SpeB is a cysteine protease virulence factor that plays a critical role in the pathogenesis of local infectious disease (36), and SpeB-deficient GAS further increased VEGF levels at the local infection site compared with wild-type GAS (Fig. 7A), although SpeB in GAS culture supernatant barely degraded VEGF (Fig. S4). This evidence concerns the gene CTSB and infection.