly, Fernandez et al.12 found that fetuses exposed to ZV in-utero had non-structural viral protein 2B in the optic nerve, choroid, and retina. Adults that present with ocular ZV infection tend to have mild or absent symptoms, and ophthalmic complications that occur in fetal stages tend to be more severe20.
In multicellular organisms, cell autonomous refers to a genetic trait where only genotypically mutant cells exhibit the mutant phenotype. On the contrary, non-autonomous is a trait where genotypically mutant cells cause other cells, irrespective of their genotype, to exhibit a mutant phenotype.30,34 For ZV, cell-autonomous impact on Nuclear Pore Complexes (NPCs) in the brain and non-cell-autonomous also add to ZV pathology21. Ho et al.22 asserted that apoptosis was observed in both infected and non-infected cortical cells in a 20-week-old fetus. Olmo et al.16 similarly carried out cell culture studies which showed that ZV induces apoptosis through a non-cell-autonomous process, by discharging cytotoxic elements, including glutamate and interleukin 1β among others. Other viral reservoirs that could lead to long-term consequences include microglia and glial cells. Notably, microglia are the primary macrophage cells in the central nervous system and are the primary target of the ZV based on the examination of human fetal brain tissue from terminated pregnancies.58 A study by Sarno et al.23 indicated that ZV replicates in human microglia cells among other cells such as placenta, endothelial and epithelial, peripheral blood mononuclear cells, and astrocyte cells. This observation was made from the assessment of fetal brain tissue in pregnancies that were terminated in a study by Lum et al24. Wang et al.25 further established that infected primary microglia can inhibit the proliferation of NPCs. The findings of these studies suggest that there are specific cell types in the nervous system that have higher susceptibility of the ZV infection and collectively contribute to the pathophysiology of the virus.
Initial studies on the transcriptional dysregulation in human neural progenitor cells in infants ZV-infected with Zika virus showed that it alters cell-cycle dynamics, protein localization, and transcription29. Ghouzzi et al30 examined whether ZV interacted with genetic risk factors that could eventually lead to microcephaly. The study identified p53 activation and confirmed it to be a hub of a ZIKV-activated gene network, and the structural C protein was shown to interact with MDM2, a protein involved in the p53 apoptosis pathway.30 In a different study, Garcez et al31, showed that ZV affected gene ontology categories such as cellular stress pathways, cellular differentiation, and cell cycles. Teng et al32 also explained that ZV infection affects genes related to microRNA biogenesis, RNA processing, and ribosomal proteins.
There has been a growing appreciation of the role RNA modification plays in cellular functions, as well as the capacity of RNA-binding proteins to contribute to the interaction between the ZV and the host cell33. It has been suggested that in the Zika genome, methyl-transferase of NS5 enables translation of viral RNA, while host methyl-transferase accelerates replication. This also enables the viral RNA to evade detection as an exogenous nucleic acid, as it uses the intracellular machinery of the host cell to facilitate translation34. More research needs to be done on the selectivity of the viral RNA to better understand the role of key meta-structures in viral replication and regulation.
According to Chavali et al35, the Musashi protein family, an RNA binding protein that regulates the translation of target mRNAs during neural development, is crucial for ZV replication. ZV directly binds to MSI1, one member of the protein group, reducing its interactions with cell cycle proteins micro-cephalin and CDK636. Other non-structural (NS) proteins include NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5 which facilitate genome replication, processing of polyproteins, and countering the host innate antiviral response9,25.
The natural, conserved degradation of cells that removes dysfunctional or unnecessary components through a lysosome dependent regulated mechanism is known as autophagy.9,34 This process significantly contributes to anti-viral and pro-viral reactions, based on the cell type. For instance, NS4 has been found to inhibit protein kinase B in targets of rapamycin as well as autophagy pathways to affect fetal NPC functions.34 Signaling by the mechanistic target of rapamycin (mTOR) kinase is crucial for cell survival and proliferation and ZV is known to hijack this pathway for their replication. Therefore, inhibition of mTOR by rapamycin results in reduction in ZV protein expression and progeny production hence reduced ZV replication and transmission. Nonetheless, assert that in human umbilical vein endothelial cells, ZV prompts autophagy40 and hence limits viral replication. In a study by Cao et al41, autophagy improved fetal and placental outcomes in mouse models, particularly for ZV transmission.
