The curious case of Zika virus (by Joanna Zmurko and Joana Rocha-Pereira)

Versão em português aqui.

 Aedes aegypti is an old enemy of Brazilians.  Recently, besides dengue, chikungunya fever and zika virus are new threats related to this mosquito. The association between zica virus and microcephaly described in Brazil raised concerns:

 - How about Zika virus sexual transmission?

 - Which is the mechanism involved in microcephaly?
- Why the association of microcephaly and Zika virus was described only last year in Brazil if other countries already presented this virus in the past?

  Altogether with the increase of Zika victims, Conspiracy theories emerged with Brazilian creativity and lack of answers. Now, few Brazilian scientists are focusing on Zika virus, however our experience with this virus is scarce. 

  Thus, this post was written by Dr. Joana Zmurko and Dr. Joana Rocha Pereira, from Virology and Antiviral Research Laboratory of Prof. J. Neyts  KU Leuven, Belgium. Due to this international collaboration, post will be available in Portuguese and English versions. I strongly recommend you to add the Lab profile on facebook (search by Virology and Antiviral Research Laboratory of Prof. J. Neyts  KU Leuven). 
 Thank you very much Joana Pereira and Joana Zmurko! 

Zika virus (ZIKV) is a mosquito borne human pathogen, closely related to dengue virus, yellow fever virus, West Nile virus and Japanese encephalitis virus. The name ‘’Zika’’ comes from Ugandan ‘’Zika forest’’, where in 1947 the virus was first isolated from monkeys ¹.  It is currently well established that ZIKV has been circulating in the second part of the twentieth century time, with scientific reports of the presence of ZIKV in Africa and Asia (countries where ZIKV was reported are depicted on Fig. 1).

Countries with ZIKV. 

  This spread involved predominantly non-human primates, big mammals (such as sheep, goats, zebras )and rodents 2, and a broad spectrum of potential mosquito vector species, including Aedes aegypti 3 (the same vector of dengue). Between 1966 and 2010 sporadic ZIKV infections of humans were reported in Gabon4, Nigeria5, Senegal6, Malesia, Cambodia5and Micronesia 3 Until then, we knew that the sporadic infection with ZIKV in humans may lead to a self-limiting and relatively mild disease called Zika fever, characterized by headache, transient fever, malaise, conjunctivitis (Fig.2a) maculopapular rash (Pic. 2b and 2c) and back pain 7.

The visible symptoms of ZIKV (A) Conjunctivitis (B) Maculopapular rash on the back .Pictures are adopted from Kutsuna, S. et al. Two cases of Zika fever imported from French Polynesia to Japan, December 2013 to January 2014. Euro Surveill. 19, 1–4 (2014).

However, in the last decade ZIKV grew to a much bigger scale. In 2007, an epidemic of fever and rash associated with ZIKV was reported in Yap State, Federated States of Micronesia. In this outbreak, 185 cases of ZIKV infections were confirmed with a prevalence of anti-ZIKV antibodies in 73% of the population3. During the recent ZIKV outbreak in French Polynesia [FP] between October 2013 and February 2014 over 30 000 people suffered from Zika fever and sought medical care, demonstrating that this is a truly emerging human pathogen 8,9. In this outbreak several patients showed serious neurological complications: encephalitis, meningo-encephalitis 7,10, indicating that the emergence of ZIKV posed a threat to human health and should be taken seriously. During the outbreak of 2014 in FP, ZIKV spread to New Caledonia (with 114 autochthonous cases reported) and the Cooks Islands 3 and as of 2015 infections with ZIKV have also been reported in South and Central America: Brazil 11,12, Chile’s Easter Island and the Dominican Republic 13, Colombia, Suriname, and also in Cape Verde. In Brazil, since its first appearance in 2015, ZIKV has been reported in 18 states with the total number of cases estimated between 440 000 to 1 300 000 cases, according to the Brazilian Ministry of Health. Moreover, an increasing number of travelers feeling sick upon returning from endemic regions were diagnosed with ZIKV 14–17. Importantly, Aedes aegypti and Aedes albopictus mosquitos, the primary vectors of ZIKV, are expanding in all tropical regions of the world, in southern regions of Europe and in California, being currently present in all continents (except Antarctica).

