Resumen de Bases moleculars de les vies de senyalització de l'activació immune innata com a reguladors de la susceptibilitat i evolució clínica d'infeccions virals
The innate immune system is the first to respond against a pathogen invasion that threatens the host. An innate immune response is characterized by inducing innate immune activation, IFN signaling and inflammatory pathways that generate an antiviral state able to limit pathogen spread and induce cell death of damaged cells. The identification of HIV host restriction factors, such as SAMHD1, has provided insights linking nucleotide metabolism, innate immune activation and viral pathogenesis. Hence, this thesis evaluates the relationship between viral and host factors that strongly affect innate immune modulation and IFN pathways that have the potential to alter viral outcome and progression of associated diseases.
Through the study of HIV infection, we have identified that HIV induces an innate antiviral mechanism associated to IFN-I production and interferon stimulated gene activation. Moreover, HIV induces a cell cycle arrest at G2/M mediated by p21 leading to elevated levels of cell death in monocyte derived macrophages. On the other hand, accessory protein Vpx from HIV-2/SIV, which targets the downregulation of SAMHD1 and TASOR, also triggers innate immune activation signatures characterized by induction of IFNs and expression of ISGs which may hold key in designing strategies targeting reactivation of latent HIV.
The discovery that mutations in SAMHD1 and TREX1 are associated to autoimmune disease Aicardi-Goutières syndrome (AGS) and the fact that both genes have a role in HIV replication, suggests that evaluation of nucleic acid sensors in AGS may have potential for identifying host factors regulating viral replication. Indeed, a screening of AGS genes in primary macrophages has identified ADAR1 as a negative regulator of RIG-I like receptor RLR-MAVS signaling pathway contributing to innate immune activation and IFN production. ADAR1 downregulated cells show increase expression of RNA sensors, MDA5 and RIG-I, enhanced phosphorylation of transcriptional factor IRF7 and increase type I IFN production. ADAR1 in-vitro evaluation have shown a proviral role in HIV, but an antiviral role in HCV and HPV, suggesting ADAR1 role depends on the specific virus host combination. Finally, ADAR1 in-vivo genetic variations are associated to poor clinical outcomes and affect treatment response and disease progression.
In summary, this thesis demonstrates that dysfunction of intracellular nucleic acid sensing pathways that trigger strong innate immune activation and IFN signatures hold promising in the design of novel therapeutic strategies aiming to modulate viral replication and disease progression and infection outcomes.
