Yersinia pestis subverts the dermal neutrophil response in a mouse model of bubonic plague.
Yersinia pestis subverts the dermal neutrophil response in a mouse model of bubonic plague.
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DOI：
10.1128/mbio.00170-13
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发表时间：
2013-08-27
期刊：
影响因子：
6.4
通讯作者：
Hinnebusch BJ
中科院分区：
文献类型：
--
作者：
Shannon JG;Hasenkrug AM;Dorward DW;Nair V;Carmody AB;Hinnebusch BJ
大多数人类鼠疫耶尔森氏菌感染是由于受感染跳蚤的叮咬将细菌引入皮肤造成的。一旦进入真皮，鼠疫杆菌可以逃避宿主的先天免疫反应，随后传播到引流淋巴结（dLN）。在那里，病原体大量复制，造成黑死病的典型淋巴腺鼠疫。在这项研究中，使用了几种细胞术和显微镜技术来表征早期宿主对皮内(i.d。鼠疫杆菌感染。用表达dsred的鼠疫菌全毒力株和减毒株感染小鼠，用流式细胞术对小鼠组织进行分析。感染后4 h，感染真皮中出现大量中性粒细胞，大多数细胞相关细菌与中性粒细胞相关。我们观察到毒力质粒（pCD1）对真皮层细菌存活和中性粒细胞活化的显著影响。鼠疫杆菌感染的活体显微镜显示招募的中性粒细胞和细菌之间的动态相互作用。相比之下，很少有细菌与树突状细胞（dc）相互作用，这表明这种细胞类型在鼠疫杆菌感染的早期可能没有发挥主要作用。使用中性粒细胞缺失和CCR7敲除小鼠进行的实验表明，鼠疫杆菌从真皮向dLN的传播不依赖于中性粒细胞或dc。综上所述，本研究的结果表明，真皮中嗜中性粒细胞对鼠疫杆菌的反应非常迅速、强烈，而毒力质粒pCD1对于逃避这种反应很重要。今天，鼠疫耶尔森氏菌仍然是一个令人关切的公共卫生问题，因为世界各地都有零星的鼠疫暴发，而且它有可能被非法用作生物恐怖主义武器。由于黑死病的发病机制是由鼠疫杆菌进入皮肤引起的，因此我们试图在皮内感染后早期描述宿主先天免疫细胞对细菌的反应。我们发现中性粒细胞，吞噬和破坏微生物的先天免疫细胞，被迅速募集到注射部位，而不管菌株的毒力如何，这表明鼠疫杆菌无法破坏中性粒细胞募集到感染部位。然而，我们发现与含有pCD1质粒的鼠疫杆菌菌株相关的中性粒细胞活性降低，pCD1质粒对毒力至关重要。这些发现表明pcd1编码因子在体内抑制这些细胞的激活/刺激中起作用。
The majority of human Yersinia pestis infections result from introduction of bacteria into the skin by the bite of an infected flea. Once in the dermis, Y. pestis can evade the host’s innate immune response and subsequently disseminate to the draining lymph node (dLN). There, the pathogen replicates to large numbers, causing the pathognomonic bubo of bubonic plague. In this study, several cytometric and microscopic techniques were used to characterize the early host response to intradermal (i.d.) Y. pestis infection. Mice were infected i.d. with fully virulent or attenuated strains of dsRed-expressing Y. pestis, and tissues were analyzed by flow cytometry. By 4 h postinfection, there were large numbers of neutrophils in the infected dermis and the majority of cell-associated bacteria were associated with neutrophils. We observed a significant effect of the virulence plasmid (pCD1) on bacterial survival and neutrophil activation in the dermis. Intravital microscopy of i.d. Y. pestis infection revealed dynamic interactions between recruited neutrophils and bacteria. In contrast, very few bacteria interacted with dendritic cells (DCs), indicating that this cell type may not play a major role early in Y. pestis infection. Experiments using neutrophil depletion and a CCR7 knockout mouse suggest that dissemination of Y. pestis from the dermis to the dLN is not dependent on neutrophils or DCs. Taken together, the results of this study show a very rapid, robust neutrophil response to Y. pestis in the dermis and that the virulence plasmid pCD1 is important for the evasion of this response. Yersinia pestis remains a public health concern today because of sporadic plague outbreaks that occur throughout the world and the potential for its illegitimate use as a bioterrorism weapon. Since bubonic plague pathogenesis is initiated by the introduction of Y. pestis into the skin, we sought to characterize the response of the host’s innate immune cells to bacteria early after intradermal infection. We found that neutrophils, innate immune cells that engulf and destroy microbes, are rapidly recruited to the injection site, irrespective of strain virulence, indicating that Y. pestis is unable to subvert neutrophil recruitment to the site of infection. However, we saw a decreased activation of neutrophils that were associated with Y. pestis strains harboring the pCD1 plasmid, which is essential for virulence. These findings indicate a role for pCD1-encoded factors in suppressing the activation/stimulation of these cells in vivo.