"Emerging and re-emerging Infectious Diseases (EIDs) are defined as ""infections that have newly appeared in a population or have existed previously but are rapidly increasing in incidence or geographic range"". Over the last decades, a number of new emerging diseases, such as HIV/AIDS and SARS, as well as re emerging diseases that increase in incidence or whose geographic range is changing, such as chikungunya or dengue fever, continue to pose a significant threat to populations in Europe and world wide. Some of these EID are caused by the Alphavirus which are emergent arthropod borne viruses with a worldwide distribution.
One of the most established antiviral pathways induced by dsRNAs is the Interferon inducible 2’5’ oligoadenylate synthetase (OAS) / endoribonuclease L (RNAse L) system. OAS is activated upon binding to dsRNA and generates, from ATP, short 2’-5’ linked oligoadenylates (2’5’A) which activate a latent RNAse L. RNAse L cleaves ribosomal and viral RNA, inducing apoptosis and blocking viral infection. In turn, viruses developed means to escape the host antiviral response. Studies on Ebola, HCV, Influenza, Vaccinia and HIV showed that viral nsPs can inhibit RNAse L/OAS system through direct binding to one of these enzymes or through the sequestration of dsRNA, 2’5’A or other cellular mediators. However, mechanisms involved in the anti-apoptotic action of several RNA viruses including alphaviruses are unknown.
I will unravel the molecular aspects of the viral evasion produced via the inhibition of OAS/ RNAse L pathway by non-structural proteins of alphavirus. Subsequenlty, I will determine the structure and biophysical properties of these nsPs. The ultimate goal is to know which nsPs or subdomains of these proteins are important in the inhibition of OAS/ RNAse L pathway through molecular and cell biology experiments and relate to the structure obtained by crystalography possibiliting the design of future inhibitors targeting these proteins or sub-domains."
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