Characterization of Staphylococcus aureus mediated inhibition of IAV-induced type I IFN signalling

• Autor(a) principal: Ramos, Bruno Carvalho
• Data de Publicação: 2018
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/25360

Viral and bacterial infections act in concert, when both are present in the lower respiratory tract. This cooperation turns them into a bigger threat and, consequently, one of the highest causes of global mortality. Influenza A viruses (IAV) and Staphylococcus aureus (S. aureus) are among the most common examples and considering the nowadays problematic multi-drug-resistant S. aureus strains, co-infections are a major medical concern. Since both pathogens manipulate certain cellular signalling pathways for own purposes during internalisation, replication or to elude the immune system, these molecular cascades are widely studied to unravel new therapeutic approaches. Targeting cellular factors will prevent the direct action on the pathogens and avoid resistances build-up, which brings future complications and a “loop” in medicine research. Within the present work, it could be shown that S. aureus capacity to inhibit the JAK-STAT pathway depends on the challenged strain as we clearly saw no effect provoked by S. aureus LS1. On the contrary, S. aureus SH1000 reveals similar effectiveness on the inhibition of type I IFN-mediated signalling to the S. aureus 6850 strain. As a matter of fact, not only S. aureus SH1000 wt strain displayed this mechanism but also several mutants, which differed in expression of important virulence regulators of the bacteria. Additionally, one of the mutants (Δagr) presents a more impactful outcome on the interferon stimulated gene (ISG) transcription, which is supported by an almost total impairment of the STAT1-STAT2 dimerization. Moreover, we also show contrasting internalisation efficacy of the S. aureus SH1000 ΔsigB, Δagr, ΔsarA and Δagr+ΔsarA mutant strains in comparison to the S. aureus SH1000 wt strain. However, as it’s possible to acknowledge their inferior capacity to infect, their ability to cause immune response inhibition doesn’t get affected. Ultimately, we pave the way for the next research studies as the hypothesis of a S. aureus toxin-mediated inhibition is weakened and a bacterial structural protein premise is strengthened. Ultimately, with the data we detain on this subject, a future pairing with more sensitive and precise methods, such as mass spectrometry-based proteomics, will provide more conclusive results.