Etiology

Zika virus is a single-stranded RNA virus of the Flaviviridae family (genus Flavivirus ), and is related to the dengue, yellow fever, West Nile, and Japanese encephalitis viruses. [47] A 3-dimensional map of the virus structure has shown that the Zika virus is similar in structure to the West Nile virus, Japanese encephalitis virus, and Dengue virus. [48] The structure of nonstructural protein 5 (NS5) has also been reported, providing an important target for future drug therapy. [49] The complete genomes for the Asian- and African-lineage viruses have been sequenced. [50] [51] There are two major lineages: the African lineage (reported in Africa only) and the Asian lineage (reported in Asia, the Western Pacific Region, the Americas, and Cabo Verde). [26]  Phylogenetic analysis has revealed that current epidemic strains have accumulated multiple substitutions from their Asian ancestor which may make the current strains more virulent to humans. [52]

Transmission to humans is primarily through the bite of an infected Aedes species mosquito. It is most commonly transmitted by the A aegypti species which lives in tropical regions, but can also be carried by A albopictus which lives in temperate regions. [47] [53] [54] The same species of mosquito transmits the chikungunya, dengue, and West Nile viruses, although the Culex species of mosquito is the primary vector for West Nile virus. There is emerging evidence that Zika virus could also be spread by C quinquefasciatus , [55] although this has been disputed. [56] [57] [58] Nonhuman and human primates are likely to be the main reservoirs of the virus, and anthroponotic (human-to-vector-to-human) transmission occurs during outbreaks. [54]

Nonvector transmission events (e.g., perinatal, [59] in utero, [60] [61] sexual, [59] [62] [63] and transfusion transmission [64] [65] [66] ) have also been reported. [67] Transmission via platelet transfusion has been reported in Brazil. [68] Infection has been reported in a small series of hepatic and renal transplant recipients, [69] and infection with Zika was strongly suspected in a pediatric patient who developed Guillain-Barre syndrome after hematopoietic stem cell transplant in one case report. [70] Further studies are required to investigate these modes of transmission. [71]

Nearly all reported cases of sexual transmission involved vaginal or anal sex with men during, shortly before onset of, or shortly after resolution of symptomatic illness consistent with acute Zika virus infection. However, there have been 2 cases of asymptomatic male to female transmission. [72] Sexual transmission from women to their sexual partners has been reported, [73] as has male-to-male sexual transmission. [74] There is the possibility of oral transmission of the virus through semen. [75] Evidence suggests that the virus is present in semen and urine for longer periods than in blood or saliva. [76] [77] [78] A cohort study of 184 men with confirmed symptomatic infection found that Zika virus RNA was detected in 61% of semen samples collected within 30 days of symptom onset, 43% of samples collected within 31 to 60 days of symptom onset, and 21% of samples collected within 61 to 90 days of symptom onset. Less than 7% of samples had detectable levels of Zika virus RNA more than 90 days after symptom onset. [79]

Zika virus RNA has been detected in body fluids other than blood and semen, including amniotic fluid, CSF, urine, saliva, vaginal secretions, and ocular fluids; however, transmission via these body fluids has not yet been fully elucidated. [61] [80] [81] [82] [83] [84] [85] The virus may persist for up to 80 days in the blood, [86] and persists in the blood longer than plasma. [87] The virus has been detected in the genital tract of an infected woman, which may have implications for vertical transmission. [88] It has also been detected in fetal tissue. Viremia has been reported in a newborn at least 67 days after birth. [89] While the virus has been detected in breast milk, there are no reports of transmission via breastfeeding. [90]

Occupational exposure in healthcare personnel is possible via a percutaneous injury (e.g., needlestick injury) or direct contact of mucous membrane (or nonintact skin) with blood, tissue, or other body fluids that are infectious. [91]

The Centers for Disease Control and Prevention (CDC) investigated how a family contact of a patient who died of Zika virus infection in Utah became infected. The deceased patient had very high levels of circulating virus, and the family member had close contact with the patient (i.e., kissing and hugging). The mechanism of transmission remains unknown, but was likely to be from person-to-person contact with the index patient. [92]

