Interrelationship between Dendritic Cell Trafficking and Francisella tularensis Dissemination following Airway Infection
Interrelationship between Dendritic Cell Trafficking and Francisella tularensis Dissemination following Airway Infection
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DOI：
10.1371/journal.ppat.1000211
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发表时间：
2008-11-01
期刊：
影响因子：
6.7
通讯作者：
Velan, Baruch
中科院分区：
文献类型：
--
作者：
Bar-Haim, Erez;Gat, Orit;Velan, Baruch
土拉热弗朗西丝菌是吸入性土拉菌病的病原体，在多种培养的哺乳动物细胞中繁殖。然而，其在体内细胞内驻留的证据是不太确定的。树突状细胞（DC），适用于吞噬细菌和向淋巴器官迁移，可以作为潜在的目标，细菌的居留和运输。在这里，我们集中在体内相互作用的F。小鼠气道感染后用DC感染土拉热菌。用活疫苗株（LVS）对小鼠进行致死性气道感染导致CD 11b（高）/CD 11 c（中）/自体荧光（低）DC亚群从呼吸道运输至引流纵隔淋巴结（MdLN）。同时，MdLN发生快速、大量的细菌定植，其特征在于大的细菌灶形成。MdLN中细菌的分析揭示了细胞外细菌的主要群体，其与细胞内细菌的相当大部分共存。细胞内细菌是活的，并且驻留在针对DC标志物表达分选的细胞中。此外，体内活体染色实验表明，大多数这些细胞内细菌（类似于75%）驻留在感染后从气道迁移到MdLN的细胞中。通过操纵DC通过两个独立的途径迁移到MdLN，进一步证明了DC和MdLN中细菌积累之间的相关性。通过鞘氨醇-1-磷酸受体激动剂（FTY 720）或D前列腺素受体1激动剂（BW 245 C），DC迁移至MdLN的损害导致MdLN的细菌定植减少。此外，BW 245 C治疗延迟了感染小鼠的发病和死亡时间。这些结果表明，DC可以作为F.土拉热在感染的早期阶段，DC运输在病原体传播中起作用。这强调了DC迁移损害药物在兔热病治疗中的治疗潜力。
Francisella tularensis, the etiological agent of the inhalation tularemia, multiplies in a variety of cultured mammalian cells. Nevertheless, evidence for its in vivo intracellular residence is less conclusive. Dendritic cells ( DC) that are adapted for engulfing bacteria and migration towards lymphatic organs could serve as potential targets for bacterial residence and trafficking. Here, we focus on the in vivo interactions of F. tularensis with DC following airway infection of mice. Lethal airway infection of mice with the live vaccine strain (LVS) results in trafficking of a CD11b(high)/CD11c(med)/autofluorescence(low) DC subset from the respiratory tract to the draining mediastinal lymph node (MdLN). Simultaneously, a rapid, massive bacterial colonization of the MdLN occurs, characterized by large bacterial foci formation. Analysis of bacteria in the MdLN revealed a major population of extracellular bacteria, which co-exists with a substantial fraction of intracellular bacteria. The intracellular bacteria are viable and reside in cells sorted for DC marker expression. Moreover, in vivo vital staining experiments indicate that most of these intracellular bacteria (similar to 75%) reside in cells that have migrated from the airways to the MdLN after infection. The correlation between DC and bacteria accumulation in the MdLN was further demonstrated by manipulating DC migration to the MdLN through two independent pathways. Impairment of DC migration to the MdLN, either by a sphingosine-1-phosphate receptor agonist (FTY720) or by the D prostanoid receptor 1 agonist (BW245C), resulted in reduced bacterial colonization of MdLN. Moreover, BW245C treatment delayed the onset of morbidity and the time to death of the infected mice. Taken together, these results suggest that DC can serve as an inhabitation niche for F. tularensis in the early stages of infection, and that DC trafficking plays a role in pathogen dissemination. This underscores the therapeutic potential of DC migration impairing drugs in tularemia treatment.