Center for Frontier Oral Science, Graduate School of Dentistry, Osaka Universitygrid.136593.b, Osaka, Japan.
Research Institute for Microbial Disease, Osaka Universitygrid.136593.b, Osaka, Japan.
mBio. 2022 Aug 30;13(4):e0123322. doi: 10.1128/mbio.01233-22. Epub 2022 Jul 5.
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. Sepsis caused by Streptococcus pyogenes is a life-threatening condition. Blood vessel endothelial cells should serve as a barrier to infection, although we recently reported that endothelial cells allow intracellular GAS proliferation due to defective xenophagy. In this study, we revealed that administration of VEGF augmented both xenophagy and lysosomal activity in these cells, leading to the efficient killing of intracellular GAS. By comparison, the opposite relationship was observed , as low serum VEGF concentrations were accompanied by high-severity sepsis in both a mouse model and in human patients. Administration of VEGF reduced mortality in the GAS sepsis model. Based on these findings, we hypothesize that during acute infection, strong VEGF stimulation boosts the intracellular defense system of the endothelium to provide a stronger blood vessel barrier, thereby helping to prevent bacterial dissemination.
A 组链球菌（GAS）是一种有害的人类致病菌，可引起危及生命的疾病，如败血症和坏死性筋膜炎。我们最近报道，GAS 在血管内皮细胞内存活和复制，因为这些细胞在胞质自噬方面存在内在缺陷。由于血管内皮细胞是相对无菌的环境，可能需要特定的刺激来充分诱导胞质自噬。在这里，我们探讨了血管内皮生长因子（VEGF）如何促进内皮细胞中的胞质自噬和溶酶体活性。这些作用是通过 cAMP 介导的钙释放来放大转录因子 TFEB 的激活来实现的，TFEB 对于溶酶体/自噬生物发生至关重要。在 GAS 局部感染的小鼠模型中，感染部位的 VEGF 水平显著升高。有趣的是，在 GAS 侵袭性菌血症的小鼠模型和严重 GAS 诱导的败血症患者中，血清 VEGF 水平较低。此外，VEGF 的给药改善了 GAS 感染小鼠的存活率。我们提出了一种关于内皮细胞中 GAS 感染的新理论，即全身循环中的 VEGF 浓度起着关键作用。由化脓性链球菌引起的败血症是一种危及生命的疾病。血管内皮细胞应该作为感染的屏障，尽管我们最近报道内皮细胞由于胞质自噬缺陷而允许细胞内 GAS 增殖。在这项研究中，我们揭示了 VEGF 的给药增强了这些细胞中的胞质自噬和溶酶体活性，从而有效地杀死细胞内 GAS。相比之下，观察到相反的关系，因为在小鼠模型和人类患者中，低血清 VEGF 浓度伴随着高严重程度的败血症。VEGF 的给药降低了 GAS 败血症模型的死亡率。基于这些发现，我们假设在急性感染期间，强烈的 VEGF 刺激增强了内皮细胞的细胞内防御系统，提供了更强的血管屏障，从而有助于防止细菌传播。
