Zika virus poses a significant risk to the worldwide population. The mosquito-borne flavivirus has long fascinated the medical community, particularly in the year 2016 as it came to the fore, spreading rapidly and causing symptoms previously not recognised. Since its discovery in 1947, Zika virus has progressed from causing relatively mild illness in regions of Africa to becoming a worldwide epidemic with severe consequences for many infected individuals. Zika virus is now known to cause congenital abnormalities such as microcephaly as well as neurological disease in adults. The mechanisms by which Zika virus elicits its effects are not yet fully understood, though congenital abnormalities indicate the possibility of vertical transmission from mother to child, and evidence shows that the virus may be sexually transmitted. In many ways, Zika virus has defied expectations and confounded researchers, breaking many of the so-called “rules” and pre-conceived notions that we have regarding viruses. This article further explores the history, pathophysiology, and mechanisms of transmission of Zika virus, as well as summarises the ongoing research and current recommendations regarding prevention.

Introduction

Zika virus is an arbovirus primarily transmitted by mosquitoes between human or animal hosts. It is classified as a flavivirus, a genus comprised of over 70 viruses, many of which are common and potentially deadly human pathogens causing infections such as Dengue fever, Japanese encephalitis, and yellow fever [1].

A brief history

Zika virus was first identified in 1947 in the Zika forest of Uganda. Researchers placed rhesus monkeys in cages suspended in the canopy of the forest for the express purpose of being bitten by mosquitoes. In April 1947, one monkey came down with a fever which, according to a blood test, could not be attributed to any of the previously identified arboviruses such as yellow fever virus or dengue virus [2]. Thus, a new virus was discovered, and named after the forest from which it came.

Zika virus was not identified in a human subject until 1952 [3]. In 1954, a ten-year-old Nigerian girl experienced headache and fever, but no more serious symptoms. Results of blood tests from members of the girl’s village showed that 60% of the population had antibodies to Zika virus, and therefore must have previously been infected [4].

Despite only 14 reported cases of human Zika virus between 1947 and 2007, it is theorised that Zika virus has been endemic in African populations for thousands of years, existing as a relatively mild illness [5].

The first indication that Zika virus was spreading was in 2007 when the Pacific Island of Yap, part of the Federated States of Micronesia, experienced a large outbreak. 73% of the population became infected over the course of six months, but again experienced only mild influenza-like symptoms [6].

This outbreak is likely explained by a lack of immunity on the island of Yap, allowing a huge proportion of the population to become ill quickly upon exposure to the pathogen. African populations were consistently exposed, leading to sporadic rather than epidemic patterns of disease. Furthermore, it is possible that the clinical similarity between Zika virus and a variety of other arboviruses such as yellow fever virus and dengue virus led to a lack of reporting of previous outbreaks.

French Polynesia was the next area to be hit by a major outbreak in 2013. Ten percent of the population, approximately 30,000 people, were infected with Zika virus. This time, however, doctors noticed an unusual increase in the incidence of Guillain-Barré Syndrome (GBS), an autoimmune disorder attacking the peripheral nervous system and resulting in acute peripheral neuropathy, paralysis, and paresis [7]. The incidence rate was 20 times greater than expected [8], and the temporal and spatial association with the Zika virus outbreak could not be ignored.

The first locally acquired cases of Zika virus occurring in the Americas were reported in Brazil in May of 2015, but it was not until later in the year that more serious side effects began to be noticed. There was an increase in the number of patients with GBS post-infection, as could be expected following evidence from the French Polynesian outbreak, but an even more unusual pattern of complications also arose.

Approximately eight to nine months after the first cases of Zika virus, paediatricians and obstetricians working with new-borns were seeing far more babies with microcephaly than they ever had before. In an example of the importance of open communication between physicians, doctors throughout Brazil consulted one another and made the connection between Zika virus and microcephaly [9]. Subtler birth defects were also seen, such as cerebral calcifications, ventricular enlargement, spasticity, eye defects, and growth restriction, all of which are indicative of abnormal CNS development [10].

One main question for researchers remained: why is what was thought to be a mild virus suddenly spreading and causing severe complications not previously seen? Several factors contribute to this unusual epidemiological pattern. In the areas in Africa where Zika virus is endemic, most girls are infected as children, prior to puberty and before they become pregnant. Thus, they are immune by the time they are having children. Foetuses are therefore not exposed to the pathogen and the congenital complications seen elsewhere are not present. Furthermore, because of the spread to non-immune populations, there are simply more cases now than have ever been reported before, allowing for clearer correlation between cause and effect.

pathophysiology and transmission

Flaviviruses such as Zika virus are single stranded, non-segmented, positive-sense RNA viruses. The envelope protein surrounding the virion can bind to receptors on host cells and allow internalisation of the virus. Once within the cell, the viral RNA is released and endogenous mechanisms are utilised to replicate and produce further virions. These virions are then exocytosed to further the infection [11]. Unlike many DNA viruses such as HIV or herpes viruses, Zika virus does not integrate into the host genetic material or form viral reservoirs. This means the virus can be completely eradicated by the immune system or by antiviral treatment.

Transmission of Zika virus is typically vector-borne following a bite from an infected mosquito. On infection, 80% of healthy adults are asymptomatic, while the remaining 20% experience fever, rash, joint pain, myalgia, and headaches which subside after a few days [12].

As mentioned previously, a rare but serious side effect of Zika virus infection is Guillain-Barré Syndrome. Scientists do not yet fully understand the mechanisms underlying the development of GBS in patients with Zika virus, but it is possible that the virus contains peptides which bear significant resemblance to those in the host, leading to cross-reactivity and autoimmune destruction of host tissue [12]. In this case, the host tissue affected is the myelin sheath of the peripheral nervous system.

