Uncovering potential targets for new host-directed antiviral therapies against influenza A virus infection

• Autor(a) principal: Marques, Mariana Campos
• Data de Publicação: 2023
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/39493
• topic: Viral infection; Influenza A virus; Cellular proteostasis; Protein aggregation; Peroxisomes; Peroxisome metabolism; Antiviral response

Influenza A virus (IAV) arises every year as a threat to human health, being the causative agent of most of the seasonal respiratory epidemics and the major influenza pandemics in the last century. Influenza, or flu, is associated with high levels of morbidity and mortality in high-risk populations, such as the elderly and immunocompromised individuals. Nowadays, IAV spreading and severe disease can be prevented by annual vaccination and the administration of antiviral therapeutics that have been designed against viral components to prevent viral replication. Nevertheless, the continuous emergence of novel genetic variants or new viral strains of IAV due to its rapid ability to evolve, hampers the efficacy of virus-directed therapeutics. It is, hence, essential to study the interactions between IAV and the host cell, in order to further discover potential cellular factors that can in due course act as targets for the development of novel host-directed therapies. In this work, we present two distinct overviews of this interplay that focus on the one hand on a comprehensive analysis of host cell proteostasis during IAV infection, and, on the other hand, on the study of the role of peroxisome metabolism on antiviral defense and IAV propagation. In the first study, we explored the interplay between IAV and the host’s proteostasis at different stages within a single infection cycle. Our results demonstrate that IAV infection induces the accumulation of protein aggregates, upon high rates of viral protein translation. We also demonstrate the concomitant deregulation of the IRE1 branch of the unfolded protein response (UPR), and the attenuation of virus production upon its inhibition. The accumulation of the virus-induced protein aggregates seems to be further associated with a virus-induced deregulation of the host cell RNA metabolism. Moreover, interference with the accumulation of these aggregates by the presence of a quinoline-steroid compound specifically designed to prevent the formation of proteins aggregates, strongly hinders the proper formation of new infectious virus particles. In the second study, we investigated the previously described anti-viral/pro-viral dual role of peroxisomes during a viral infection. We have identified specific peroxisomal proteins and mechanisms that are required for a proper antiviral response against RNA viruses or that play a critical role during IAV replication. We also showed that the metabolic and physical interplay with other organelles is essential for the establishment of a robust innate immune response. Altogether, both projects allowed us to identify previously undescribed cellular mechanisms that play important roles not only during IAV replication but also for the establishment of an efficient antiviral response by the host cell. Further studies are proposed to follow these results and ultimately uncover novel targets for innovative host-directed therapeutics with antiviral activity.