Zika: From Godzilla to “Science can fix it.”

It has been called “the Godzilla of infections,” a virus that attacks only the most vulnerable of humankind – unborn children in the womb. Once born, these same children face a limited life of neurological challenges caused by microcephaly or diminished skull size.

No wonder the Zika virus, which burst upon the world stage one year before Brazil hosted the 2016 Olympic Games (causing some athletes to back out), seemed the very picture of a Brazilian-made Biblical plague. The disease, believed to have originated in Uganda in the 1940s, had the potential to emerge as a global pandemic in areas warm enough to host the Aedes Aegyptii mosquito, also responsible for transmitting the less serious chikungunya and dengue fevers. It was reported in 23 other countries in the region.

But two years later, it appears those responsible for alarmist Zika headlines in the mainstream media (and perhaps some epidemiologists too) were guilty of over-reaction.

First, the Zika epidemic has been quickly brought under control in Brazil, where it never led to more than 215,000 cases, leading to no more than 5,000 babies showing symptoms of microcephaly. At a first rough count, this suggested birth defects affect only a single-digit sample of all mother-and-baby patients affected by the Zika virus.

There are solid grounds for hope, too, that an antiviral drug targeting Zika will soon be available. Already, Brazilian researchers have broken Zika’s genetic code by describing the three-dimensional structure of the NS5 protein responsible for the replication of Zika virus in infected cells — an important step towards developing an antiviral drug.

Now most importantly, new research is showing that only a tiny proportion of those unborn babies infected by the mother being exposed to Zika, will eventually exhibit microcephaly.

What may be happening is that mothers-to-be who have had prior exposure to the flu-like symptoms of dengue virus also carried by the Aedes Aegyptii mosquito, have acquired some immunity from Zika.

Either way, acquired  immunity or the discovery of Zika’s protein structure, offer hope the disease will soon be controlled.

Acquired Immunity through Dengue.

Proof that some populations have greater immunity comes from  Brazil’s São José do Rio Preto Medical School (FAMERP) in São Paulo state, where researchers monitored a group of 55 women with a confirmed diagnosis of Zika virus infection during their pregnancy.

The research was coordinated by FAMERP Professor Maurício Lacerda Nogueira. His presentation at the São Paulo School of Advanced Science in Arbovirology, has done much to dispel the lingering terror of Zika.

All the women in the FAMERP study took their pregnancies to term. The babies were born alive and no cases of microcephaly or any severe neurological alterations were identified.

“About 28% of the infants were found to have some kind of alteration at birth, such as minor brain calcifications, small lesions in brain blood vessels, unilateral hearing loss or retina damage. Some only had the virus in their organisms and displayed no symptoms. No serious neurological alterations were observed,” Nogueira said.

Comparative images of  microcephaly effect on infants. Image courtesy of  CDC

Comparative images of microcephaly effect on infants. Image courtesy of CDC

All the children included in the study would have been considered normal by health services and would not have been diagnosed as victims of Zika if they had not taken part in a research protocol, he added.

However there is no room for complacency. The pattern observed in São José do Rio Preto contrasts markedly with that observed in several states in Brazil’s Northeast region and in Rio de Janeiro, which formed the basis of another study.

A study published in the New England Journal of Medicine by researchers affiliated with the Oswaldo Cruz Foundation (FIOCRUZ) found that 39.2% of 125 pregnant women with a confirmed diagnosis of Zika virus infection in Rio de Janeiro had babies with major neurological alterations and that 7.2% did not take the pregnancy to term, resulting in a total of 46.4% with negative outcomes. Four infants were born with microcephaly, corresponding to just over 3% of the study sample.

“The Rio de Janeiro study was the first description of Zika in pregnant women,” Nogueira said. “We’re now adding a new population in a new environment, and the results are very different. We’re showing a different pattern of outcomes for Zika infection during pregnancy.”

Data from the city of Salvador, the capital of Bahia State, were also presented during the São Paulo School of Advanced Science in Arbovirology by Dr. Albert Icksang Ko, a researcher affiliated with Yale University in the United States. Ko has been working in partnership with a group at FIOCRUZ in Bahia.

Ko and collaborators monitored all births occurring at a public hospital in Salvador during November and December 2015, when the Zika epidemic peaked in the state. The study therefore also included women without a confirmed diagnosis of Zika virus infection.

Aedes Aegyptii mosquito  responsible for a trio of infectious diseases

Aedes Aegyptii mosquito responsible for a trio of infectious diseases

“We found a completely different pattern of outcomes from that observed in São José do Rio Preto. In our study, some 10% of infants were born with severe congenital alterations, including microcephaly,” Ko said.

Scientists then investigated whether there had been a viral mutation in those hotter and more tropical areas of Brazil than had been responsible for the greater virulence of Zika in Bahia than in the interior of São Paulo state.

“This hypothesis has been refuted by recent studies showing that the diversity of Zika is still negligible in the Americas,” Prof. Nogueira said. “The virus that’s circulating here in São José do Rio Preto is basically the same as the virus found in Bahia or Rio de Janeiro. So, if the difference isn’t in the virus, then it must be in the human host. Some genetic factor must be protecting certain people, or it may be prior exposure to other viruses.”

Data from Ko’s study in Bahia suggest that the presence of antibodies against dengue virus in the pregnant women who took part in the study was associated with a lower risk of microcephaly in their offspring. Further studies are needed to confirm this preliminary finding.

For Paolo Zanotto, a researcher affiliated with the University of São Paulo’s Biomedical Science Institute (ICB-USP), one of the possibilities to be investigated is the occurrence of maternal co-infection as a risk factor for microcephaly and other severe congenital alterations.

