Cecum lymph node dendritic cells harbor slow-growing bacteria phenotypically tolerant to antibiotic treatment.
Cecum lymph node dendritic cells harbor slow-growing bacteria phenotypically tolerant to antibiotic treatment.
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DOI：
10.1371/journal.pbio.1001793
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发表时间：
2014-02
期刊：
影响因子：
9.8
通讯作者：
Hardt WD
中科院分区：
文献类型：
--
作者：
Kaiser P;Regoes RR;Dolowschiak T;Wotzka SY;Lengefeld J;Slack E;Grant AJ;Ackermann M;Hardt WD
沙门氏菌可以通过采用一种缓慢生长的“持久”状态来耐受抗生素，这种状态隐藏在宿主树突状细胞中，并可以在治疗结束后重新发起感染。这可以通过用先天免疫刺激剂补充抗生素治疗来避免。在体内，抗生素的效率往往比体外低得多，而且可能会复发。体内活性差的原因仍不完全清楚。我们在复杂沙门氏菌病的动物模型中研究了氟喹诺酮类抗生素环丙沙星。大剂量环丙沙星治疗有效地降低了粪便和大多数器官中的病原菌载量。然而，盲肠引流淋巴结(CLN)、肠道组织和脾保留了存活的细菌。在CLN中，大约10%-20%的细菌仍然活着。这些表型耐受菌主要寄宿在CD103+CX3CR1−CD11c+树突状细胞内，对环丙沙星保持遗传易感性，足以在治疗结束后重新开始感染，并表现出极慢的生长速度，混合接种感染和分离质粒实验表明。生长缓慢足以解释对抗生素治疗的顽固性。因此，树突状细胞内生长缓慢的耐药细菌可以解释体内抗生素活性差和复发的原因。内毒素或CpG是已知的先天免疫防御的诱导者，它的注射减少了耐受性细菌的负荷。因此，操纵先天免疫可能会增强抗生素在体内的活性。已知的在体外杀死细菌的抗生素在体内的效果可能较差。造成这种情况的原因仍然鲜为人知。使用沙门氏菌腹泻的小鼠模型，我们发现在抗生素环丙沙星存在的情况下会发生细菌持久性，因为沙门氏菌可以以两种不同的状态存在：作为在宿主组织中传播的快速增长的种群和作为缓慢增长的“持久”亚群。这种生长缓慢的细菌会感染并隐藏在宿主免疫系统的树突状细胞内，不会受到抗生素的攻击--因此，尽管它们对药物具有遗传敏感性，但它们却变得“耐受”。这些耐受细菌形成了一个活细胞储存库，这些细胞能够在停止抗生素治疗后重新发起感染。然而，幸运的是，这些耐受的沙门氏菌细胞并不是不可战胜的，可以通过添加直接刺激宿主免疫防御的药物来杀死它们。将先天免疫刺激剂与抗生素治疗相结合，可能会为改进抗菌治疗提供新的机会。
Salmonella bacteria can tolerate antibiotics by adopting a slow-growing “persister” state that hides in host dendritic cells and can re-initiate infection after treatment ends. This can be avoided by supplementing antibiotic treatment with stimulants of innate immunity. In vivo, antibiotics are often much less efficient than ex vivo and relapses can occur. The reasons for poor in vivo activity are still not completely understood. We have studied the fluoroquinolone antibiotic ciprofloxacin in an animal model for complicated Salmonellosis. High-dose ciprofloxacin treatment efficiently reduced pathogen loads in feces and most organs. However, the cecum draining lymph node (cLN), the gut tissue, and the spleen retained surviving bacteria. In cLN, approximately 10%–20% of the bacteria remained viable. These phenotypically tolerant bacteria lodged mostly within CD103+CX3CR1−CD11c+ dendritic cells, remained genetically susceptible to ciprofloxacin, were sufficient to reinitiate infection after the end of the therapy, and displayed an extremely slow growth rate, as shown by mathematical analysis of infections with mixed inocula and segregative plasmid experiments. The slow growth was sufficient to explain recalcitrance to antibiotics treatment. Therefore, slow-growing antibiotic-tolerant bacteria lodged within dendritic cells can explain poor in vivo antibiotic activity and relapse. Administration of LPS or CpG, known elicitors of innate immune defense, reduced the loads of tolerant bacteria. Thus, manipulating innate immunity may augment the in vivo activity of antibiotics. Antibiotics that are known to kill bacteria in vitro can be less efficacious in vivo. The reasons for this have remained poorly understood. Using a mouse model for Salmonella diarrhea, we found that bacterial persistence occurs in the presence of the antibiotic ciprofloxacin because Salmonella can exist in two different states: as a fast-growing population that spreads in the host's tissues and as a slow-growing “persister” subpopulation. The slow-growing bacteria infect and hide out inside dendritic cells of the host's immune system and cannot be attacked by the antibiotic—they are thereby rendered “tolerant,” despite their genetic susceptibility to the drug. These tolerant bacteria form a reservoir of viable cells that are able to reinitiate the infection on cessation of antibiotic therapy. Fortunately, however, these tolerant Salmonella cells are not invincible, and can be killed by adding agents that directly stimulate the host's immune defense. Combining innate immune stimulants with antibiotic treatment may offer new opportunities to improve antibacterial therapies.
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