Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.
Autophagy. 2011 Sep;7(9):957-65. doi: 10.4161/auto.7.9.16435. Epub 2011 Sep 1.
Autophagy plays a significant role in innate and adaptive immune responses to microbial infection. Some pathogenic bacteria have developed strategies to evade killing by host autophagy. These include the use of 'camouflage' proteins to block targeting to the autophagy pathway and the use of pore-forming toxins to block autophagosome maturation. However, general inhibition of host autophagy by bacterial pathogens has not been observed to date. Here we demonstrate that bacterial cAMP-elevating toxins from B. anthracis and V. cholera can inhibit host anti-microbial autophagy, including autophagic targeting of S. Typhimurium and latex bead phagosomes. Autophagy inhibition required the cAMP effector protein kinase A. Formation of autophagosomes in response to rapamycin and the endogenous turnover of peroxisomes was also inhibited by cAMP-elevating toxins. These findings demonstrate that cAMP-elevating toxins, representing a large group of bacterial virulence factors, can inhibit host autophagy to suppress immune responses and modulate host cell physiology.
自噬在先天和适应性免疫对微生物感染的反应中起着重要作用。一些致病菌已经开发出了逃避宿主自噬杀伤的策略。这些策略包括使用“伪装”蛋白来阻止靶向自噬途径，以及使用形成孔的毒素来阻止自噬体成熟。然而，到目前为止，还没有观察到细菌病原体对宿主自噬的普遍抑制。在这里，我们证明炭疽杆菌和霍乱弧菌的细菌 cAMP 升高毒素可以抑制宿主的抗微生物自噬，包括沙门氏菌和乳胶珠吞噬体的自噬靶向。自噬抑制需要 cAMP 效应蛋白激酶 A。雷帕霉素诱导的自噬体形成和过氧化物酶体的内源性周转也被 cAMP 升高的毒素抑制。这些发现表明，cAMP 升高的毒素，代表了一大类细菌毒力因子，可以抑制宿主自噬，从而抑制免疫反应并调节宿主细胞的生理学。
