SARS-CoV-2 Nsp2 reprograms host immunity to drive pathogenic inflammation

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. Putative functions of the non-structural protein 2 (Nsp2) have been studied in vitro, but how Nsp2 affects pathogenesis and overall viral fitness in vivo has yet to be demonstrated. Here, we generated a recombinant SARS-CoV-2 lacking Nsp2 (ΔNsp2) to investigate its role in viral replication and disease. While ΔNsp2 replicated comparably to wild-type virus in vitro and in vivo, its deletion resulted in markedly attenuated disease in K18-hACE2 mice. Wild-type virus infection induced a strong pro-inflammatory response associated with increased recruitment of monocytes and macrophages, whereas ΔNsp2 virus 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.IMPORTANCEThe COVID-19 pandemic has officially ended, yet the virus that causes it continues to circulate and evolve, making it important to understand what makes it cause severe disease. This study focuses on a viral protein called Nsp2 and asks what role it plays in driving illness. Using an animal model, we observed that when Nsp2 was removed from the virus, infected animals became far less sick, even though the virus itself replicated just as well. Instead of triggering the harmful, excessive inflammation typically seen with the full virus, the modified virus prompted a more balanced immune response. Further investigation revealed that Nsp2 interacts directly with the host's genetic machinery, suggesting a mechanism by which the virus hijacks immune signaling to worsen disease. These findings pinpoint Nsp2 as a driver of COVID-19 severity and a promising target for future therapies aimed at reducing inflammation rather than simply fighting the virus itself.