Zika In Fetuses And Embryos
CZS is estimated to affect 4-9% of infants born from ZV-positive pregnancies, with defects ranging from microcephaly to cardiological malformations42. Although much is still unknown about the route of transmission of ZV from mother to the embryo, studies have suggested several plausible methods through which the virus is able to bypass the placenta and lead to congenital infection. Miner et al18, used mice to study ZV and vertical transmission. Using placentas from female mice known to be infected with ZV, researchers were able to confirm the presence of ZV RNA in trophoblast cells, suggesting that the virus enters fetal circulation and compromises the placenta through these cells18. Bayer et al43 similarly found ZV RNA in human trophoblast cells, however, they also determined that this method of vertical transmission is only applicable during earlier stages of pregnancy as trophoblastic cells begin to produce type three interferons, which aid in fetal protection43. This suggests that in order for the virus to gain access to the fetal compartment via the trophoblastic route at later stages in pregnancy, the virus must either evade or bypass antiviral signaling43. Another study by Chen et al44 suggests that the placental lipidome is a target for viral replication. ZV alters the placental lipidome environment by enhancing neutral lipids to increase viral RNA production and produce an increased number of virions44. The researchers also found evidence that ZV uses the endoplasmic reticulum-mitochondrial junctions in cells to funnel ZV proteins into these membranes, damaging placental mitochondria in order to disrupt the placenta’s innate defense mechanisms and allow the virus easier access into the fetal chamber44.
In a study completed by Honein et al45, 26 of 442 studied pregnancies with laboratory-confirmed potential for recent ZV infection were found to have infants with birth defects potentially associated with CZS 21 of these were from live births and 5 were associated with pregnancy loss45. Of the 26 noted cases, 22 had brain abnormalities ranging from microcephaly and intracranial calcifications to brain atrophy45. The most common defect, present in 18 of the 26 cases, was microcephaly45. Eye abnormalities and hearing impairments were observed in infants without noted brain abnormalities as well45. Cortez et al46 similarly studied a group of 214 women with laboratory confirmed ZV and found brain mass loss, ventriculomegaly, cortical malformations, and colossal abnormalities to be amongst the most common findings. Cardiac defects were also found in a study by Cavalcanti et al47, who employed the use of the echocardiogram to find septal defects in 14 out of 103 subjects studied, suggesting that congenital heart disease is highly associated with CZS.
In the same study that followed 214 ZV-positive pregnant women, fetal magnetic resonance imaging and ultrasound were used to detect brain abnormalities. The mean age of the first testing was 21.92±5.5 weeks, and the mean age of the first detected brain abnormalities was 28.4±5.3 weeks46. Looking at a variety of brain abnormalities, an enlarged subarachnoid space, ventriculomegaly, and decreased brain volume were most commonly seen in this first round of imaging, with other deformations appearing slightly later46. In the study that employed the use of the electrocardiogram to find septal defects in the subjects, tests were performed at a mean age of 8.29 weeks, suggesting that septal defects in infants can be found at an earlier gestational age47. A timeline for auditory or ocular defects has yet to be explored definitively, and further research should be done to delineate the timeline for the development of these impairments45.
Heart Defects Seen With Congenital Zika Syndrome
CHDs are present in about 1% of newborns in the US, making them the most common type of birth defects48. While CHDs include about 1/3 of all congenital birth defects, the origins of heart defects are multifactorial49,50. Based on several studies conducted so far, the prevalence of CHD in infants with CZS lies between 11% and 13.5%, compared to the 1% prevalence in healthy infants47,51,52,53, 54. CHDs seen in infants with CZS include atrial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosus.
While many CHDs are asymptomatic and resolve spontaneously, some are associated with life-long complications. It is therefore essential to identify and monitor infants with CHDs55.
ASD has an estimated incidence rate of 0.056%-0.1%, and is the 3rd most common type of CHD56. Most cases are idiopathic, but some have been associated with inherited genetic mutations, fetal alcohol syndrome, and maternal cigarette smoking56. This defect results in the abnormal communication between the left and right sides of the heart, and allows for the formation of a left to right shunt56. Most ASDs have asymptomatic presentation, as the defect is small enough to restrict shunting and are discovered incidentally56. Arrais, et al51 conducted a study examining 51 patients with confirmed or probable diagnosis of CZS from the Federal University of Rio Grande do Norte between 2015-2020. They found that 13% of the patients in their study had mild CHD. Of those children with CHDs, 43% had the ASD type51. Cavalcanti, et al47 performed a retrospective analysis using echocardiograms of 103 infants with presumed CZS from Recife, Brazil, and found that 35% of patients affected with CHD had a patent ostium secundum ASD47.
