Although ISG15/ISGylation has been proposed as an efficient host defense response to various viral infections, increasing evidence implied this antiviral mechanism may be virus-specific and ISG15/ISGylation may be exploited by some viruses to facilitate viral replication and production by either negatively regulating host immunity [26, 27] or directly promoting viral replication through blunting IFN antiviral activity [15, 28]. Here, ISG15 is linked to viral infectious disease.