Zika virus may also cross the placental barrier and gain access to the intra-uterine environment, resulting in maternal-foetal transmission. In fact, due to the placental tropism of Zika virus, concentrations of Zika virus RNA were found to be 1000 times greater in the placenta of mice than in maternal serum. Zika virus induces apoptosis of trophoblast cells, causing a smaller placenta and compromising the placental barrier, thus permitting foetal infection. Placental insufficiency and malformed placental vasculature can result in decreased foetal growth, commonly seen in Zika virus infected pregnancies [13].

Infected pregnant women may experience the same symptoms as their non-pregnant counterparts, but the consequences of infection are much more serious for the developing foetus. As described previously, Zika virus outbreaks have been closely associated with an increase in the incidence of microcephaly and a number of other congenital abnormalities. Zika virus is neurotropic, meaning it preferentially targets the nervous system. In particular, the virus has been shown to inhibit the proliferation of human cortical neural progenitor cells [14].

Mouse models have shown that Zika virus upregulates genes involved in immunity and apoptosis, while pathways involved in cell proliferation, differentiation, and organ development were downregulated, many of which involve specific genes associated with microcephaly [15].

The neurotropic effects of Zika virus within the foetal brain could explain the consequential congenital syndrome post-infection, though microcephaly is thought to be multifactorial in causation, and may also be related to cross-reactivity and autoimmunity. The severity of the congenital syndrome varies according to the gestational age at which Zika virus is contracted, with the more serious cases occurring earlier in pregnancy [13].

The Zika virion can interact with AXL, a receptor tyrosine kinase found on the surface of human radial glial cells, cortical astrocytes, and microglia. AXL has been shown to increase in the brain tissue of foetal mice infected with Zika virus, indicating that it may provide a means of entry for the virions into the host cell. Similarly, toll-like receptor 3 (TLR3) is upregulated in the brain tissue of infected mice [15]. Zika virus may activate TLR3 in the CNS, leading to inhibition of Sonic Hedgehog and Ras-ERK signalling pathways which will cause an increase in apoptosis [16]. AXL expression is also increased in the developing retina, which may account for the optic defects seen in congenital Zika virus [17].

Zika virus may also be transmitted sexually. Two male American scientists conducting research in Senegal contracted Zika virus in 2008 and were symptomatic on returning home, with one of the scientists having haematospermia. Subsequently, his wife became ill, with classic symptoms of Zika virus infection. The wife had not been present in Senegal, nor had she travelled anywhere else where Zika virus might have been present. At the time, the climate at the patients’ home was not permissive to vector-borne transmission dynamics. Direct contact or exchange of non-sexual body fluids could be ruled out, as the children of the scientists did not become infected. Further, the couple reported having vaginal intercourse one day after the male’s return home [18]. Thus, sexual transmission was ruled the most likely method. Prior to this, there had never been a report of sexual transmission of an arbovirus.

Since 2008, many more cases of sexual transmission of Zika virus have been reported. In the 2013 outbreak in French Polynesia, a man experienced hematospermia approximately two weeks post-infection with Zika virus. Despite his blood containing no detectable Zika virus, there was a high load of Zika virus RNA found in semen samples [19]. In fact, one study found that Zika virus persisted in the semen for at least 62 days after the patient was symptomatic [20]. This indicates that sexual transmission may occur for a prolonged period post-infection. The current recommendation is that men who may have contracted Zika virus should wait six months before having unprotected sex [21].

Thus far, all reported cases of sexual transmission have been either male-to-female or male-to-male. One study analysed cervical mucous samples of a woman with Zika virus infection, and found that Zika virus was present in her genital tract at least 11 days after the onset of symptoms, again despite negative results on urine and blood samples [22]. This suggests the possibility of female-to-male sexual transmission.

recommendations and research

Since the Brazilian epidemic in 2015, Zika virus has continued to spread rapidly across the world. To date, 69 countries have reported evidence of mosquito borne Zika virus transmission. 13 countries have reported person-to-person transmission, 29 reported microcephaly and congenital neural malformations, and 21 countries reported an increase in the incidence of GBS [23]. Research continues, and there are still many unanswered questions. At present, the Centres for Disease Control and Prevention have made a number of recommendations based on the currently available evidence.

There is currently no vaccine available against Zika virus, so prevention relies upon safe practice by the population. Persons should avoid mosquito bites by using insect repellent, wearing long-sleeved shirts and long trousers, and using mosquito netting [24]. In order to prevent sexual transmission, men who have travelled to areas with Zika virus should use condoms or not have sex for six months after travel, and women for eight weeks after travel. If living in an area with Zika virus, persons should use condoms or not have sex for the entire time that Zika virus is present [21]. Pregnant women or couples planning on becoming pregnant should avoid travelling to areas with Zika virus transmission if possible, and women should wait eight weeks after infection before attempting pregnancy [25].

Research is currently focused on risk assessment, management, and prevention of Zika virus. Many longitudinal cohort studies are being conducted to assess the long term effects of Zika virus infection [26], and 31 vaccines are in development [27].

conclusion

There is no denying the significant risk that Zika virus poses to the worldwide population. It is a virus with a fascinating history of scientific discovery and is a prime example of the importance of the pursuit of information and openness to new findings. The speed with which Zika virus spread in the past few years has been matched by the huge gains of knowledge made by researchers and physicians across the globe. It is hoped that in the coming years, as we conduct further investigations and new information comes to light, we will be able to control and manage Zika virus.

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