Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Infect Immun. 2012 Dec;80(12):4317-32. doi: 10.1128/IAI.00808-12. Epub 2012 Oct 1.
Throughout infection, pathogenic bacteria induce dramatic changes in host transcriptional repertoires. An understanding of how bacterial factors influence host reprogramming will provide insight into disease pathogenesis. In the human respiratory pathogen Bordetella pertussis, the causative agent of whooping cough, pertussis toxin (PT) is a key virulence factor that promotes colonization, suppresses innate immune responses during early infection, and causes systemic disease symptoms. To determine the full extent of PT-associated gene regulation in the airways through the peak of infection, we measured global transcriptional profiles in the lungs of BALB/c mice infected with wild-type (WT) or PT-deficient (ΔPT) B. pertussis. ΔPT bacteria were inoculated at a dose equivalent to the WT dose and at a high dose (ΔPT(high)) to distinguish effects caused by higher bacterial loads achieved in WT infection from effects associated with PT. The results demonstrated that PT was associated with a significant upregulation of immune and inflammatory response genes as well as several other genes implicated in airway pathology. In contrast to the early, transient responses observed for ΔPT(high) infection, WT infection induced a prolonged expression of inflammatory genes and increased the extent and duration of lung histopathology. In addition, the administration of purified PT to ΔPT(high)-infected mice 1 day after bacterial inoculation exacerbated and prolonged inflammatory responses and airway pathology. These data indicate that PT not only is associated with exacerbated host airway responses during peak B. pertussis infection but also may inhibit host mechanisms of attenuating and resolving inflammation in the airways, suggesting possible links between PT and pertussis disease symptoms.
在整个感染过程中，病原菌会引起宿主转录谱的剧烈变化。了解细菌因素如何影响宿主重编程将有助于深入了解疾病的发病机制。在人类呼吸道病原体百日咳博德特氏菌中，百日咳毒素（PT）是一种关键的毒力因子，它促进定植，抑制早期感染期间的先天免疫反应，并导致全身疾病症状。为了确定在感染高峰期通过呼吸道中 PT 相关基因调节的全部程度，我们测量了 BALB/c 小鼠肺部中感染野生型（WT）或 PT 缺陷型（ΔPT）B. pertussis 的全局转录谱。将ΔPT 细菌以与 WT 剂量相当的剂量和高剂量（ΔPT(high)）接种，以区分在 WT 感染中实现的更高细菌负荷引起的作用与与 PT 相关的作用。结果表明，PT 与免疫和炎症反应基因的显著上调以及其他几个与气道病理学有关的基因有关。与ΔPT(high)感染观察到的早期短暂反应相反，WT 感染诱导了炎症基因的长时间表达，并增加了肺组织病理学的程度和持续时间。此外，在细菌接种后 1 天向 ΔPT(high)感染的小鼠中给予纯化的 PT，加剧和延长了炎症反应和气道病理学。这些数据表明，PT 不仅与百日咳博德特氏菌感染高峰期宿主气道反应的加剧有关，而且可能抑制宿主减轻和解决气道炎症的机制，提示 PT 与百日咳病症状之间可能存在联系。
