Sunday, 31 January 2016

From nowhere to everywhere - Zika virus

It seems to have come out of nowhere, and spread like wildfire. A new virus is rampaging through Brazil and parts of the Americas, and causing major global concern. Just as Ebola finally subsided in Africa, enter Zika virus from left stage. I’ll be honest, until a couple of weeks ago, I’d never heard of Zika virus, and I’m probably not alone. So I’ve decided to put together this blog post to discuss some aspects of this virus and the current outbreak. 
Countries where Zika virus has been found - from the New York Times

To being, let’s look at the virus itself: Zika virus is a member of the Flaviviridae family, which includes the much better known dengue, West Nile and yellow fever viruses, and like these is transmitted by mosquitoes. Because no-one really cared about Zika until recently, the virus has little published scientific literature. Typing "Zika virus" into PubMed (the major search engine of academic literature) yields 155 published articles, compared to the 9198 that are returned from searching "dengue virus” (at the time of posting). However, being that we know the virus family, this already tells us a lot. Like other flaviviruses, Zika is small with a genome of just 10.8 kilobases of positive sense single stranded RNA, which can encode 10 genes. The genome being positive sense and single stranded means that once it is released into a cell, the RNA will be treated just like any other cellular, protein encoding, RNA and interact with ribosomes to produce new protein. The 10 proteins that are produced by a cell following a Zika virus infection are responsible for taking over that cell and replicating the virus so it can spread new particles to new cells. Again, as with other flaviviruses, the Zika particle is small, and has one protein, the E protein, protruding on the surface. This protein is involved with attaching to a cell and responsible for the subsequent events that culminate in release of the genome into that cell. The E protein also makes up the main target for the immune system to tackle the virus. 
The structure of a flavivirus - from ViralZone

Zika virus was first identified in 1947 from a Rhesus macaque monkey which was being used as sentinel for yellow fever. At the time, sentinel monkeys were commonly used to detect the presence of yellow fever in an area since tests for viruses weren’t quite what they are today (at the time there weren’t even cell line to use in a lab to infect with the virus to study it!). This particular monkey, Rhesus 766, developed signs of a viral infection while in the Zika forest of Uganda. Blood was taken and used to inoculate mice, all of which became sick. Virus was isolated from the brains of deceased mice, but determined to be different from yellow fever - thus Zika virus was defined. The first human cases of the viral infection were reported in 1968 from Nigeria. Zika virus then remained largely undetected outside of Africa and parts of Asia, until 2007 and 2013 which saw epidemics in Yap Island and French Polynesia, respectively. 

Zika virus generally causes very mild symptoms in human infection, if any symptoms at all - only about 25% of cases are symptomatic. For that reason, little attention had been paid to it, until recently of course. The 2013 outbreak in French Polynesia was the first real indication that Zika infection could have more serious consequences than just rash, fever, malaise, and all the other general symptoms the initial infection can cause. During the outbreak, a spike in the cases of Guillain–BarrĂ© syndrome (GBS) were reported, with 73 individuals being diagnosed with the disease. GBS results from damage to the perisperhal nervous system (i.e. not the brain or spinal cord), causing rapid onset muscle weakness, and in severe cases, can result in paralysis. GBS can be life threatening since the peripheral nervous system is responsible for controlling the muscles involved with breathing and the heart beat. This coincidence of Zika virus spread and GBS was the first indication that Zika could potentially damage the nervous system.

