Exploratory Proteomic Profiling of SARS-CoV-2 Infected THP-1 Macrophages Reveals Alterations in Inflammatory Response and Cellular Metabolism

Macrophages are key players in innate immunity and inflammation during viral infections, including COVID-19. This study explored the cellular and proteomic responses of THP-1-derived macrophages following exposure to SARS-CoV-2. Despite lacking ACE2 expression, these cells internalized the virus, although no productive replication was observed up to 48 hours post-infection. The virus triggered an inflammatory response marked by increased secretion of TNF-α, IL-6 and IL-10 at 24 hours, and elevated levels of TNF-α, IL-6 and GM-CSF at 48 hours post-infection. Proteomic analysis revealed early downregulation of G6PD and upregulation of FABP4 at 24 hours post-infection, suggesting metabolic reprogramming. At 48 hours, a broader set of proteins showed reduced abundance, including those involved in NADH metabolism, cytokine mediated signaling and endoplasmic reticulum (ER) stress pathways. These proteomic insights, while requiring molecular validation, macrophage responses in COVID-19 pathogenesis, highlighting the THP-1 model's value for investigating host inflammatory and stress responses independent of productive viral replication, and revealing key proteins and pathways involved in COVID-19 pathogenesis.