PRE2023-MECHANISMS OF CORONAVIRUS PATHOGENESIS IN ACUTE INFECTION AND POST-ACUTE SEQUELA OF COVID (PASC) AND PROTECTION STRATEGIES IN YOUNG AND OLDER ADULTS-PID2022-140328OB-I00

The project proposes the development of next-generation SARS-CoV-2 vaccines, consisting in replication-competent propagation-deficient RNA replicons for intranasal administration. We have demonstrated that MERS-CoV and SARS-CoV-2 replicons induce mucosal sterilizing immunity and provide100% protection in mice. In this project, we will optimize the safety and efficacy of SARS-CoV-2 RNA-replicons. SARS-CoV-2 RNA replicons will be engineered to deliver immunomodulatory miRNAs that enhance efficacy in older adults, which are the most susceptible population to severe COVID and death, because immunosenescence diminishes immune responses. Post-acute sequelae of COVID (PASC) includes a variety of respiratory, neurological, thrombotic and cerebrovascular manifestations, that follow SARS-CoV-2 infection in 4-20% of people, independently of age or disease severity. No diagnostic biomarkers or effective treatments are still available, which justifies the urgent need of research to understand and mitigate PASC. Two main hypotheses will be addressed. The presence of defective RNA genomes that reduce viral dissemination, inducing proinflammatory reactions in specific tissues will be studied in human samples and in a mouse model for PASC. Different mechanisms, previously shown by our group to modulate inflammation in acute infection, like virus accessory genes and post-transcriptional regulation of gene expression mediated by small non-coding RNAs or RNA-protein complexes, will be analyzed.