Neuropathogenic flaviviruses : isolation and characterization of Zika and tick-borne encephalitis viruses from human brains

Research output: ThesisDoctoral Thesis

Abstract

Flavivirus is a genus that consists of small RNA viruses transmitted by arthropod vectors, mosquitos and ticks. Flaviviruses cause human diseases of global concern, such as dengue fever, Yellow fever, West Nile disease and Japanese encephalitis, with hundreds of millions of infections every year. Zika virus (ZIKV), a mosquito-borne flavivirus, recently caused a major epidemic with severe and unexpected consequences. Circulating in sylvatic cycles for decades and traditionally causing only mild self-limiting disease, ZIKV quickly spread through the Americas between 2015 and 2016, leading to an unforeseen epidemic that affected hundreds of thousands of people. Following this outbreak of acute ZIKV infections, the number of microcephaly cases reported in neonates accumulated; a causal relationship was suspected and the World Health Organization declared a Public Health Emergency of International Concern in February 2016. We were able to provide a key piece of evidence in proving the causal relationship between ZIKV infection and microcephaly. We described a case of prolonged maternal viremia from an expectant mother infected with ZIKV at the 11th week of gestation, which led to brain damage in the fetus. Subsequently, we isolated the virus FB-FWUH-2016 from the brain tissue of the fetus in human neuroblastoma cells. There is no specific anti-viral treatment for ZIKV infections nor is there a fully effective vaccine. Thus, we screened several anti-cancer compounds known to possess anti-viral activities to determine their anti-Zika virus effectivity. We found that gemcitabine, saliphenylhalamide and obatoclax, the latter of which is a novel compound, inhibited ZIKV replication and virus production in retinal pigment epithelial cells. Furthermore, we found that the compounds differentially affect the metabolism of infected cells. These data provide novel information for anti-virus drug development, as these compounds affect the functions of infected cells instead of the virus itself. We further characterized the new epidemic virus isolate and conducted a study on cell tropism. In this study, we compared four ZIKV isolates, three of which were from the epidemic Asian lineage and the other was a prototypic virus of the African lineage. We found differences in cell susceptibility that favored the new strain and a closely related French Polynesian strain, particularly in cell lines originating from the placenta, umbilical veins, kidney and brain. Tick-borne encephalitis virus (TBEV), another flavivirus that affects the central nervous system, is endemic in many parts of Europe and in the Northern parts of Asia. Three subtypes of the virus, namely, the European, Siberian and Far Eastern subtypes, can cause encephalitis with different degrees of severity. The European subtype is most prominent in most of Europe, but the Siberian subtype is also found in the Baltic countries and Finland. Fatalities are rare, which made the Kotka Archipelago in Finland a new focus after the report of two fatal TBE cases in 2015 from the same island in the archipelago along with two other infected individuals. We isolated the virus from the brain of one of the deceased patients in human neuroblastoma cells and obtained sequence data on both fatal cases. Surprisingly, the viruses were the Siberian and European subtypes. During this and previous studies, we also found both viruses in ticks from the archipelago, which shows that the subtypes coexist in the same focus.
Original languageEnglish
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-3801-9
Electronic ISBNs978-951-51-3802-6
Publication statusPublished - 2017
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • 3111 Biomedicine

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