It’s hot and humid in the Zika forest. It always is. In this part of the world, wiping away sweat becomes muscle memory, the squeal of mosquitoes a constant, cacophonous presence. The forest, whose name in the local tongue means overgrown, has for millennia been left to become just that. Rain is plentiful, nearby Lake Victoria provides continuous nutrients and sunshine beats down on the lush canopies below. As the forest grew thicker and more complex, interest from the scientific community was piqued. By the 1930s, The Rockerfeller Institute began funding research into the numerous species of mosquitoes, and the infectious agents they transmitted.
It was here in 1947 that African, American and European researchers from the firmly established Yellow Fever Research Centre scaled the trees in Zika with the intention of studying the prevalence of jungle yellow fever, known to be carried by the numerous mosquitoes in the area. Their unsuspecting test subject was a caged rhesus monkey hung from the treetops. The researchers would return and establish if jungle yellow fever was circulating around Zika. What they discovered was entirely unexpected. They discovered that the monkey had fallen ill due to a previously undiscovered agent, whose identity was confirmed when serum samples from the infected macaque were injected into a series of mice, all of which fell ill in the same way.
Flying Under the Radar
Zika virus belongs to a group of viruses known as arboviruses, meaning that they spend a portion of their life cycle carried by arthropod hosts, known as vectors, that shuttle the virus between vertebrate hosts. Arboviruses have become increasingly important in the last century, with numerous agents capable of causing human disease having been discovered, including the causative agents of Dengue fever, West Nile fever and Japanese encephalitis.
The question researchers are now tasked with answering is just how Zika went from an exotic agent restricted to rural Uganda (even here it has only caused a handful of cases) to an increasingly severe pandemic, which how snow spread its way through the Pacific Islands and extensive areas of South America.
The virus has threatened to emerge from the depths of Africa before. There have been sporadic cases of Zika fever in South East Asia since 1947, but in 2007 the disease was suddenly detected in frightening numbers in the Yap Island chain in the South Pacific, highlighting a separate incursion event and the first detection of Zika infection outside of Africa and Asia. In April 2015 Zika was detected Brazil and has since spread throughout Southern and Central America, with additional cases imported into Europe and North America. It is thought that upwards of 1.5 million people have been infected in the 10 months since the outbreak was thought to have begun. Genetic analysis suggests that the virus was imported into Brazil in 2014, around the time of two major sporting events, the 2014 FIFA World Cup and Va’a World Canoeing Sprint Championships, which welcomed teams from Pacific Islands in which Zika was endemic. Its pattern of spread is highly characteristic of an emerging virus and follows the same route as another arbovirus, Chikungunya.
An Increasingly Deadly Threat
Diseases caused by arboviruses are largely the same in their basic symptoms, though some may be more severe than others. Zika, even during this epidemic, presents with largely mild symptoms including fever, aching joints, myalgia (pain felt deep in muscles), a distinctive skin rash and headache. In uncomplicated cases, the disease is mild and self-limiting; those infected recover within a week or so with appropriate rest. However, in recent months Zika has taken on an entirely new face as concerning reports of severe complications come flooding in from affected regions. Most pressing is the claim that Zika can act as a teratogen, disrupting normal foetus development.
Researchers have been scrambling to establish whether the alarming reports of microcephaly are associated with Zika infection in pregnant women. In some of the worst affected areas, such as Bahia in Brazil, rates of abnormal development are dozens of times higher than usual. This highlights one of the great challenges of working with an emerging virus – so little is known about the effects of Zika infection that it is difficult to definitively say that Zika is the cause of these cases of microcephaly. Without thorough case-control and epidemiological studies, we can only make relatively uninformed assumptions.
Zika is also proving the thinking that only mild, self-limiting disease is caused amongst those infected. Increasing numbers of complications involving the central nervous system have been reported. Most severe of these is Guillain-Barre syndrome, a life-threatening disease in which the immune system mistakes the nerves for viral molecules, destroying them and leaving the body unable to coordinate its normal functions. Patients are frequently rendered at least partially paralysed and death by asphyxiation is common. As of yet, with so little known about how Zika causes disease, we have little hope of prevented these cases before they happen or treating them when they do. When patients recover, they face an arduous rehabilitation.
