Margaroli Camilla, Oberle Susanne, Lavanchy Christine, Scherer Stefanie, Rosa Muriel, Strasser Andreas, Pellegrini Marc, Zehn Dietmar, Acha-Orbea Hans, Ehirchiou Driss
Department of Biochemistry CIIL, University of Lausanne, Epalinges, Switzerland.
Swiss Vaccine Research Institute, Centre des laboratoires d'Epalinges, Epalinges, Switzerland.
Eur J Immunol. 2016 Jun;46(6):1427-37. doi: 10.1002/eji.201545857.
The ability of pathogens to influence host cell survival is a crucial virulence factor. Listeria monocytogenes (Lm) infection is known to be associated with severe apoptosis of hepatocytes and spleen cells. This impairs host defense mechanisms and thereby facilitates the spread of intracellular pathogens. The general mechanisms of apoptosis elicited by Lm infection are understood, however, the roles of BH3-only proteins during primary Lm infection have not been examined. To explore the roles of BH3-only proteins in Lm-induced apoptosis, we studied Listeria infections in mice deficient in Bim, Bid, Noxa or double deficient in BimBid or BimNoxa. We found that BimNoxa double knockout mice were highly resistant to high-dose challenge with Listeria. Decreased bacterial burden and decreased host cell apoptosis were found in the spleens of these mice. The ability of the BH3-deficient mice to clear bacterial infection more efficiently than WT was correlated with increased concentrations of ROS, neutrophil extracellular DNA trap release and downregulation of TNF-α. Our data show a novel pathway of infection-induced apoptosis that enhances our understanding of the mechanism by which BH3-only proteins control apoptotic host cell death during Listeria infection.
病原体影响宿主细胞存活的能力是一种关键的毒力因子。已知单核细胞增生李斯特菌（Lm）感染与肝细胞和脾细胞的严重凋亡有关。这会损害宿主防御机制，从而促进细胞内病原体的传播。虽然Lm感染引发凋亡的一般机制已为人所知，但是仅含BH3结构域的蛋白质在初次Lm感染过程中的作用尚未得到研究。为了探究仅含BH3结构域的蛋白质在Lm诱导的凋亡中的作用，我们研究了缺乏Bim、Bid、Noxa的小鼠，以及同时缺乏BimBid或BimNoxa的双缺陷小鼠中的李斯特菌感染情况。我们发现，BimNoxa双敲除小鼠对高剂量李斯特菌攻击具有高度抗性。在这些小鼠的脾脏中发现细菌载量降低且宿主细胞凋亡减少。BH3缺陷小鼠比野生型小鼠更有效地清除细菌感染的能力与活性氧浓度增加、中性粒细胞胞外DNA陷阱释放以及肿瘤坏死因子-α的下调有关。我们的数据显示了一条感染诱导凋亡的新途径，这增进了我们对仅含BH3结构域的蛋白质在李斯特菌感染期间控制凋亡性宿主细胞死亡机制的理解。