So that brings us to the current outbreak occurring in Brazil, where once again, there appears to be circumstantial evidence linking Zika virus to damage of the nervous system - this time in the form of microcephaly in new born infants. Microcephaly, meaning abnormal smallness of the head, can be caused by multiple factors. Other infections can be responsible, such as rubella virus, cytomegalovirus or toxoplasmosis. As can poisoning of a foetus from alcohol, mercury or radiation. Mother malnourishment and diabetes may also be linked to microcephaly. In about 15% of microcephaly cases, the infant just has a head of smaller size, but in other cases, this small head is connected with poor development of the brain which can result in developmental delays, intelligence deficits and hearing loss, as well as premature death.  
Microcephaly - from Wikipedia

In the previous paragraph you may have noticed my wording that there is circumstantial evidence linking Zika virus to microcephaly cases; it is not clear that Zika infection is responsible. However, as Zika has begun to spread in Brazil and parts of the Americas, there has been a phenomenal spike in the number of microcephaly cases. Until 2014, there were around 150-200 cases of microcephaly in Brazil each year. The birth index for Brazil is estimated at 14.72/1000 population, in a country of around 200 million, this means just under 3 million as an estimate for the number of births in Brazil each year - so cases of microcephaly were rare. However, in 2015, there were nearly 3000 microcephaly cases, with the vast majority of these being reported in the latter part of the year, right around the time Zika virus cases started to become more common.

As I’ve stated, it is still not clear that Zika virus is responsible for the rise in microcephaly cases, though it is clearly the major culprit. More time is needed to follow pregnant women and determine if they become infected with the virus during their pregnancy. However, there will still be difficulties to determine if Zika alone is responsible. The best way to confirm a Zika virus infection is to look for the viral RNA genome in the blood of patients, however, the time in which this can be done is limited to the first week of infection. After that, diagnosis relies on finding antibodies against the virus in a patient’s blood. However, these serological tests are complicated by the fact that antibodies against Zika virus can cross-react with dengue virus - making it difficult to tell which virus was truly responsible for the presence of those antibodies. That dengue virus is endemic in Brazil, and the vast majority of people are positive for antibodies against dengue, compounding the issues with truly detecting Zika virus. However, with studies now aimed at determining if Zika virus is truly responsible for microcephaly, pregnant women will be tracked much more carefully, therefore raising the prospects of being able to catch an infection in the first week where viral RNA can be used to confirm a Zika virus infection.

Finally, what can be done? The short answer is not a great deal. We currently have no antiviral drugs to tackle any flavivirus infection, let alone Zika. Work is under way around the world trying to find broad-spectrum antiviral drugs that could be used to combat infection from multiple viruses, but whether a drug intervention would be of much use in a disease that generally causes few symptoms, except in pregnant women who may be unable to take the drugs, remains unclear. A better prospect would be the development of a vaccine, but we are a long way from that. Vaccines to Ebola were starting to undergo trials towards the end of the recent West Africa outbreak, but these had been years in the making through research on Ebola. Very little study has gone into Zika virus and potential for vaccines against it. However, there is a vaccine against yellow fever virus, and one idea would be to modify this to have the E protein of Zika, instead of yellow fever. The yellow fever vaccine is one of the best vaccines we have developed, but generating a Zika vaccine, and testing it, will take many years. Making things worse is the ethical issues of testing the vaccine in the population that seem most at risk from Zika virus, pregnant women. 

For the time being, our best option may be to tackle the mosquitoes which transmit the virus. There are the basic measures of wearing clothes to cover the skin and the use of bed nets when sleeping. Additionally, clearing standing water pools, such as in flower pots, or the inside of old tires, where mosquitoes lay their eggs will help to disrupt the mosquito life cycle. And in terms of more complex measures, many tests are under way to release genetically altered male mosquitos which cannot produce viable offspring. Additionally, work on the bacteria Wolbaccia may still hold hope for reducing the risk posed by mosquitoes (this is something I’ve previously posted on). Tackling mosquitoes seems to be one of the biggest challenges we face in the coming years. The Aedes species, responsible for transmitting Zika virus also transmit dengue virus and Chikungunya virus. The Culex species transmit West Nile virus, and the Anopheles species transmit malaria. Along with global warming, the habitable zones of these mosquitoes will spread, putting more people at risk. The best way we can tackle the dangers posed by mosquitoes is through continued scientific research, both on the mosquitoes themselves, and the viruses they harbour.

The most pressing issue now for Zika virus is determining that it is indeed the virus that is causing microcephaly, and finding ways to tackle its spread by mosquitoes. 

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