Spatiotemporal differences of early type i interferon response in acute and chronic viral infections

• Autores: Valentina Casella
• Directores de la Tesis: Andreas Meyerhans (dir. tes.), Jordi Marquès Argilaguet (codir. tes.)
• Lectura: En la Universitat Pompeu Fabra ( España ) en 2021
• Idioma: español
• Tribunal Calificador de la Tesis: Andrea Cerutti (presid.), Cristina López Rodríguez (secret.), Gennady Bocharov (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad Pompeu Fabra
• Materias:
  • Ciencias de la vida
    • Biología humana
    • Inmunología
    • Biología molecular
  • Ciencias médicas
    • Patología
      • Inmunopatología
• Enlaces
  • Tesis en acceso abierto en: TDX
• Resumen

  • Type I interferons (IFN-I) play a critical role in shaping the antiviral immune response early after an infection (McNab et al., 2015, Nature Reviews). However, the dynamics by which different immune cell subsets regulate the IFN-I response during the early stages of acute and chronic infections is not completely understood (Trinchieri, 2012, Cell Host & Microbe). Here in this thesis we used the Lymphocytic Choriomeningitis Virus (LCMV)-infection mouse model system to characterize the dynamics of the IFN-I response in acute and chronic infections. Time-resolved spleen-transcriptomes revealed that during an acute infection, IFN-I showed two waves of expression at days 2 and 5 post-infection, while in chronically infected mice a single wave of IFN-I genes was induced at day 1. We identified metallophilic marginal zone macrophages as an important source of the second wave of IFN-I only during acute infection. Moreover, we characterized a polyfunctional role for the second wave of IFN-I, which was required to induce pro-inflammatory macrophages and virus-specific CD8 T cells. In contrast, during chronic infection, the early depletion of metallophilic marginal zone macrophages mediated by CD8+ cells, resulted in a lack of IFN-I production and the pro-inflammatory response was not induced. Importantly, we also discovered that CD8 T cell response induced by the second wave of IFN-I determines the development of lymphoid tissue fibrosis during acute LCMV infection. Of great interest for the therapeutic setting, we demostrated that aPDL1-mediated immunotherapy to restore CD8 T cells functionality in chronic infection, does not increase fibrosis in lymphoid tissues. Together our data demonstrate that the spatiotemporal regulation of IFN-I production in the early stages of infection is crucial for the induction of IFN-I dependent sequential events that lead to viral infection resolution. Further studies are ongoing to decipher the regulatory mechanisms underlying the characterized events, thus revealing universal concepts related to infection fate decisions that are also relevant for persistent human infections such as HIV or HCV.