Lacasse, E.; Dubuc, I.; Leclerc, J.; Gravel, A.; Gudimard, L.; Joly-Beauparlant, C.; Faure, M.; Fortin, P.; Blanchet, M.-R.; Droit, A.; Flamand, L.

Despite the end of the COVID-19 pandemic, SARS-CoV-2 continues to circulate endemically, highlighting the need to better understand the viral determinants of pathogenesis. Non-structural protein 2 (Nsp2) has been implicated in host-virus interactions, yet its function remains poorly defined in the context of infection. Here, we generated a recombinant SARS-CoV-2 lacking Nsp2 ({Delta}Nsp2) to investigate its role in viral replication and disease. While {Delta}Nsp2 replicated comparably to wild-type virus in vitro and in vivo, its deletion resulted in markedly attenuated disease in K18-hACE2 mice. Wild-type infection induced a strong pro-inflammatory response associated with increased recruitment of monocytes and macrophages, whereas {Delta}Nsp2 infection promoted a more balanced antiviral response characterized by enhanced lymphocyte and NK cell recruitment. This was accompanied by reduced pulmonary and systemic inflammation and distinct transcriptional programs, including downregulation of pathways related to RNA processing and translation. Mechanistically, CLIP-seq and proximity labeling suggest that Nsp2 interacts with host RNA and components of the translational machinery. Together, our findings identify Nsp2 as a key virulence factor that drives immunopathology by skewing host immune responses, highlighting its role as a regulator of host-pathogen interactions.