Evaluation of antivirals against alphaviruses using the example of Chikungunya Virus

Hucke, Friederike (2022): Evaluation of antivirals against alphaviruses using the example of Chikungunya Virus. Dissertation, LMU München: Tierärztliche Fakultät

Abstract

Alphaviruses are enveloped single-stranded RNA arboviruses of the Togaviridae family and are geographically widely distriguted [1, 2]. They cause various diseases in humans and animals such as encephalitis, arthritis fever, rash and arthralgia [1]. Among the medically relevant members of the alphaviruses are Venezuelan, Western, and Eastern Equine Encephalitis viruses (VEEV, WEEV, and EEEV), Ross River virus (RRV) and Chikungunya virus (CHIKV). The Equine Encephalitis viruses are categoriesed as potential agents for bioterrorism since they can all be transmitted via aerosols, causing severe disease [3-7]. Chikungunya virus (CHIKV) is categorised as a(n) (re)emerging disease and is mainly transmitted by Aedes spp. mosquitoes [8]. CHIKV is the causative agent of chikungunya fever (CHIKF) which is characterised by high fever, headache and myalgia and polyarthralgia [9]. Especially the polyarthralgia may last for months or even years and leave patients with a severely deteriorated quality of life. CHIKV has repeatedly been responsible for outbreaks that caused serious economic and public health problems in the affected countries [8]. To date, no vaccine or specific antiviral therapies are available. This thesis focusses on in vitro antiviral testing against a wild type CHIKV isolate and selecting possible hit to lead compounds. Climate change leads to the introduction of vectors in more temperate zones and thus it is possible that new diseases emerge with these vectors [10]. Consequently, the need for specific antivirals to treat such emerging diseases like CHIKV is current. Most of these in vitro antiviral assays are conducted in Vero cells, a cell line that originated from the kidney of an African green monkey [11]. Although this cell line is the model cell line to probagate CHIKV in, it lacks the clinical relevance of the disease and is not of human origin. Therefore, another goal of the thesis was to identify a human cell line with clinical relevance (especially for neurogenic CHIKV disease) to test antivirals in. This study was the first to describe the human glioblastoma cell line U138 in extensive antiviral tests against CHIKV. Furthermore, different assay methods were compared for their usefulness in antiviral tests against CHIKV in Vero-B4 and U138 cells.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Antivirals, Alphaviruses, CHIKV, neurological cell line model, U138, U251, favipiravir, T-1105, nsP2, nsP4 inhibitors
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 590 Tiere (Zoologie)
• Fakultäten: Tierärztliche Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 30. Juli 2022
• 1. Bericht­erstatter:in: Sutter, Gerd