The Origins and Emergence of Zika Virus, the Newest TORCH Infection: What's Old Is New Again

When the Zika virus emerged onto the global public health stage from Brazil in 2015, the West African Ebola epidemic, centered in Guinea, Sierra Leone, and Liberia, was still an active threat. Unlike Ebola virus disease, which had more than 15 minor and major outbreaks before its devastating occurrence for the first time in West Africa, the Zika virus was a previously little-known flavivirus, which was unfamiliar to the public at large and to most health care workers. A Zika virus outbreak had previously occurred on Yap Island in the Federated States of Micronesia in 2007, where it produced a relatively mild illness characterized by rash, arthralgia, and conjunctivitis, but it received scant notice.1 Six years later, the virus resurfaced, this time in French Polynesia, and subsequently spread through the Pacific to involve the Cook Islands, Vanuatu, Solomon Islands, New Caledonia, and eventually Easter Island between September 2013 and March 2014.2,3,4 This was to be the largest epidemic of Zika virus that had occurred since the initial discovery of the virus in the Zika Forest of Uganda in 1947.5 As the Zika virus spread rapidly through the French Polynesian islands, it infected an estimated 28 000 persons, representing approximately 11.5% of the Polynesian population.6,7 However, the Oceanic epidemic of the Zika virus infection did not receive much global attention, especially because the West African Ebola epidemic was increasing in severity at the same time that the Zika virus epidemic was in decline.In early 2015, a widespread illness characterized by skin rash and fever was reported to be occurring in several states of northeastern Brazil. The disease was initially thought to be the result of dengue virus infection because its symptoms resembled those of dengue fever, but testing excluded that virus as well as others. On April 29, 2015, the Bahia State Laboratory reported that patient samples tested positive for Zika virus, which was soon confirmed by polymerase chain reaction in Brazil's National Reference laboratory on May 7, 2015. On July 17, 2015, Brazil reported the occurrence of neurologic disorders associated with a history of infection, primarily from the northeastern state of Bahia. Among these reports, there were 49 cases of confirmed Guillain-Barré syndrome. In October and November of 2015, Brazil reported the occurrence of a large increase in the incidence of fetuses and infants with congenital microcephaly and other malformations, which led the Pan American Health Organization (PAHO) and the World Health Organization (WHO) to issue an epidemiologic alert to report cases of neurologic disorders including microcephaly. On December 1, 2015, PAHO and WHO issued an alert regarding the association of Zika virus infection with neurologic syndromes and congenital malformations in the Americas. As the number of fetuses and newborns with congenital microcephaly who were being reported from Brazil increased, on February 1, 2016, WHO declared that the recent association of Zika infection with clusters of microcephaly and other neurologic disorders constituted a Public Health Emergency of International Concern. After many months of intensive collaborative research, during which pathology studies had a prominent role, on April 13, 2016, the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, issued a statement that Zika virus was a cause of microcephaly and other severe fetal brain defects.8,9The most recent reports have confirmed that Zika virus is highly neurotropic, infects the placenta, is hematogenously transmitted to the developing fetus via a transplacental mechanism, and is potentially teratogenic, producing fetal malformations collectively termed the congenital Zika syndrome (CZS).10Where did the Zika virus come from? In the early decades of the 20th century, it was yellow fever, another mosquito-borne flavivirus disease, that was one of the most-feared epidemic infections in many regions of the New and Old Worlds. Yellow fever, called yellow-jack or the black vomit, had been known for several centuries, causing devastating epidemics in Europe, Africa, and South America. The yellow fever outbreak that occurred in 1793 in Philadelphia, Pennsylvania, the capital of the newly created United States, was so devastating that it caused members of the newly formed federal government (including President George Washington, Secretary of State Thomas Jefferson, and Treasury Secretary Alexander Hamilton) to flee the city, and resulted in the deaths of 9% of the city's inhabitants. Yellow fever continued to be a global scourge through the 1800s until the beginning of the 20th century. During that time, a connection between arthropods and human disease remained largely unknown, and yellow fever was believed to be spread by direct human contact.After many years of research, in 1881, Carlos J. Finlay, MD, a Cuban physician, epidemiologist, and microbiologist, first proposed that yellow