PAD4 inhibition impacts immune responses in SARS-CoV-2 infection

Protein arginine deiminase 4 (PAD4) has emerged as a potential therapeutic target for various diseases due to its role in promoting neutrophil extracellular trap (NET) formation. NETs, composed of DNA and antimicrobial proteins, serve as a defense mechanism against pathogens but can also drive lung injury, particularly in SARS-CoV-2 infection. In this study, we examined the effects of PAD4 inhibition on clinical outcomes and adaptive immunity within the context of SARS-CoV-2 infection. Our results show that PAD4 pharmacological inhibition reduced lung NET concentration and improved clinical outcomes, similar to treatment with recombinant human DNase (rhDNase), which degrades NET structure. However, in contrast to rhDNase, PAD4 targeting diminished virus-specific T cell responses by impairing dendritic cell antigen presentation and reducing IL-2 signaling by affecting its production by T cells. In line with these observations, PAD4 pharmacological inhibition diminished antigen-specific T cell responses in a model of lung inflammation. These findings highlight the importance of carefully evaluating PAD4 as a therapeutic target in COVID-19, given its potential to compromise adaptive immune responses crucial for fighting the virus.