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Introduction
In 2014, a rare and mysterious disease began to be seen in newborns in Brazil. Babies afflicted with this disease had several distinctive features: severe microcephaly accompanied by neurological, developmental, and prominent skull abnormalities; decreased range of motion; and, in some cases, eye damage. The number of miscarriages and stillbirths also increased in the affected areas. The disorder spread rapidly throughout Latin America and to travelers to this region. The condition was named congenital Zika syndrome after the outbreak was found to be caused by Zika virus (ZIKV). This virus had previously been confined to eastern Africa, Southeast Asia, and some Pacific Ocean islands. The disease was originally self-resolving and typically associated with rash and painful joints, before it morphed to a severe, devastating disease of fetuses, newborns, and infants. ZIKV infection was later found also to be linked to Guillain–Barré syndrome (GBS), a rare neuromuscular condition in adults.
ZIKV is transmitted primarily by the bite of two species of mosquitoes, one of which prefers to live in close proximity to human habitations. It is also transmitted from mother to fetus and sexually long after infection. Brazil was preparing to host the Summer Olympics, and the fear of infection by attendees and their spouses overshadowed this long-anticipated event. Fortunately, the severe outbreak subsided almost as mysteriously as it had begun and concern about the infection soon disappeared from the media and from the attention of the general public, reduced again to obscurity. Since the precise factors that led to both the appearance and disappearance of this disease are unknown, the possibility of another outbreak continues to loom, especially given the wide range of the mosquito vectors in both eastern and western hemispheres and the similarity of ZIKV and dengue virus (DENV). The latter flavivirus is spread by the same mosquito vectors as ZIKV and is currently responsible for a pandemic in most parts of the world.
History
Zika virus was first reported in the Zika Forest of Uganda in 1947 among nonhuman primates, initially in a febrile sentinel rhesus macaque placed in the forest canopy. In the same year, it was also discovered in humans in Nigeria. A 1957 study detected neutralizing antibodies against ZIKV and another flavivirus, Wesselsbron virus, in 4.0% and 15.9%, respectively, of people who were tested in Mozambique. ZIKV spread across Southeast Asia in the late 1960s and 1970s and was first detected in Malaysia in 1969 and in Indonesia in 1977. In 2007, the virus had reached Yap Island of Micronesia and then was reported in French Polynesia in 2013. Although initially occurring sporadically or in small clusters, the outbreak in Yap Island was large and had a 73% infection rate for those older than 3 years, with 18% of those who were infected developing mild symptomatic illness. Disease during the Yap Island and French Polynesia outbreaks was self-resolving, characterized primarily by rash and painful joints, although it was also responsible for 42 cases of GBS in adults in the French Polynesia outbreak.
In 2014–15, ZIKV spread to the western hemisphere. Infections were then reported in Brazil, Chile, Colombia, Surinam, Guatemala, El Salvador, Mexico, Paraguay, Venezuela, and Panama, with most of the cases being in Brazil. ZIKV may have been introduced to that country during an international canoe-racing event, which included racers from the Pacific Islands. The virus also rapidly spread northward, reaching Mexico by November 2015. ZIKV was determined to have a causal relationship with what was to be named “congenital Zika syndrome” in Brazil, as evidenced by the increased incidence of this form of ZIKV-associated disease soon after its introduction into the region. In Brazil, a combination of rare exposure and rare detective criteria was seen and corroborated by epidemiologic data, meeting many of Shepard’s and Bradford Hill criteria for causality.
Travel-associated cases were then reported in other parts of southern North America. In addition to many travel-related infections, autochthonous transmission of ZIKV from infected mosquitoes to humans was seen in Brownsville, Texas, and in Miami-Dade County, Florida, in late 2016. In 2016, Florida had 1325 reported cases, more than 200 of which were reported in pregnant women. By far, most of the cases (1042) were travel related; however, 262 were due to local transmission. Nevertheless, by the end of November 2016, South Florida appeared to have eliminated local transmission. ZIKV in the western hemisphere peaked in 2016 and dropped substantially during the 2017–18 and 2018–19 seasons, despite its spread to many countries in South and Central America and Caribbean islands. Small, isolated outbreaks were also reported in other countries in Southeastern Asia and parts of Europe until 2019. No large “second wave” has occurred.
The Diseases
Mild Disease
The majority of ZIKV infections either remain asymptomatic (80%) or result in only mild disease. In the latter, the most common symptoms of Zika infection are fever, maculopapular rash, headache, muscle and joint pain, conjunctivitis, and vertigo that lasts for several days to a week.
Congenital Zika Syndrome and Other Disorders
Symptoms of congenital Zika syndrome in babies include severe microcephaly with partial collapse of the skull, intracranial calcifications, excessive and redundant scalp skin, clubfoot and other conditions related to limited range of motion of the joints and excessive muscle tone, or scarring or pigment changes in the back of the eye. These, and additional features, such as the brain overlapping the cranial sutures, a prominent occipital bone, and neurologic impairment, are consistent with fetal brain disruption sequence. The diameter of the head of babies with microcephaly is much smaller than that found in normal babies of the same sex and age. Microcephaly also leads to smaller brain size and brain tissue and may be accompanied by improper nervous system development. Babies who had been infected prior to birth may also experience damage to their eyes, including macular lesions and optic nerve abnormalities or damaged visual cortex, negatively impacting visual development, even in the absence of microcephaly. Some infected infants without signs of microcephaly at birth later develop postnatal microcephaly. Infection is additionally associated with miscarriage and stillbirth, hydranencephaly, and placental insufficiency, leading to intrauterine growth restriction. Arthrogryposis (joint contracture) is present in both arms and legs of 86% of infected children and may lead to limb paralysis.
