Interferon-stimulated gene 15 (ISG15) is an interferon-stimulated gene and a ubiquitin-like protein, traditionally known for its role in ISGylation. In addition to its intracellular functions, recent studies have revealed a novel role for extracellular ISG15, particularly in the context of viral infections. Beyond type I interferons, various stimuli, including viral and bacterial infections, have been found to trigger its secretion. Notably, the integrin receptor LFA-1 has been identified as a receptor for extracellular ISG15. Despite these advancements, the precise mechanisms by which extracellular ISG15 functions—such as the pathways regulating its secretion and receptor interactions—remain unclear. Viral proteins and de-ISGylating enzymes are known to influence ISG15 secretion levels, thereby impacting its immunomodulatory potential. This mini-review summarizes the existing studies aimed at understanding the mechanisms behind the secretion and functions of extracellular ISG15, with a particular focus on its immunomodulatory effects during infection. We also explore the contrasting roles of extracellular ISG15 in mice and humans, highlighting the need for more species-specific research. Further investigation into the role of extracellular ISG15 may uncover novel therapeutic strategies for infectious diseases, cancer, and inflammatory conditions.

The pandemic of SARS-CoV-2 is characterized by the emergence of new variants of concern (VOCs) that supplant previous waves of infection. Here, we describe our investigation of the lineages and host-specific mutations identified in a particularly vulnerable population of predominantly older and immunosuppressed SARS-CoV-2-infected patients seen at our medical center in Chicago during the transition from the Delta to Omicron wave. We compare two primer schemes, ArticV4.1 and VarSkip2, used for short read amplicon sequencing, and describe our strategy for bioinformatics analysis that facilitates identifying lineage-associated mutations and host-specific mutations that arise during infection. This study illustrates the ongoing evolution of SARS-CoV-2 VOCs in our community and documents novel constellations of mutations that arise in individual patients. The ongoing evaluation of the evolution of SARS-CoV-2 during this pandemic is important for informing our public health strategies.