VSDs are responsible for up to 40% of CHD48. They are generally defined as an opening between the ventricles, however, openings can range in size, leading to different degrees of severity57. The defect can result from the lack of complete formation of the interventricular septum, failure of fusion of atrioventricular cushions, or failure of complete septal closure50. Many VSDs present as small muscular defects that often spontaneously resolve within one year of life50. This type of defect may cause shunting of blood between the left and right ventricles57. While smaller defects are more hemodynamically restrictive, larger ones may increase blood flow to the lungs, leading to pulmonary hypertension57. In some cases, pulmonary vascular resistance becomes greater than systemic vascular resistance, causing blood to reverse in flow and travel from the right to left ventricle, a potentially fatal phenomenon known as the Eisenmenger reaction57. VSDs are typically diagnosed by the presence of a heart murmur, and by using imaging techniques such as echocardiography and color-flow Doppler interrogation57. Symptoms from this type of defect generally appear within 4-8 weeks of life. 65% of the 103 infants with presumed CZS subjects from the study conducted in Recife, Brazil had ventricular septal defects47. Most had small apical muscular VSD, and one infant had a large membranous VSD47.
In the first reported case study of a child with CZS-associated CHD, the child presented with hypoplastic left heart syndrome, along with mitral and aortic atresia, severely hypoplastic aorta, moderate tricuspid regurgitation, and moderate right ventricular dysfunction58. The Rio Grande do Norte also found that 29% of their 51 patients had small interventricular communications51. Other findings from this study included patent foramen ovale, mild pulmonary hypertension, and mild left pulmonary stenosis51. Furthermore, 43% of their patents showed persistence of small ductus arteriosus51. Santana, et al52 evaluated the echocardiograms of 18 children with probable CZS and found two patients with CHD. The CHDs were consistent with anomalous drainage of the pulmonary veins, total atrioventricular septal defect, and a persistent ductus arteriosus in one patient, and right atrial and ventricular dilation in another patient52.
For most patients, CZS-associated CHDs are not severe, and are not associated with death51,53. In the study evaluating 51 patients from Rio Grande do Norte, two children repeated their echocardiogram and had spontaneous resolution of their CHD51. Orofino, et al53 conducted a cross sectional study on infants with confirmed maternal exposure to ZV between November 2015 to January 2017, and found that the frequency of major defects was higher in infants whose mothers had a rash or infection in the second trimester of pregnancy, altered Central Nervous System imaging postnatally, or preterm deliveries53. No difference in the frequency of cardiac defects was found between infants with and without microcephaly53.
Potential Mechanism For The Development Of CHD In CZS Patients
Based on the pathophysiology of ZV, we propose that CZS-associated CHD occur due to increased endothelial compatibility with ZV. ZV enters host cells by binding to cell surface receptors, including AXL59. ZV has been shown to cross the placental barrier via use of the AXL receptor, infecting the developing fetus60, 61. By binding to AXL, ZV is able to enter the bloodstream and reach vital organs, including the heart60. It has been shown that AXL expression is significantly elevated in cardiac tissue62, suggesting that ZV preferentially binds to cardiac tissue. In addition, ZV has been shown to cause apoptosis of trophoblasts59, and a similar mechanism may lead to observed CHDs in CZS patients. Furthermore, studies have found infants with CZS to have vascular injury and fewer and more abnormally shaped capillaries, both of which prevent proper fetal growth and development59. Sequestration of fetal blood from maternal blood by trophoblast and fetal endothelial cells is usually protective60, however, disruption of these cells by ZV may provide a mechanism for ZV to reach to the fetus’s blood and spread throughout the body.
AXL also plays a role in mediating inflammatory processes59. Higher levels of inflammatory cytokines IP-10, IL-6, IL-8, VEGF, MCP-1, G-CSF, and tissue factor have been discovered in amniotic fluid of mothers infected with ZV59,63. Furthermore, ZV infection and increased levels of cytokines, and has been shown to lead to increased apoptosis of neural progenitor cells63,64. Research should be done to see if ZV triggers a similar increase in apoptosis in cardiac progenitor cells, as that can be a likely cause for the development of the CZS-associated CHD. While not yet proven, it is likely these factors directly affect the development of the fetal heart. Further studies should be conducted to fully examine and elucidate the mechanism of ZV and its association with CHDs.
Conclusion
The prevalence of CHD in infants with CZS is 11-13%, which is about 10-fold higher than in healthy counterparts around 1%47,51,52,53,54. Many of these CHDs present asymptomatically, but can potentially have long-term impacts on the patient’s heart and health. It is therefore crucial for infants with CZS to undergo a comprehensive cardiac workup to avoid overlooking a CHD and to ensure early management. As echocardiography and electrocardiograms are easily accessible in most hospitals and can detect these congenital heart defects, infants with CZS, or with suspected CZS, should undergo these screening and diagnostic tests to check for CHDs. More research should be done to further elucidate the mechanism by which congenital ZV infection may lead to CHD.
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