The long and winding road: how picornaviruses and coronaviruses evolve to overcome host innate antiviral defenses

A successful viral infection relies on complex interactions between the virus and the host. As obligate intracellular pathogens, viruses exploit cellular resources to support their replication. In response, the host detects byproducts of viral replication and disruptions in cellular processes, triggering antiviral responses that aim to restrict viral infection. RNA viruses, including picornaviruses and coronaviruses, generate double-stranded RNA (dsRNA) as a replication intermediate. Normally absent in healthy cells, the dsRNA is recognized as a danger signal, activating innate immune responses. These include the type I interferon (IFN-I) pathway, which induces an antiviral state in infected and neighboring uninfected cells to limit viral spread, and the integrated stress response (ISR), which halts protein synthesis to block production of new viral particles. In this thesis, I describe how we set out to characterize viral antagonists of host cellular immune responses encoded by picornaviruses and coronaviruses and to elucidate their mode of action. Integrating different approaches—including ectopic expression of viral proteins and genetically engineered viruses—we studied how the 2A protease (2Apro) of enteroviruses (family Picornaviridae) and the nucleocapsid protein (N) of coronaviruses disable host-specific pathways to ensure successful infection. This work uncovers how SARS-CoV-2 N blocks ISR signaling by binding and sequestering dsRNA, a feature conserved in other coronaviruses, and highlights the critical role of enterovirus 2Apro in disrupting essential cellular functions to promote viral replication and to suppress immune responses, particularly at early stages of infection. These findings provide novel insights into the virus-host interactions and may guide the development of future antiviral therapies targeting picornavirus and coronavirus infections.