fever was transmitted by a mosquito and, 1 year later, specifically by a mosquito belonging to the genus Aedes (Figure 1). His hypothesis was later proven by Walter Reed, MD, Jesse Lazear, MD, and other members of the US Army Yellow Fever Commission working in Cuba, making yellow fever the first recognized arbovirus. Following this important discovery, the recently established Rockefeller foundation (New York, New York) made the control and eradication of yellow fever an international priority. The Foundation initially undertook a comprehensive yellow fever eradication project in Mexico, which proved highly successful. Its International Health Division then established laboratories and field sites in other endemic regions of South America and, later, Africa. After World War II, the Rockefeller Foundation investigators, looking for a new location to study yellow fever transmission, came across the Zika Forest, an isolated area of dense vegetation and swampland in Eastern Uganda (ziika means overgrown in the Luganda language; the second i was dropped by Europeans). Located in the Buganda Kingdom, the 62-acre forest was situated adjacent to an inlet of Lake Victoria, approximately 15 miles (24.1 km) from the capital city of Kampala, and was a little-known area even to the people of Uganda. The Rockefeller scientific team was composed of a Scottish virologist, George W. A. Dick, MBChB, MPH, of the National Institute for Medical Research in London; Alexander J. Haddow, MBChB, DSc, a physician and entomologist from the University of Glasgow; and Stuart F. Kitchen, MD, of the Rockefeller Institute's Yellow Fever Laboratory. After their decision to establish a field site (Figure 2), they imported supplies, built cages, and constructed 120-foot (36.6-m) tall steel towers (referred to as Haddow towers after Dr Haddow who designed them) (Figure 3), where mosquitoes, birds, bats, and a variety of animals could be captured and studied. They also used captive monkeys, which were placed into 6 cages and suspended among the jackfruit and mango trees of the forest where mosquitoes bred (Figure 4). Because the feeding preferences of mosquitoes vary by the height above ground (in addition to the species and time of day), animals and collection cages could be suspended at differing heights from the steel towers (Figure 5). Termed sentinel monkeys, their blood was periodically tested for the presence of yellow fever and other arboviruses. On April 18, 1947, one of the rhesus macaques, named Rhesus 766, developed a fever of 39.7°C, about 2°C higher than reference range. The monkey was sent to the laboratory at Entebbe, Uganda, where a blood sample was taken and injected via the intracerebral and intraperitoneal routes into Swiss albino mice and, subcutaneously, into an uninfected (“clean”) rhesus macaque named Rhesus 771. The mice inoculated intraperitoneally and Rhesus 771 failed to develop symptoms; however, mice injected via the intracerebral route developed illness beginning 10 days after inoculation. A small virus (then termed a filterable agent) was recovered from brain tissue of the inoculated mice. Although Rhesus 766 never developed any symptoms, except fever, the same filterable agent was isolated from its serum. On January 11 and 12, 1948, the scientists were again trapping mosquitoes in the Haddow towers in an attempt to isolate the yellow fever virus. They homogenized 86 captured Aedes africanus mosquitoes (Figure 6), combined the ground mosquitoes with a blood-saline solution, and injected the mixture into the brains of 6 mice and, subcutaneously, into another rhesus macaque, named Rhesus 758. After 7 days, the mice “appeared inactive,” and testing revealed the same “filterable agent” that had been isolated from Rhesus 766.5 Although Rhesus 758 never developed signs of illness, its serum produced illness and death when injected intracerebrally into uninfected mice. The Rockefeller team named their “hitherto unrecorded virus” the Zika virus.5,11–15 In view of the recent autopsy pathology findings from microcephalic fetuses and infants infected with Zika virus,16 an interesting and unusually prophetic conclusion from Dr Dick is his statement that “Zika virus is highly neurotropic in mice and no virus has been recovered from tissues other than the brains of infected mice.”17How did the term TORCH originate? In the 1960s, diagnosis based upon the clinical evaluation of neonates with suspected congenital infections was challenging. Because many of the infectious agents that are transmitted from mothers to their infants produce little or no maternal morbidity and fetal and neonatal infections were clinically indistinguishable from one another, it could be difficult to make a reliable diagnosis of a specific infectious etiology. At that time, prenatal diagnostic methods, such as amniocentesis, were risky and not highly effective; laboratory testing was largely based on serologic methods, microbiologic cultures, and pathology studies, including direct visualization of the agent by light and electron