Uncovering the impact of peroxisome biogenesis deficiencies on the susceptibility to influenza A virus infections

• Autor(a) principal: Luís, Catarina Isabel dos Santos Nunes Governo
• Data de Publicação: 2023
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
• Texto Completo: http://hdl.handle.net/10773/40787
• topic: Peroxisomes; Viruses; Influenza A virus; Peroxisome biogenesis disorders; Zellweger spectrum disorders

Peroxisomes are ubiquitous organelles, that perform a wide range of essential functions. The importance of this organelle in human health has become evident by the existence of rare genetic disorders (peroxisome biogenesis disorders (PBDs)) caused by defects in peroxisomal biogenesis factor (PEX) genes that encode peroxisomal proteins. PBDs can be divided into three subtypes, being Zellweger Spectrum disorders the most prominent subgroup. Patients born with this spectrum present multiple congenital malformations and display a broad range of clinical severity. Peroxisomes have also emerged as important players in the context of viral infections, either as platforms for antiviral signaling or as metabolic organelles, essential for the proper formation of infectious viral particles. To our knowledge, no studies have yet addressed the susceptibility of PBD patients to viral infections. Given the importance of understanding how children with mutations in peroxisomal proteins respond to viral infections, we aimed to initiate this study by specifically analyzing the susceptibility of cells from a PEX10-deficient PBD child to be infected by influenza A virus (IAV), a respiratory virus commonly known as the cause of flu. Our results shown that the PEX10 deficiency significantly compromises the immune response not only in the context of IAV infection, but also in the context of a non-specific viral RNA stimulation. However, apparently the virus is not able to take advantage of this cellular condition, as, in PEX10-deficient cells, we observed a lower number of new infectious viral particles being produced. These results indicate that PEX10, or the metabolic consequences of its mutation, plays an important role in IAV infection. Additionally, we also investigated the potential significance of the overall peroxisomal metabolism in the propagation of IAV, in cells with impaired peroxisomal luminal protein import. These results indicate that IAV is able to replicate more efficiently in these cells, which may be a direct result of the heavily impaired immune response previously observed in these conditions. Overall, our results shed some light on how PBD mutations may lead to significant changes in infection susceptibility and highlight once again the importance of peroxisomes in the context of viral infections.