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Zika virus infections and their consequences

Infections caused by mosquito-borne Zika viruses during pregnancy can lead to severe brain defects in babies. The European Union has provided funding of around ten million euros for an international research programme on Zika virus infections in which the University Hospital of Heidelberg plays a key role.

Three-dimensional reconstruction of the Zika virus replication factories in infected human cells. Zika virus infection induces invaginations in the membrane of the endoplasmic reticulum (blue), which look like small bubbles. The Zika virus genome replicates in these membrane vesicles. New Zika virus particles (brown spheres) form in the immediate vicinity of these membrane vesicles and are released from the cell. © Mirko Cortese and Prof. Dr. Ralf Bartenschlager, Molecular Virology, Centre for Infectious Diseases, University Hospital Heidelberg

In October 2015, the Brazilian government alarmed the world with an announcement that Zika virus infections had assumed epidemic dimensions in Brazil. Zika virus infections were suspected to be the cause of the enhanced incidence of severe brain malformations (microcephaly) in newborn babies. On February 1, 2016, the World Health Organisation declared Zika infections that were associated with microcephaly and other neurological diseases such as the Guillain-Barré syndrome a “Public Health Emergency of International Concern”. This declaration applied for a period of ten months. At the time, locally transmitted Zika infections had already been reported by more than 20 countries in the Americas. There was also a Zika virus infection epidemic involving thousands of people on the Cape Verde islands off the West African coast. Isolated cases spread by international air traffic were reported in many other countries, including Germany. For some time, Zika was seen as a new and insidious epidemic and was widely covered by the media; the authorities even considered postponing the 2016 Summer Olympic Games in Brazil. However, when it became apparent that the epidemic would not spread to Europe, media and public interest in the virus quickly died down.

In June 2017 it was reported that the European Union (EU) had allocated around 10 million euros for a multidisciplinary, multinational research consortium called ZIKAlliance (Global Alliance for the Control and Prevention of the Zika Virus). A timely reminder that the aforementioned dangers have not yet gone away and that the answers to many important questions are still elusive.

Heidelberg as a centre of Zika research

Dr. med. Thomas Jänisch, PhD, Division of Clinical Tropical Medicine, Centre for Infectious Diseases at the University Hospital of Heidelberg. © Dr. med. Thomas Jänisch, PhD, Universitätsklinikum Heidelberg

The Centre for Infectious Diseases at the Heidelberg University Hospital is investigating these issues. The University Hospital is part of the aforementioned EU-funded research consortium and is recognised as an international centre for research into Zika virus infections. The funding recognises that "Heidelberg has already carried out important preliminary work and become part of international networks of research into related viruses, such as the dengue virus," as the tropical medicine specialist and epidemiologist Dr. med. Thomas Jänisch, PhD, from the Division of Clinical Tropical Medicine explains. Jänisch is coordinating two work packages in the ZIKAlliance consortium, having previously coordinated two dengue virus consortia at the University Hospital of Heidelberg.1

Cofactors that trigger the development of brain malformations

As part of a dengue research group that Jänisch headed up, the scientist and his colleagues were active in the north-east of Brazil at the time the Zika epidemic broke out. From a very early stage, Jänisch focused on assessing the actual risk of developing microcephaly and other malformations for babies carried by women who became infected with Zika virus during pregnancy. This involved the scientists carrying out an analysis of the numbers reported by the Brazilian government.

Jänisch noticed that there were huge, unresolved differences between different regions in Brazil. In a report published in the World Health Organisation’s bulletin in early 2017, the researchers documented a relatively high risk in the north-east of Brazil compared to a lower risk of infection with the Zira virus in the state of Rio de Janeiro, both of which suffered Zika epidemics at the same time. From this data, Jänisch and his colleagues concluded that hitherto unknown factors that enhanced Zika virus infection must exist and that these factors played a key role in why one region suffered epidemic outbreaks while the other did not. “We are already investigating some factors that seem to enhance Zika virus infection. People who have previously been infected with the dengue virus might have a different immune response from people who were not. Large-scale EU-funded projects involving pregnant women will therefore also take into account past dengue virus infections using data obtained with serological examinations.