microscopy; and some antibody-based methods (no molecular- or gene-based testing was yet available). Charles Alford, MD, a renowned pioneer in pediatric infectious diseases and congenital infections, stated in 1967, “neonatal diagnoses of infections acquired in utero, natally and postnatally, are inherently difficult.”18 Arguably, the most severe epidemic of a congenital infection occurring during that period was that of the rubella virus outbreak that travelled from Europe and swept through the United States in 1964 and 1965. Occurring as it did before the advent of the rubella vaccine, there were 12.5 million new cases reported. Among these, approximately 50 000 pregnant women were exposed to the virus; it affected 1% of all pregnancies in the United States. Rubella infections occurring in pregnancy resulted in 20 000 children born with congenital rubella syndrome (CRS), of whom, 11 000 were deaf, 3500 were blind, and 1800 had intellectual disabilities. In addition, there were 2100 neonatal deaths and 11 000 abortions.19–22 In addition to rubella, congenital infections caused by cytomegalovirus, toxoplasmosis, and herpes simplex virus were recognized as public health problems among pregnant mothers and their infants, but it was difficult to differentiate one virus from another clinically.Recognizing this situation, in 1971, a group of investigators in Atlanta, Georgia, led by Andre Nahmias, MD, developed an acronym to identify 4 of the most-frequent causes of vertically transmitted infections that were recognized at that time. The acronym that they devised—TORCH—represented TOxoplasma, Rubella virus, Cytomegalovirus, and the 2 Herpes simplex viruses (type 1 and type 2).23 After the introduction of this acronym into the medical literature, it was later modified to reflect the occurrence of additional congenital infections that had potentially serious consequences to the fetus and neonate. Thus, the O of TOxoplasma was changed to represent Other infections.As the term TORCH became accepted generally in the medical and, in particular, pediatrics and infectious disease medical communities, several proposals for modifying the term arose. In 1975, Harold T. Fuerst, MD, found it “particularly distressing” that an important infectious agent had been omitted from the acronym originally developed by Dr Nahmias and colleagues 4 years previously. Dr Fuerst was the first to suggest revising the term; he suggested the term STORCH to include syphilis, an important cause of congenital infections and perinatal morbidity and mortality. STORCH was German for stork, which Fuerst believed to be “highly suitable.”24 The following year, Roger Brumback, MD, proposed another modification; he suggested that the term TORCHES (TOxoplasmosis, Rubella, Cytomegalovirus, HErpes, Syphilis) be used because pediatricians were already becoming familiar with the concept of TORCH infections.25 Through the succeeding decades, increasing progress in the recognition and diagnosis of congenitally acquired infections has resulted in the O representing a number of Other infections. Since 1971, the spectrum of pathogens considered to be TORCH agents has greatly expanded.26 Before the current Zika epidemic, a listing of TORCH agents would include such pathogens as syphilis, parvovirus, coxsackievirus, listeriosis, and, in some cases, hepatitis, varicella-zoster virus, Trypanosoma cruzi, enteroviruses, and HIV.Despite the ever-increasing spectrum of congenital infectious diseases, 45 years after its initial publication, the acronym originally proposed—TORCH—continues to be the preferred term to represent all these vertically transmitted infections.Exactly what is a TORCH infection? Although there is no universal definition of what constitutes a TORCH infection, it is clear that the various descriptions used for this term have many factors in common. The agents of TORCH infections all can infect women during pregnancy; typically, but not always, they are present in the maternal bloodstream as a viremia, bacteremia, or parasitemia, and often do not produce significant disease or even symptoms in the mother. They are also characterized by vertical transmission to the fetus, most often hematogenously, through the placenta before delivery or, less often, via the birth canal around the time of labor and delivery. Following fetal infection, TORCH agents can cause a variety of potentially severe complications, which can include microcephaly, multiorgan disease, congenital malformations, and intrauterine growth restriction. The TORCH agents can also cause miscarriages, stillbirths, and neonatal deaths. Several TORCH infections have a predilection for the central nervous system, causing severe pathologic changes in the brain that can result in neurologic, sensorial, and developmental abnormalities.27,28When transmitted from the maternal bloodstream to the fetus through the placenta, most TORCH agents result in recognizable placental abnormalities. These include the presence of acute, granulomatous or chronic villitis, intervillositis, intervillous