A Pressing Need
With Zika proving more virulent and severe than thought possible, the need to develop effective therapies and a vaccine has become a matter of urgency, especially with the devastation caused by Ebola virus so fresh in the memory.
The problem with Zika, and indeed all emerging viruses, is that we are trying to stop the spread of something we know very little about. We need to know a great deal about a virus before effective therapies and vaccines can be developed; the precise genome of the circulating strain, or strains, the structure of the virus, how it interacts with the cells in the body, its precise life cycle (including all vectors and obligatory hosts), how the virus causes disease and the long-term effects of infection, such as whether they virus remains dormant in certain areas.
An often-unappreciated stage in vaccine development is the establishment of a vaccination strategy. Epidemics of emerging viruses tend to be short and explosive. Wide-scale preventative vaccination simply wouldn’t be cost effective and sometimes simply isn’t logistically feasible; the countries from which these viruses originate are often affected by conflict and do not have proper infrastructures in place. On the other end of the spectrum, a strategy of stockpiling a potential vaccine and rolling it out when cases arise may not be substantial to counter rapid outbreaks. These two tactics must be balanced once a potential vaccine has been researched.
With Zika spreading so rapidly, the time required to establish these things simply isn’t there. The need to stop this virus in its tracks is too great. While there are positives – sequencing the genomes of viruses isolated from patients has never been easier or faster – it is clear that additional measures have to be discussed. Archaic advice such as that given the potential mothers not to get pregnant is an indication how bare our arsenal currently stands. Increasingly, attention has been paid to the possibility of targeting the vector, the Aedes mosquito. The virus cannot spread without its arthropod vector. It is has been put forward, not for the first time with similar steps suggested to curb the spread of Malaria, that genetic modification and sterilisation of male mosquitos could curb the Aedes population. Intial models suggest that a tandem approach of vector destruction and vaccine development provides the best chance of stopping the spread of the virus.
With additional, but unconfirmed reports of the virus beginning to spread sexually and through contaminated blood, it may well be that as well as proving more deadly than first appreciated, the virus also has additional weapons in its arsenal to facilitate its spread. It is clear that Zika virus prevention is the key priority for the virology community.
An Evolving Picture
It is clear from the increasing number of new and deadly viruses that emerging viruses present one of the most pressing public health concerns. The question on many people’s lips is ‘why now?’. Why in recent years more than any other are more and more exotic agents emerging from forests and swamps and spreading around the globe?
The answer requires further examination of the question. What may seem like viruses spreading to human populations is in fact the expansion of human populations into viral hotbeds. Viruses, particularly those with a complex interaction with arthropod vectors are continually evolving in tandem in their ecological niche. However, as urban overcrowding spills out into traditionally unpopulated areas, such as the hot and humid swamps on the banks of Lake Victoria, these niches are being perturbed and from that comes emergence of ‘unimportant’ slumbering viruses. Their evolution within their ecological niches undoubtedly leads to hitherto unappreciated interactions with their vectors and mechanisms of infection. With development in the traditional homes of these viruses, such as equatorial Africa, showing no signs of slowing, nine of the twenty fastest growing cities in the world are in Africa, it is crucial that we understand the consequences of viral evolution in these delicate ecosystems.
The development of therapy is another area that requires addressing. With the number of emerging viruses only going one way, it seems less and less likely that developing a drug to target each one individually is a viable option. Instead, there is an increasing move towards developing a one-drug-fits-all approach, studying emerging and well characterised viruses alike to determine common structures and patterns of infection. Should such a similarity exist, this may be a way to target viruses that are yet to emerge.
The entire story of Zika is one centred around adaptation and evolution. It is thought that the story began around a thousand years ago, when North African villagers began to store water in their dwellings. This prompted an adaptation in Aedes mosquitos to infest these water sources and begin feeding on humans. Later, with the co-evolution of virus and vector, Zika began to circulate in these mosquitos and just like that the virus had found its new host.
It is becoming increasingly clear that these complex interactions between virus, vector and ecosystem are constantly happening. As we relentlessly expand We may not know that these viruses even exist before they begin to spread amongst our constantly expanding populations. Emerging viruses such as Zika pose new questions for the virology community that will undoubtedly influence therapy and vaccine development and the way we think about the way viruses spread.
It’s hot and humid in the Zika forest. It always is.