Prof. Dr. Ralf Bartenschlager, Molecular Virology, Centre for Infectious Diseases at the University Hospital of Heidelberg. © Prof. Dr. Ralf Bartenschlager, Universitätsklinikum Heidelberg

Jänisch and his colleagues from the Heidelberg University Hospital have been able to acquire additional research funds from the German Centre for Infection Research (DZIF). The interdisciplinary research project "ZIKAPath" (Clinical and Molecular Investigation of Zika Virus Pathogenesis) aims to identify the key factors of Zika virus pathogenesis and to understand their mode of action. This work is being carried out in cooperation with renowned university partners in Germany and Brazil. Amongst other things, the project partners analyse the blood samples of infected people from different regions in Brazil in the hope of finding out whether an antibody-dependent enhancement (ADE) of the infection increases the risk of malformations. For these investigations, Ralf Bartenschlager and his team in the Department of Molecular Virology use Zika virus and dengue virus cell culture models that were developed in the Centre for Infectious Diseases at the University Hospital of Heidelberg. Bartenschlager has received a number of awards for his research into the hepatitis C virus and the development of antiviral drugs. The cell culture models used are suitable for carrying out detailed investigations of the molecular and cellular changes associated with a Zika infection, and for comparing Zika virus infections with dengue virus infections, for example. These model systems are also important for gaining an in-depth understanding of the antibody-induced inhibition or enhancement of viral infections. This knowledge is crucial for the development of a vaccine against the Zika virus. As part of the ZIKAPath project, new antiviral drugs will be tested in vitro and vivo in preclinical model systems at the Helmholtz Centre for Infection Research in Braunschweig.

The spread of the Zika virus and its vectors

The Zika virus is a mosquito-borne RNA virus from the Flaviviridae family which includes, amongst others, the yellow fever virus, dengue virus and West Nile virus. The Zika virus was discovered in a captive rhesus monkey in the Zika Forest in Uganda. The virus was later also isolated from Aedes africanus mosquitoes found in the same forest. In the following decades, infections in humans, which were generally mild, were observed in many countries in Africa and Southern Asia. However, up until 2007 interest in the Zika virus remained relatively low. This was the year when the first epidemic caused by Zika viruses occurred on the Pacific island of Yap. Six years later, a large number of people from French Polynesia infected with the Zika virus also developed the Guillain-Barré syndrome, a disorder characterised by the inflammation of the nervous system. The first report of a Zika virus infection in Brazil dates from May 2015; some time later, a connection with the Guillain-Barré syndrome and eventually also with newborn microcephaly was found. Since then, Zika virus infections have spread through many countries in tropical America and across the Atlantic to the Cape Verde islands.

The yellow fever mosquito Aedes aegypti is the major Zika virus vector in Brazil. The mosquito cannot survive in our comparatively cold winters. An epidemic is therefore unlikely in Europe. The first Zika virus infection case (Hamburg, 2013) was introduced from the tropics. The same applies to subsequent isolated cases. These days, Aedes aegypti is found throughout the southern states of the USA and on the Portuguese Atlantic island of Madeira (which suffered a dengue fever outbreak affecting several thousand people in 2012), where concern that a Zika virus epidemic could occur is quite high. However, the danger of a Zika virus epidemic occurring in Germany should not be dismissed. A species closely related to the yellow fever mosquito, the Asian tiger mosquito Aedes albopictus, is making its way from Greece and Italy into Central Europe. Some Aedes albopictus colonies that are able to overwinter in this area have already been documented in Southwest Germany. Aedes albopictus can also transfer Zika and dengue viruses, but less effectively than Aedes aegypti. Jänisch therefore pointed out that the EU research funds are not only an excellent investment for helping people in South America, but also for preventing Zika virus outbreaks in Europe.

Further reading:

1 BIOPRO article: https://www.gesundheitsindustrie-bw.de/en/article/news/dengue-fever-the-neglected-infectious-disease/

Jaenisch T, Rosenberger KD, Brito C, Brady O, Brasil P, Marques ETA: Risk of microcephaly after Zika virus infection in Brazil, 2015 to 2016. Bull World Health Organ 2017; 95:191-198. doi:http://dx.doi.org/10.2471/BLT.16.178608

Cortese M, Goellner S, Acosta EG, Neufeldt CJ, Oleksiuk O, Lamppe M, Haselmann U, Funaya C, Schieber N, Ronchi P, Schorb M, Pruunsild P, Schwab Y, Chatel-Chaix L, Ruggieri A, Bartenschlager R: Ultrastructural characterization of Zika virus replication factories. Cell Rep.2017; 18(9): 2113-2123. doi: 10.1016/j.celrep.2017.02.014

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