A significant proportion of patients with COVID-19 disease, caused by SARS-CoV-2, develop acute respiratory distress syndrome characterized by pro-inflammatory cytokine secretion and dampened IFN-mediated antiviral response. To uncover the mechanisms by which SARS-CoV-2 drives this dysregulation, we conducted transcriptomic profiling of N-expressing monocyte-derived macrophages treated with different stimuli that activates several pattern recognition receptors. To capture differences in immunoinflammatory responses to different SARS-CoV-2 Nucleocapsids, we performed a comparative proteomics analysis between the hyper inflammatory Delta N protein and less inflammatory Omicron N protein. Both Nucleocapsids expressed in monocyte-derived macrophages were pulled down for affinity purification mass spectrometry (APMS) and their differential protein interactors were identified; revealing Delta N interacts more strongly with stress granule proteins compared to Omicron N, which may explain Delta N pro-inflammatory phenotype. This project was a collaboration between the labs of Dr. Melody Li, Dr. Alexander Hoffmann, and Dr. Mehdi Bouhaddou at UCLA.