Replication, Virus-host Interactions and Protection in Coronavirus

Research Summary

Our group studies the mechanisms of CoV replication and pathogenesis with a special focus on virus-host interactions in infections with deadly human viruses SARS-CoV-2, SARS-CoV and MERS-CoV. This information is applied to the design of vaccines and the selection of antivirals to protect against acute severe respiratory CoV infections and post-acute sequelae of COVID (PASC). We aim to understand in detail the innate immune response caused by these conditions and develop modulating mechanisms for both young and elderly populations.

Research Lines

 The main aims of our research are:

• To understand the mechanisms of Long-COVID or PASC, two main hypotheses are being investigated. The presence of defective RNA genomes that reduce viral dissemination, inducing proinflammatory reactions in specific tissues, is being studied in human samples and in a mouse model for PASC. Other mechanisms, previously shown by our group to modulate innate responses and inflammation in acute infection are being analyzed. Host factors interacting with virus determinants of virulence that mediate cystic fibrosis transmembrane conductance regulator (CFTR) reduction have being identified as potential targets for antiviral drugs. The contribution of SARS-CoV-2 accessory genes 6, 7a, 7b and 8 is being studied using virus deletion mutants. Post-transcriptional regulation of gene expression mediated either by viral and host small non-coding RNAs or by RNA-protein complexes including viral N and host MOV10 proteins are being analyzed. This information will serve as the basis for new therapeutic interventions.
• Development of next generation SARS-CoV-2 vaccines consisting in replication-competent propagation-deficient RNA replicons and to determine their efficacy in animal model systems. Vaccine development includes: (i) Engineering the SARS-CoV-2 RNA-replicons by deleting or modifying viral genes responsible for propagation and virulence, using reverse genetics; (ii) Development of packaging cell lines that efficiently complement the generation of virus-like particles (VLPs); (iii) Engineering simplified and safer versions by reducing the replicase size; (iv) Optimizing the efficacy of vaccines in older adults by expressing immunomodulatory miRNAs that downregulate immunosenescence.
• To determine the relevance to the inflammatory pathology of post-transcriptional regulation of gene expression. We study the contribution to dysregulated inflammation of small non-coding RNAs (host miRNAs and virus-derived RNAs) and RNA-protein complexes. RNAs and proteins involved in these regulatory networks represent potential antiviral targets.
• Identification of cell-signaling pathways involved in CoV replication and pathology. Understanding how CoV spreads in the body at a molecular level can help select antiviral drugs that inhibit these pathways. We study PBM-PDZ protein-protein interactions and viral accessory genes involved in the innate immune and inflammatory responses, since activation of these pathways is responsible for virulence.

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