Immunity to Pulmonary Pathogens Section, Laboratory of Intracellular Parasites/Rocky Mountain Laboratories/National Institute of Allergy and Infectious Disease/National Institutes of Health, Hamilton, MT 59840, USA.
J Immunol. 2011 Aug 15;187(4):1845-55. doi: 10.4049/jimmunol.1100377. Epub 2011 Jul 13.
Active suppression of inflammation is a strategy used by many viral and bacterial pathogens, including virulent strains of the bacterium Francisella tularensis, to enable colonization and infection in susceptible hosts. In this study, we demonstrated that virulent F. tularensis strain SchuS4 selectively inhibits production of IL-12p40 in primary human cells via induction of IFN-β. In contrast to the attenuated live vaccine strain, infection of human dendritic cells with virulent SchuS4 failed to induce production of many cytokines associated with inflammation (e.g., TNF-α and IL-12p40). Furthermore, SchuS4 actively suppressed secretion of these cytokines. Assessment of changes in the expression of host genes associated with suppression of inflammatory responses revealed that SchuS4, but not live vaccine strain, induced IFN-β following infection of human dendritic cells. Phagocytosis of SchuS4 and endosomal acidification were required for induction of IFN-β. Further, using a defined mutant of SchuS4, we demonstrated that the presence of bacteria in the cytosol was required, but not sufficient, for induction of IFN-β. Surprisingly, unlike previous reports, induction of IFN-β by F. tularensis was not required for activation of the inflammasome, was not associated with exacerbation of inflammatory responses, and did not control SchuS4 replication when added exogenously. Rather, IFN-β selectively suppressed the ability of SchuS4-infected dendritic cells to produce IL-12p40. Together, these data demonstrated a novel mechanism by which virulent bacteria, in contrast to attenuated strains, modulate human cells to cause disease.
积极抑制炎症是许多病毒和细菌病原体（包括弗朗西斯菌属的毒力菌株）用来在易感宿主中定植和感染的策略。在这项研究中，我们证明了毒力弗朗西斯菌属菌株 SchuS4 通过诱导 IFN-β 选择性抑制原代人细胞中 IL-12p40 的产生。与减毒活疫苗株不同，毒力 SchuS4 感染人树突状细胞未能诱导许多与炎症相关的细胞因子（例如 TNF-α 和 IL-12p40）的产生。此外，SchuS4 积极抑制这些细胞因子的分泌。评估与抑制炎症反应相关的宿主基因表达的变化表明，SchuS4 而非活疫苗株在感染人树突状细胞后诱导 IFN-β 的产生。SchuS4 的吞噬作用和内体酸化是诱导 IFN-β 的必要条件。此外，使用 SchuS4 的定义突变体，我们证明了细胞质中细菌的存在是诱导 IFN-β 所必需的，但不是充分的。令人惊讶的是，与之前的报告不同，弗朗西斯菌属诱导 IFN-β 对于激活炎症小体不是必需的，与炎症反应的加重无关，并且在外源添加时也不能控制 SchuS4 的复制。相反，IFN-β 选择性抑制了 SchuS4 感染的树突状细胞产生 IL-12p40 的能力。这些数据共同证明了一种新的机制，即与减毒菌株相比，毒力细菌可调节人体细胞导致疾病。
