Dottorato in INNOVATION IN IMMUNO-MEDIATED AND HEMATOLOGICAL DISORDERS

Titolo della tesi: Activation of the Nrf2 anti-oxidative response and its impact on antiviral immunity and metabolism

Dengue virus (DENV) is a mosquito-borne pathogen that annually threatens about half of the world's population with an estimated 100-400 million infections each year. Among the factors that influence dengue disease severity, the damage induced by oxidative stress has been correlated with inflammation and progression towards the severe forms of disease. Control of antioxidant enzyme expression is mediated in part through Nrf2, a global transcriptional regulator involved in the maintenance of redox homeostasis. Metabolic regulation is increasingly recognized as a powerful mechanism guiding the development of inflammatory and antiviral responses to viruses and microbial pathogens. The endogenous metabolite itaconate, a by-product of Krebs cycle metabolism, enables Nrf2 release and links metabolism to anti-oxidant response. In this study, we investigated the metabolic changes induced by the Nrf2 agonist 4-octyl-itaconate (4-OI) during DENV infection. We demonstrated that 4-OI increased DENV replication in a Nrf2-independent manner and impaired the activation of type I IFN response and inflammation. Moreover, we described that the proviral effect relied on the 4-OI – induced metabolic switch from glycolysis to fatty acid β-oxidation through the activation of the PDK4-CPT1 axis, thus identifying PDK4 as a key metabolic factor involved in modulation of viral replication. These results have direct relevance to dengue immunopathogenesis, since disease severity has been directly associated clinically and experimentally with lipid metabolism disorders and chronic inflammation.