Although infection by influenza and Zika (ZIKV) viruses has been shown to increase ISGylation, SARS-CoV-2 PLpro mediates the de-ISGylation of ISGylated proteins, increasing the level of free (unconjugated) ISG15 in macrophages, which increases the ratio of free ISG15 to the conjugated ISG15. Here, ISG15 is linked to infection.