Viremic travelers (who are often asymptomatic) have introduced the virus into countries where susceptible Aedes species mosquitoes become infected and initiate and perpetuate local transmission cycles. [93]

Possible coinfection with dengue and chikungunya viruses has been reported; however, this is yet to be confirmed. [94] [95] [96] [97] There has been a case report of triple coinfection with Zika, chikungunya, and dengue viruses. [98]

The Brazilian government is investigating whether factors other than Zika virus infection (e.g., poor hygiene, coinfection with other viruses) are involved in the development of microcephaly because there is an unexpected and uneven distribution of cases of microcephaly across Brazil. [99]

Pathophysiology

The incubation period after transmission is between 3 and 14 days. [100] The pathogenesis of infection is unclear; however, flaviviruses in general are thought to replicate initially in dendritic cells near the site of inoculation and spread to the blood and lymph nodes. [101] Viremia generally lasts up to 1 week in patients with clinical illness.

Zika virus is a neurotropic virus which has been shown to target neural progenitor cells, as well as neuronal cells at different states of maturity but to a lesser extent. [7] In one in vitro study, a strain of Zika virus was serially passaged in monkey and mosquito cells and efficiently infected human neural progenitor cells derived from induced pluripotent stem cells. Zika virus infection increased cell death and dysregulated cell-cycle progression, resulting in attenuated cell growth. [102] Another study found that the virus infects human cortical progenitor cells leading to cell death by apoptosis and autophagy. [103]

Despite mild clinical symptoms, gestational Zika virus infection is associated with fetal death, placental insufficiency, fetal growth restriction, and CNS injury. [104] Based on an average full-term gestation, the 24-week period from the peak of the Zika virus outbreak to the peak in reported microcephaly occurrence suggests that the greatest risk for microcephaly is associated with Zika virus infection during the first trimester and early in the second trimester of pregnancy. [105] However, CNS abnormalities have been reported with exposure as late as 39 weeks’ gestation. [106] A case report found that fetal microcephaly may be caused by a loss of intermediately differentiated postmigratory neurons through an apoptotic mechanism in the midgestational fetal brain. [107] It has been suggested that the germinal matrix is the principal target for the virus. [108] Mouse studies provide evidence for a direct causal link between Zika virus infection and microcephaly by causing cell-cycle arrest, apoptosis, and inhibition of neural precursor cells. [109] [110] [111] [112] It appears that the virus triggers cell behaviors that alter normal cell proliferation and survival of neural progenitor cells during critical periods of brain development. [113] The role of the placenta in fetal microcephaly is not clear but it has been hypothesized that the placenta might facilitate viral transmission to the fetus, or alternatively to contribute a damaging immune response. [114] One hypothesis is that the virus gains access to the fetal compartment by directly infecting placental cells, thereby disrupting the placental barrier. [115] There are data to suggest that for the virus to enter the fetal compartment, it must evade trophoblast-derived interferon-lambda-1. [116] Another study found that placental infection induces proliferation and prominent hyperplasia of Hofbauer cells in the chorionic villi. [117] The virus can continue to replicate in infants’ brains after birth, and can persist in the placenta for months. [118] Further studies are required to understand the full spectrum of Zika-associated congenital abnormalities and their pathogenesis, including systematic exam of fetal and neonatal autopsy tissues and placental tissue from living infants with microcephaly. [119]

A case report of Guillain-Barre syndrome developing while the Zika virus was still present in serum suggests that the virus may exert its neurotropic effects by either direct neural injury or a rapid cellular-mediated response to the virus with cross-reactivity against peripheral nerves. The neuroinvasion processes are not fully understood and further study is needed. [120] Mouse studies suggest adult neural stem cells are also vulnerable to Zika neuropathology. [121]

The presence of antibodies against other flaviviruses may enhance Zika infection, resulting in more severe infection; however, this hypothesis has only been tested in animal models so far, and further research is warranted. [122]

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