VEGF-Mediated Augmentation of Autophagic and Lysosomal Activity in Endothelial Cells Defends against Intracellular Streptococcus pyogenes

Group A Streptococcus (GAS), a deleterious human-pathogenic bacterium, causes life-threatening diseases such as sepsis and necrotic fasciitis. We recently reported that GAS survives and replicates within blood vessel endothelial cells because these cells are intrinsically defective in xenophagy. Because blood vessel endothelial cells are relatively germfree environments, specific stimulation may be required to sufficiently induce xenophagy. Here, we explored how vascular endothelial growth factor (VEGF) promoted xenophagy and lysosomal activity in endothelial cells. These effects were achieved by amplifying the activation of TFEB, a transcriptional factor crucial for lysosome/autophagy biogenesis, via cAMP-mediated calcium release. In a mouse model of local infection with GAS, the VEGF level was significantly elevated at the infection site. Interestingly, low serum VEGF levels were found in a mouse model of invasive bacteremia and in patients with severe GAS-induced sepsis. Moreover, the administration of VEGF improved the survival of GAS-infected mice. We propose a novel theory regarding GAS infection in endothelial cells, wherein VEGF concentrations in the systemic circulation play a critical role.