Role of autophagy-related proteins and cellular microRNAs in chikungunya and dengue virus infection

Abstract

Dengue virus (DENV) and chikungunya virus (CHIKV) are the causative agents of febrile diseases with a wide range of clinical manifestations worldwide, for which there are no specific treatments or fully efficacious vaccines available. Research on the cellular host factors involved in the control of the replication of these viruses is urgently needed in order to better understand their pathogenesis and to provide potential therapeutic targets. Autophagy is a cellular mechanism that aids in the degradation of cellular components in vesicles known as autophagosomes during stress conditions, such as viral infection. First, we investigated the role of proteins involved in autophagy (ATG proteins) in the replication of DENV and CHIKV in human cell lines. We found that ATG proteins differentially modulate the replication of these viruses. Even more, we identified a protein, e.g., BNIP3, which regulates CHIKV infection via mechanisms independent of the functions that have been described in the literature so far. We showed that depletion of BNIP3 favours CHIKV at an early stage in the replication cycle, resulting in higher infectivity and viral production. Next we also investigated the changes that occur in the expression of small non-coding RNAs, microRNAs (miRNAs), in macrophages infected with DENV. We found the virus to change the expression of several miRNAs. Furthermore, we found miR-3614-5p to have antiviral activity against DENV, possibly through the regulation of the expression of the cellular protein ADAR1. In conclusion, this thesis provides evidence of the role of cellular host factors in the control of viral infection.