An evaluation of ISG15 protein expression at the site of infection and within the serum confirmed that ISG15 and ISG15 conjugates were induced during CHIKV infection in WT mice (Figure 6B,C). As we previously described during neonatal SINV infection [45], the expression of ISG15 during CHIKV infection was also dependent upon intact IFN signaling since IFNAR−/− pups infected with CHIKV did not induce detectable levels of ISG15 (Figure S2). Here, ISG15 is linked to infection.