Francisella tularensis induces aberrant activation of pulmonary dendritic cells
Francisella tularensis induces aberrant activation of pulmonary dendritic cells
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DOI：
10.4049/jimmunol.175.10.6792
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发表时间：
2005-11-15
影响因子：
4.4
通讯作者：
Dow, SW
中科院分区：
文献类型：
--
作者：
Bosio, CM;Dow, SW
图拉氏方济氏菌是一种专性胞内细菌，通过呼吸道途径感染时会导致严重的、急性的、通常是致命的疾病。尽管这种病原体很严重，但人们对其吸入后与呼吸道和肺部的关键靶细胞(肺泡巨噬细胞和呼吸道树突状细胞(DC))的相互作用知之甚少。在这项研究中，我们证明了图拉氏原虫在原代DC中的复制。感染后早期，图拉氏丝虫可诱导DC表面MHC-H和CD86表达增加，但不能诱导巨噬细胞表达。紧随其后的是呼吸道和肺部的DC耗尽。尽管DC呈对数复制和表型成熟，但图拉氏丝虫未能诱导DC产生几种关键的促炎细胞因子，包括肿瘤坏死因子-α和白介素6。然而，图拉氏丝虫感染确实诱导了强大的免疫抑制细胞因子-转化生长因子-β的产生。此外，图拉氏华支睾吸虫能有效抑制DC分泌细胞因子的能力，以响应特定的TLR激动剂。最后，我们还发现，肺部DC和巨噬细胞的感染似乎实际上增加了图拉氏肺吸虫肺部感染的严重程度。例如，感染前耗尽呼吸道树突状细胞和肺泡巨噬细胞可显著延长存活时间。综上所述，这些数据表明，图拉氏F菌能够选择性地将肺部关键抗原前体细胞分泌的致炎细胞因子与抗原提呈功能分离，这可能有助于创造一个相对免疫抑制的环境，有利于机体的复制和传播。
Francisella tularensis is an obligate intracellular bacterium that induces severe, acute, often fatal disease when acquired by the respiratory route. Despite the seriousness of this pathogen, very little is understood about its interaction with key target cells in the airways and lungs (alveolar macrophages and airway dendritic cells (DC)) after inhalation. In this study we demonstrate replication of F. tularensis in primary DC. Early after infection, F. tularensis induced increased expression of MHC class H and CD86 on DC, but not macrophages. This was followed by depletion of DC from the airways and lungs. Despite logarithmic replication and phenotypic maturation of DC, F. tularensis failed to induce production of several key proinflammatory cytokines, including TNF-alpha and IIL-6, from DC. However, F. tularensis infection did elicit production of the potent immunosuppressive cytokine, TGF-beta. Furthermore, F. tularensis actively suppressed the ability of DC to secrete cytokines in response to specific TLR agonists. Finally, we also found that infection of DC and macrophages in the lungs appears to actually increase the severity of pulmonary infection with F. tularensis. For example, depletion of airway DC and alveolar macrophages before infection resulted in significantly prolonged survival times. Together, these data suggest F. tularensis is able to selectively uncouple Ag-presenting functions from proinflammatory cytokine secretion by critical APCs in the lungs, which may serve to create a relatively immunosuppressive environment favorable to replication and dissemination of the organism.