Project C1 - Identification of targets for antiviral strategies against Zika virus
Dr. Daniela Bender
Paul Ehrlich Institute
Federal Institute for Vaccines and Biomedicines
Tel.: +49 6103 77 5411
- Project description
Background: Zika viruses are still sparsely researched “aboviruses” belonging to the family of flaviviruses. Currently, three ZIKV lines have been described, the East African, West African, and Asian lines, causing an outbreak in French Polynesia (2013/14) and the current outbreak in South/Middle America, USA (Southern States). ZIKV are enveloped viruses that have a single-stranded RNA genome of positive polarity with a size of 10.8 kb. They belong to the family Flaviviridae. The WHO declared the Zika virus epidemic in South America to be a public health emergency of international concern since there are strong indications for a connection between Zika virus infection during pregnancy and the accumulation of cases of microcephaly. At present, neither vaccination nor a specific therapy are available. By inhibiting virus replication, the virus load could be significantly reduced, and thus the virus spread. In addition, the risk of intrauterine infection could be mitigated.
During our work on HCV, which like ZIKV belongs to the family of flaviviruses, it could be observed that HCV induces autophagy. The underlying mechanism could be clarified, and the importance of autophagy for the morphogenesis/release of HCV could be revealed. Based on this, necessary methods including the GFP/RFP constructs for live cell imaging were established for live cell imaging (1-7). For the WHO, the reference material for the international ZIKV NAT standard was prepared and established (8,9). For the Uganda isolate as well as for the French Polynesia isolate, infection systems were established for neuronal and epithelial cell lines. Therefore, different infection models for examining the ZIKV life cycle became available. Antibodies against ZIKV-specific antigens were generated, and qPCR-based quantitative test systems were established. By using these systems, it could be observed that both isolates tested induce autophagy in the infected cells and that the inhibition of autophagy reduced the amount of released viruses.
Scientific aims: Robust reporter viruses shall be established, facilitating the screening of substance libraries with regard to its antiviral effect against ZIKV.
As a specific approach, the ZIKV-dependent activation of autophagy and the underlying mechanisms shall be characterized in detail. The importance of autophagy for the various steps of the viral life cycle shall be clarified. The aim is to identify the target structures for antiviral substances and their characterization in order to inhibit the ZIKV replication in that way.
References C1: 1. Ploen et al. (2013) J Hepatol 58:1081-8 2. Ploen et al. (2013) EJCB 92:374-82 3. Elgner et al. (2016) Biochem J 473:145-55 4. Ren et al. (2016) J Virol ; 5. Elgner et al., (2016) J Virol; 6. Ren et al. (2017) EJCB; 7. Medvedev et al. (2017) Free Radic Biol Med; 8. Baylis et al. (2016) Transfusion, 9. Trösenmeyer et al. (2016) Genome Announc.