Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
Lab Invest. 2021 Nov;101(11):1467-1474. doi: 10.1038/s41374-021-00660-z. Epub 2021 Sep 9.
The mortality rates among patients who initially survive sepsis are, in part, associated with a high risk of secondary lung infections and respiratory failure. Given that phagolysosomes are important for intracellular killing of pathogenic microbes, we investigated how severe lung infections associated with post-sepsis immunosuppression affect phagolysosome biogenesis. In mice with P. aeruginosa-induced pneumonia, we found a depletion of both phagosomes and lysosomes, as evidenced by decreased amounts of microtubule associated protein light chain 3-II (LC3-II) and lysosomal-associated membrane protein (LAMP1). We also found a loss of transcription factor E3 (TFE3) and transcription factor EB (TFEB), which are important activators for transcription of genes encoding autophagy and lysosomal proteins. These events were associated with increased expression of ZKSCAN3, a repressor for transcription of genes encoding autophagy and lysosomal proteins. Zkscan3 mice had increased expression of genes involved in the autophagy-lysosomal pathway along with enhanced killing of P. aeruginosa in the lungs, as compared to wild-type mice. These findings highlight the involvement of ZKSCAN3 in response to severe lung infection, including susceptibility to secondary bacterial infections due to immunosuppression.
最初从败血症中存活下来的患者的死亡率部分与二次肺部感染和呼吸衰竭的高风险有关。鉴于吞噬溶酶体对于细胞内杀死病原微生物很重要，我们研究了与败血症后免疫抑制相关的严重肺部感染如何影响吞噬溶酶体的生物发生。在铜绿假单胞菌诱导肺炎的小鼠中，我们发现吞噬体和溶酶体都被消耗了，这可以从微管相关蛋白轻链 3-II（LC3-II）和溶酶体相关膜蛋白（LAMP1）的含量减少得到证明。我们还发现转录因子 E3（TFE3）和转录因子 EB（TFEB）的缺失，这两种因子对于编码自噬和溶酶体蛋白的基因的转录是重要的激活剂。这些事件与 ZKSCAN3 的表达增加有关，ZKSCAN3 是编码自噬和溶酶体蛋白的基因转录的抑制剂。与野生型小鼠相比，Zkscan3 小鼠的自噬-溶酶体途径相关基因的表达增加，并且肺部对铜绿假单胞菌的杀伤增强。这些发现强调了 ZKSCAN3 参与严重肺部感染的反应，包括由于免疫抑制导致对二次细菌感染的易感性。