According to Zanotto, who also coordinates the Zika Virus Research Network (Rede Zika) in São Paulo: “In order to know whether there has been proportionally more microcephaly in the Northeast of Brazil than in Colombia, Central America or São José do Rio Preto, we have to determine these denominators, and to do that, we need extremely reliable serological tests,” he said.

The study performed at FAMERP was supported by FAPESP through a Thematic Project for which Nogueira is the principal investigator. You can read a detailed article by Brazilian journalist Karina Toledo reporting on the FAMERP study and the São Paulo Advanced School conference by clicking here).

Unravelling secrets of the Zika Virus.

In order to probe the chemical secrets of the Zika virus, researchers need to produce large quantities of the NS5 protein from which it is built. Protein NS5 is capable of copying the virus’ RNA thousands of times until Zika breaks through cell walls, spreading through the body. (You can read an article on this topic recently published by SciDev Net by clicking here).

The research by teams at the university of Campinas in São Paulo state and at the Institute of Physics of São Paulo University led by physicist physicist Glaucius Oliva, may one day be essential to developing new drugs with specific antiviral activity against Zika.

The Campinas team stimulated a bacterium to produce large quantities of NS5. The researchers then transformed copies of the protein into crystals and mapped the spatial location of the 9,600 atoms that form its structure.

With this data, they built a detailed computer model of the structural organisation of all atoms of the protein. The complete findings were published in Nature Communications (March 2017).

“The characterisation of the molecular structure of the NS5 will allow us a more precise definition of each molecule capable of linking with specific regions of the proteins and interrupting their activity,” says São Paulo University Oliva.
The protein is produced by viruses of the genus flavivirus, which cause diseases such as yellow fever, dengue fever and hepatitis C. Because of its crucial role for virus replication in the human body, it has long been subject to research aimed at the development of drugs that can disrupt its activity.

The main drug candidate is sofosbovir (also used against viruses of the genus flavivirus, which cause diseases such as yellow fever, dengue fever and hepatitis C), and this could quickly become a therapeutic option against the Zika virus, says Oliva.

According to a paper published earlier this year in the journal Scientific Reports, sofosbovir succeeded in halting the multiplication of the virus in tissue culture, which the study says reduces the damage caused by the Zika infection.
Biologist Guilherme Milanez, from the Institute of Biology at the State University of Campinas, believes the study may be “essential” to developing new drugs with specific antiviral activity against Zika.

“Because NS5 is produced by different flaviviruses, it is likely than a single drug [such as sofosbovir] will have antiviral activity against the dengue, hepatitis C and Zika viruses”, he pointed out.

However, Milanez warns that studies are still in the early stage of development and there is a long way to go until the final formulation of a drug.
At the same time, epidemiologists and public health specialists are gaining new tools to test for Zika in the field. In place of cumbersome, and slow serum based trials, come new electronic alternatives such as this intelligent chip able to detect Zika fomr blood samples, SFB reported on in this article.

Zika Network

Zika may have earned itself a nasty reputation as the virus that took Brazil by surprise, but now more than 30 laboratories in São Paulo state are working together to take away its sting.

The Brazilian scientist at the very centre of these initiatives is Paolo Zanotto, of the Institute of Biomedical Sciences at USP (ICB/USP). A specialist in the evolution of flaviviruses, Zanotto and colleagues have been working since November 2015 to mobilize the virologists, epidemiologists, doctors and entomologists of São Paulo and abroad to study everything possible about Zika.

In late December 2015, 32 groups from São Paulo (nearly 300 researchers) agreed to unite to investigate the virus, now known as the Zika Network. You can read a detailed article by Brazilian journalist Ricardo Zorzetto about the early days of Brazil’s battle against Zika and its scientific contributions by clicking here).

Zorzetto’s article, published January 2016 in the monthly magazine Pesquisa FAPESP, is essential reading for those interested in piecing together both the history and the forensic methods used by a dedicated team of scientists spanning disciplines, regions and nationalities.

The first case in São Paulo was detected on May 19, 2015 when the Adolfo Lutz Institute, one of Brazil’s reference laboratories for viral detection, confirmed the presence of Zika in the blood of a 52-year-old male resident of Sumaré, in the Campinas region. Another case was recorded in São José do Rio Preto, in the state’s northwest, and two more in Ribeirão Preto, in the north. “It is possible that Zika has been circulating for a few months in the state, but is not widespread,” says virologist Marcos Boulos, head of the Coordinating Bureau for Disease Control of the São Paulo State Department of Health.

In large part because it constitutes a huge domestic threat to public health in Brazil and local research councils such as FAPESP have stepped up with funding; in part because international agencies such as the Center for Diseease Control in Atlanta have committed resources and skills; but most of all thanks to the dedication and perseverance of Brazilian scientists (some of whom are named above), the threat of Zika’s emerging as a global pandemic has been largely averted.

Scientific articles and other documents
FAYE, O. et al. Molecular evolution of Zika virus during its emergence in the 20th century. PLOS Neglected Diseases. January 9, 2014.
FREIRE, C.C.M. et al. Spread of the pandemic Zika virus lineage is associated with NS1 codon usage adaptation in humans. Biorxiv.org.
ZANLUCA, C. et al. First report of autochthonous transmission of Zika virus in Brazil. Memórias do Instituto Oswaldo Cruz. June 11, 2015.
CAMPOS, G.S.; BANDEIRA, A.C.; SARDI, S.I. Zika virus outbreak, Bahia, Brazil. Emerging Infectious Diseases. October 2015.
Surveillance and response protocol to the occurrence of microcephaly related to infection by the Zika virus – http://bit.ly/1REOZ2w.

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