The genus Flavivirus, to which ZIKV belongs, comprises over 70 viruses. These are also called arthropod-borne viruses, as they transmitted by mosquitos, ticks or mites which are vectors or intermediate hosts in their life cycle, while animals (primates, horses) are the final host. Human infections with these viruses are actually typically incidental, as humans are unable to replicate the virus to high enough titers to reinfect arthropods needed to continue the virus life cycle – man is a dead end host. The exceptions to this are yellow fever and dengue viruses, which still require mosquito vectors, but are well-enough adapted to humans as to not necessarily depend upon animal hosts (although both continue to have important animal transmission). The possibility of transmission by blood products has been demonstrated ¹⁸  and makes the screening for arbovirus of such products relevant in countries with autochthonous cases. Vertical transmission has been scarcely reported for dengue ¹⁹, West Nile ²⁰as well as for  ZIKV ²¹? It is surprising and interesting that  ZIKV is the first and so far only flavivirus for which a sexual transmission between humans is reported ^22,23, which poses an additional mean of flavivirus spreading. Whether this is a common mechanism of the ZIKV spread, and what viral factors contribute to this phenomena.   Another, alarming and striking feature of ZIKV is the recently reported link of ZIKV outbreaks to a spike in birth defects. This is currently happening in Brazil, where the annual rate of microcephaly has increased from 5.7 per 100.000 live births in 2014 to 99.7 per 100.000 in 2015 ^24,25ZIKA virus was reported to be found in the blood and tissues of a baby with microcephaly by the Instituto Carlos Chagas. This has lead the states such as Pernambuco and Recife (north of Brazil) to declare the state of emergency and the Ministry of Health a Public Health emergency to the national scale, recommending women and families to postpone preganancies,  when possible, due to the lack of information and until the health authorities come up with a strategy to handle exposed and potentially infected patients.

Given all facts, it seems that we currently observe the spread of yet another flavivirus (similar to dengue, West Nile or Japanese encephalitis viruses) across the globe. It has been assumed that ZIKV causes an acute and self-limiting disease without serious medical consequences. However the recent outbreaks in French Polynesia and Brazil suggest that it is an important cause of encephalitis and more cases are likely to appear.

At the moment we do not have vaccine or a specific antiviral therapy for the treatment of infections caused by ZIKV. The increasing occurrence of Zika fever highlights the need for preventive and therapeutic measures against ZIKV, together with research tools that allow for the study and development of such therapeutics. The development of a vaccine should have the best long-term solution to prevent ZIKV spread and the consequences of the disease. In addition, antiviral drugs against ZIKV should be developed. Due to the high cost of development of novel drugs, firstly the drug candidates to treat dengue disease should be tested against ZIKV (given the similarities between dengue and ZIKV) and if possible repositioned. If this approach is not successful, the development of a pan-flavivirus antiviral drug could be pursued, and would be most useful for the prophylaxis of risk populations in areas when the vector is present and/or outbreaks are ongoing.

What will we learn from the current large-scale outbreak in Brazil? For the first time the risk assessment for symptomatic infection, severe disease, vertical transmission, and even sexual transmission will be possible and (more or less) accurate. Strategies for patient handling, prevention and information to the population will need to be put in place before other outbreaks take place. Simple, fast and specific ZIKV diagnostics should be made available and an efficient surveillance network established to monitor and detect outbreaks as early as possible. The health authorities and the scientific community will certainly pain attention to ZIKV from now on. An example of this is that Zika made it into the latest list of “The most dangerous pathogens” published by the WHO.

References:

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4.           Grard, G. et al. Zika Virus in Gabon (Central Africa) - 2007: A New Threat from Aedes albopictus? PLoS Negl. Trop. Dis. 8, e2681 (2014).

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