Graduate Group in Microbiology, University of California, Berkeley, Berkeley, California, USA.
Adv Immunol. 2012;113:135-56. doi: 10.1016/B978-0-12-394590-7.00002-6.
Acquired cell-mediated immunity to Listeria monocytogenes is induced by infection with live, replicating bacteria that grow in the host cell cytosol, whereas killed bacteria, or those trapped in a phagosome, fail to induce protective immunity. In this chapter, we focus on how L. monocytogenes is sensed by the innate immune system, with the presumption that innate immunity affects the development of acquired immunity. Infection by L. monocytogenes induces three innate immune pathways: an MyD88-dependent pathway emanating from a phagosome leading to expression of inflammatory cytokines; a STING/IRF3-dependent pathway emanating from the cytosol leading to the expression of IFN-β and coregulated genes; and very low levels of a Caspase-1-dependent, AIM2-dependent inflammasome pathway resulting in proteolytic activation and secretion of IL-1β and IL-18 and pyroptotic cell death. Using a combination of genetics and biochemistry, we identified the listerial ligand that activates the STING/IRF3 pathway as secreted cyclic diadenosine monophosphate, a newly discovered conserved bacterial signaling molecule. We also identified L. monocytogenes mutants that caused robust inflammasome activation due to bacteriolysis in the cytosol, release of DNA, and activation of the AIM2 inflammasome. A strain was constructed that ectopically expressed and secreted a fusion protein containing Legionella pneumophila flagellin that robustly activated the Nlrc4-dependent inflammasome and was highly attenuated in mice, also in an Nlrc4-dependent manner. Surprisingly, this strain was a poor inducer of adaptive immunity, suggesting that inflammasome activation is not necessary to induce cell-mediated immunity and may even be detrimental under some conditions. To the best of our knowledge, no single innate immune pathway is necessary to mount a robust acquired immune response to L. monocytogenes infection.
宿主细胞胞质中复制的活细菌感染可诱导李斯特菌属单核细胞增生李斯特菌的获得性细胞介导免疫，而死亡细菌或被困在吞噬体中的细菌则不能诱导保护性免疫。在本章中，我们重点关注李斯特菌属单核细胞增生李斯特菌如何被先天免疫系统识别，假设先天免疫会影响获得性免疫的发展。李斯特菌属单核细胞增生李斯特菌感染诱导三条先天免疫途径：来自吞噬体的依赖 MyD88 的途径导致炎性细胞因子的表达；来自胞质的依赖 STING/IRF3 的途径导致 IFN-β和共同调控基因的表达；以及 Caspase-1 依赖性、AIM2 依赖性炎症小体途径的极低水平导致 IL-1β和 IL-18 的蛋白水解激活和分泌以及细胞焦亡。通过遗传学和生物化学的结合，我们确定了激活 STING/IRF3 途径的李斯特菌属配体是分泌的环二腺苷酸单磷酸，这是一种新发现的保守细菌信号分子。我们还鉴定了李斯特菌属单核细胞增生李斯特菌突变株，由于在胞质中发生细菌溶解、释放 DNA 和激活 AIM2 炎症小体，导致强烈的炎症小体激活。构建了一个异位表达和分泌包含嗜肺军团菌鞭毛蛋白的融合蛋白的菌株，该蛋白强烈激活 Nlrc4 依赖性炎症小体，在小鼠中也具有高度衰减作用，也是以 Nlrc4 依赖性方式。令人惊讶的是，该菌株是适应性免疫的不良诱导剂，这表明炎症小体的激活对于诱导细胞介导免疫不是必需的，在某些情况下甚至可能有害。据我们所知，没有单一的先天免疫途径是对抗李斯特菌属单核细胞增生李斯特菌感染产生强大获得性免疫反应所必需的。