microabscesses, viral inclusions, villous endothelial cell abnormalities, villous necrosis, avascular villi, or necrotizing inflammation involving the villi, placental membranes, or umbilical vessels.29–31 Examination of placentas from second- and third-trimester infants having congenital Zika virus infection have shown a different pathologic spectrum.32 Villitis, which is the histologic hallmark of a maternal hematogenously transmitted infection, has not been a microscopic feature in placentas of fetuses with congenital Zika virus infection.32 Inflammatory lesions of the umbilical cord (funisitis) and placental membranes (chorioamnionitis), characteristically the result of an ascending infection arising from the maternal cervicovaginal canal, are (as expected) similarly not a feature of congenital Zika virus infection. Thus, there is no evidence of a maternal inflammatory response or a fetal inflammatory response in second- and third-trimester placentas from fetuses with microcephaly that have been examined thus far. There is also an absence of necrosis directly attributable to Zika virus infection in any placental structure.32Similar to placentas from infants with some congenital TORCH infections, placentas from second- and third-trimester infants with Zika virus infection demonstrate increased numbers of Hofbauer cells within the stroma of chorionic villi.32,33 Some Hofbauer cells have been demonstrated to still be in the proliferation phase of the cell cycle,32 indicating the terminal phase of a hyperplastic response to transplacental Zika virus infection by these fetal-derived macrophages. The Zika virus has been shown to be present in the chorionic villi in placentas from infected fetuses, where the virus has been localized within Hofbauer cells using both nucleic acid32 and antigenic33 techniques. These findings from naturally infected human placentas are consistent with a recent report in which Hofbauer cells have been shown experimentally to be permissive to Zika virus replication in isolated cultures in vivo and infected with Zika virus ex vivo in chorionic villous explants.34Is the Zika virus a TORCH agent? The clinical and pathologic spectra of the effects of Zika virus infection on the developing fetus continue to expand. Zika virus infection occurring in pregnant women and their fetuses satisfies all of the characteristics of a TORCH agent—it is transmitted vertically during pregnancy from mothers who have mild or absent symptoms, it infects the placenta,32,33,35 and after intrauterine fetal infection can produce poor obstetric outcomes, including microcephaly and other fetal malformations.10,16When compared with previously recognized TORCH agents, Zika virus appears most similar to the rubella virus, which was the prototypical TORCH virus. When occurring in nongravid persons, both rubella and Zika viruses may by asymptomatic or can produce a mild illness characterized by a rash. The most serious consequences of both viruses occur when pregnant women rubella and Zika viruses are and produce a syndrome of fetal and the and brain lesions are of the syndromes produced by both There are also in the of maternal infection and for of fetal malformations in these In the of rubella, the most important the transplacental transmission and severity of fetal infection is the at which a maternal infection first Although fetal infection with rubella can occur at any time during the of fetal infection and of the with maternal infection occurring at an The in to of fetuses when maternal infection before 11 of to between 11 and at to at 15 to and after of This between maternal infection occurring in being associated with a of fetal infection and is recently being recognized for Zika virus, their In one the of fetal microcephaly by the Zika virus was found to with maternal viral infection occurring at approximately in but later than malformations caused by In a study from found that the for the of microcephaly was when Zika infection occurred in the first of They estimated that the of having a fetus with microcephaly from approximately 1% to when a developed Zika virus infection during the first There was for of the when maternal infection developed in the second and and especially the congenital syndrome associated with was a major public health the before the in of in the United State and rubella, most often in with has both the acquired and congenital of the disease from some including the United States. In April 2015, the WHO of the was declared the first in the to be of endemic rubella to rubella, the occurrence of the congenital syndrome is also a in because of the widespread of the can be as a for a TORCH virus that has been through the widespread of an is with the of an for Zika virus, the same be for mothers and their infants in this of the TORCH infections from causing fetal infection, congenital malformations, and in the and of the at the University of for in the from the Alexander Haddow also of the of Laboratory for and in to this Zika virus issue of the