Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
mBio. 2013 Feb 12;4(1):e00638-12. doi: 10.1128/mBio.00638-12.
The highly virulent Francisella tularensis subsp. tularensis has been classified as a category A bioterrorism agent. A live vaccine strain (LVS) has been developed but remains unlicensed in the United States because of an incomplete understanding of its attenuation. Lipopolysaccharide (LPS) modification is a common strategy employed by bacterial pathogens to avoid innate immunity. A novel modification enzyme has recently been identified in F. tularensis and Helicobacter pylori. This enzyme, a two-component Kdo (3-deoxy-d-manno-octulosonic acid) hydrolase, catalyzes the removal of a side chain Kdo sugar from LPS precursors. The biological significance of this modification has not yet been studied. To address the role of the two-component Kdo hydrolase KdhAB in F. tularensis pathogenesis, a ΔkdhAB deletion mutant was constructed from the LVS strain. In intranasal infection of mice, the ΔkdhAB mutant strain had a 50% lethal dose (LD(50)) 2 log(10) units higher than that of the parental LVS strain. The levels of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) in bronchoalveolar lavage fluid were significantly higher (2-fold) in mice infected with the ΔkdhAB mutant than in mice infected with LVS. In vitro stimulation of bone marrow-derived macrophages with the ΔkdhAB mutant induced higher levels of TNF-α and IL-1β in a TLR2-dependent manner. In addition, TLR2(-/-) mice were more susceptible than wild-type mice to ΔkdhAB bacterial infection. Finally, immunization of mice with ΔkdhAB bacteria elicited a high level of protection against the highly virulent F. tularensis subsp. tularensis strain Schu S4. These findings suggest an important role for the Francisella Kdo hydrolase system in virulence and offer a novel mutant as a candidate vaccine.
The first line of defense against a bacterial pathogen is innate immunity, which slows the progress of infection and allows time for adaptive immunity to develop. Some bacterial pathogens, such as Francisella tularensis, suppress the early innate immune response, killing the host before adaptive immunity can mature. To avoid an innate immune response, F. tularensis enzymatically modifies its lipopolysaccharide (LPS). A novel LPS modification-Kdo (3-deoxy-d-manno-octulosonic acid) saccharide removal--has recently been reported in F. tularensis. We found that the kdhAB mutant was significantly attenuated in mice. Additionally, the mutant strain induced an early innate immune response in mice both in vitro and in vivo. Immunization of mice with this mutant provided protection against the highly virulent F. tularensis strain Schu S4. Thus, our study has identified a novel LPS modification important for microbial virulence. A mutant lacking this modification may be used as a live attenuated vaccine against tularemia.
对弗朗西斯氏菌属的强毒亚种进行分类，将其归为 A 类生物恐怖主义制剂。已经开发出一种活疫苗株（LVS），但由于对其衰减机制的不完全了解，该疫苗仍未在美国获得许可。脂多糖（LPS）修饰是细菌病原体逃避固有免疫的常用策略。最近在弗朗西斯氏菌属和幽门螺杆菌中发现了一种新的修饰酶。这种酶，即一种双组分 Kdo（3-脱氧-D-甘露基-octulosonic 酸）水解酶，可催化 LPS 前体中侧链 Kdo 糖的去除。该修饰的生物学意义尚未得到研究。为了研究二组分 Kdo 水解酶 KdhAB 在弗朗西斯氏菌属发病机制中的作用，我们从 LVS 株中构建了一个 ΔkdhAB 缺失突变体。在小鼠鼻腔感染中，与亲本 LVS 株相比，ΔkdhAB 突变株的 50%致死剂量（LD(50)）高出 2 个对数单位。与 LVS 感染的小鼠相比，ΔkdhAB 突变株感染的小鼠支气管肺泡灌洗液中的促炎细胞因子肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）水平显著升高（2 倍）。用 ΔkdhAB 突变体体外刺激骨髓来源的巨噬细胞，可诱导 TLR2 依赖性 TNF-α和 IL-1β水平升高。此外，TLR2(-/-) 小鼠比野生型小鼠更容易受到 ΔkdhAB 细菌感染的影响。最后，用 ΔkdhAB 细菌免疫小鼠可对高毒力的弗朗西斯氏菌属亚种菌株 Schu S4 产生高水平的保护作用。这些发现表明弗朗西斯氏菌属 Kdo 水解酶系统在毒力中起重要作用，并为候选疫苗提供了一种新的突变体。
细菌病原体的第一道防线是固有免疫，固有免疫可减缓感染的进展，并为适应性免疫的发展争取时间。一些细菌病原体，如弗朗西斯氏菌属，会抑制早期固有免疫反应，在适应性免疫成熟之前杀死宿主。为了避免固有免疫反应，弗朗西斯氏菌属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属属兔的人适合佩戴什么转运
属兔人在2023 年运势较为平稳，没有明显的吉星或凶星入主。佩戴适合的饰品可以起到提升个人气场和运势的作用。以下是一些适合属兔人在 2023 年佩戴的饰品：
红宝石：红宝石是一种象征着热情和活力的宝石，它能够增强属兔人的自信心和活力，带来积极向上的能量。
紫水晶：紫水晶能够带来智慧和洞察力，同时也能够稳定情绪，帮助属兔人在 2023 年保持冷静和理智。
翡翠：翡翠是中国传统文化中的吉祥物，它能够带来好运和平安，同时也能够增加人的气场和运势。
珍珠：珍珠是一种优雅和高贵的宝石，它能够带来温柔和优雅的气质，同时也能够增加人的气场和运势。
需要注意的是，佩戴饰品并不能改变一个人的命运和运势，它只是一种辅助作用。同时，佩戴饰品也需要根据个人的喜好和风格来选择，不要盲目跟风，适合自己的才是最好的。