At autopsy, fetuses with microcephaly were found to have severely reduced brain size, no cerebral gyri, severe dilation of the cerebral lateral ventricles, dystrophic calcifications in the cerebral cortex, neuronophagy, gliosis, microglial nodules, and hypoplasia of the brain stem and spinal cord. One study found that 5.8% of infants with microcephaly developed sensorineural hearing loss, mainly due to damage to the cochlea. Some of these features may be due to the observed infiltration of mononuclear cells into the central nervous system (CNS), as discussed below. In an experimental model system, infection of mouse neural progenitor cells in vitro led to apoptosis, cell-cycle arrest, and decreased progenitor cell differentiation. Astrocytes may also be heavily infected and may serve as one source of ZIKV that infects neurons. It has been suggested that treatment with nerve growth factors may be useful in the repair of damaged brain cells.
In a mouse model system, ZIKV was injected into amniotic fluid of embryonic animals in pregnant mice. A total of 86.4% ( n = 44 pups) of the injected pups survived to birth, 76.3% of which reached adulthood. As these mice entered puberty, they displayed motor incoordination and visual dysfunctions due to anatomical defects in the cerebellar cortex. Numbers of Purkinje cells were decreased, retinas were thinner, and the optic nerves were diminished. At 40 days postinfection, surviving mice had reduced body weight, brain volume, skull length, and cranial height compared to mock-injected mice. Thickness of motor, somatosensory, and visual areas was decreased, and the dentate gyrus of the hippocampus exhibited hypoplasia. The lamination of the cerebral cortex and subcortical structures, such as striatum, was not significantly affected, however, nor was the mice’s anxiety level. Arthrogryposis caused hind limb paralysis in two of the mice.
Guillain–Barré Syndrome and Neurological Disease
GBS is a rare nervous system disorder in which the immune system damages nerve cells and may result in weakness of arms and legs and paralysis that, in severe cases, affects the muscles that control breathing. These symptoms may persist for weeks to several months and, while most people fully recover, some appear to have permanent damage. The death rate is very low, however. In 1976, some people vaccinated against the H1N1 “swine flu” developed GBS. Some regions with Zika outbreaks have also experienced increased incidence of GBS in adults. Research at the Centers for Disease Control and Prevention (CDC) indicates a strong association between GBS and Zika infection. Nevertheless, very few of those infected with ZIKV develop GBS, at least in the short term. Other neurological disorders linked to ZIKV infection include myelitis, meningoencephalitis, and brain ischemia.
Other Manifestations of ZIKV Infection
Other potential consequences of infection include retro-orbital and abdominal pain, diarrhea, thrombocytopenia with disseminated intravascular coagulation and hemorrhagic complications, hepatic dysfunction, acute respiratory distress syndrome, shock, and multiorgan dysfunction syndrome. Individuals with both CNS and hemorrhagic fever manifestations have been reported in other flavivirus infections as well. Hematospermia and orchitis have also been seen in humans and may lead to male infertility.
The Virus
ZIKV Serotypes
ZIKV is related to the four DENV serotypes, yellow fever virus (YFV), and West Nile virus (WNV). ZIKV has been split into three distinct groups: two African lineages and one Asian lineage. A clinical Asian lineage isolate produced 10-fold more virus than the prototypic African strain, supporting the contention that the Asian group is more pathogenic than the African groups. The virus present in the Americas is more closely related to the Asian lineage. Puerto Rican isolates reveal significant variability in viral replication, but not in viral binding, to dendritic cells (DCs) from different donors. ZIKV infection of DCs in the Americas results in minimal cell activation. African ZIKV and Asian ZIKV differ in their replication kinetics, with the two African lineage virus groups having more rapid replication kinetics and infection magnitude and also inducing death of infected human DC. DCs, especially the Langerhans form present in the skin, are responsible for carrying ZIKV into the bloodstream, allowing systemic infection. DC death may thus slow the dispersal of the virus, giving the immune system additional time to respond to the infection, leading to their decreased pathogenicity.
ZIKV and IFN Signaling Pathways
All studied ZIKV strains of either the African or Asian lineages block type I IFN (IFN-α and IFN-β) receptor signaling through the STAT1 and STAT2 pathways. The virus inhibits phosphorylation of these two molecules and induces STAT1 degradation in the proteasome. As is the case with other related flaviviruses, the 5′ and 3′ untranslated regions of the Zika polyprotein are involved in genome cyclization and replication. NS3 also acts together with NS2B to form the protease that cleaves the ZIKV polyprotein, a viral helicase, and nucleoside 5′-triphosphatase. Cleavage of the nucleoside triphosphates, especially ATP, provides energy for viral enzymatic activity. ZIKV NS5 induces the destruction of human STAT2 through its interaction with the human E3 ubiquitin ligase seven in absentia homolog (SIAH). Acting together, NS5 and SIAH attach ubiquitin to human STAT2, thus tagging the protein for proteasomal degradation. Virus-induced removal of the STAT proteins disrupts IFN-stimulated signaling pathways, which play a major role in the ZIKV antiviral response. Other flaviviruses, including DENV, also degrade STAT2, albeit using a somewhat different pathway.
The other major IFN signaling pathway utilizes RIG-1 and innate viral RNA sensors. This pathway is unaffected by the presence of ZIKV. Moreover, the administration of a RIG-I agonist restricts ZIKV replication in DC in vitro, demonstrating the importance of the RIG-1 pathway in anti-ZIKV defense.
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