Grigg Jonathan, Miyashita Lisa, Suri Reetika
Centre for Genomics and Child Health, Blizard Institute for Cell and Molecular Sciences, London, United Kingdom.
PLoS One. 2017 Mar 9;12(3):e0173569. doi: 10.1371/journal.pone.0173569. eCollection 2017.
Welders are more susceptible to pneumococcal pneumonia. The mechanisms are yet unclear. Pneumococci co-opt the platelet activating factor receptor (PAFR) to infect respiratory epithelial cells. We previously reported that exposure of respiratory cells to welding fumes (WF), upregulates PAFR-dependent pneumococcal infection. The signaling pathway for this response is unknown, however, in intestinal cells, hypoxia-inducible factor-1 α (HIF 1α) is reported to mediate PAFR-dependent infection. We sought to assess whether oxidative stress plays a role in susceptibility to pneumococcal infection via the platelet activating factor receptor. We also sought to evaluate the suitability of nasal epithelial PAFR expression in welders as a biomarker of susceptibility to infection. Finally, we investigated the generalisability of the effect of welding fumes on pneumococcal infection and growth using a variety of different welding fume samples. Nasal epithelial PAFR expression in welders and controls was analysed by flow cytometry. WF were collected using standard methodology. The effect of WF on respiratory cell reactive oxygen species production, HIF-1α expression, and pneumococcal infection was determined using flow cytometry, HIF-1α knockdown and overexpression, and pneumococcal infection assays. We found that nasal PAFR expression is significantly increased in welders compared with controls and that WF significantly increased reactive oxygen species production, HIF-1α and PAFR expression, and pneumococcal infection of respiratory cells. In unstimulated cells, HIF-1α knockdown decreased PAFR expression and HIF-1α overexpression increased PAFR expression. However, in knockdown cells pneumococcal infection was paradoxically increased and in overexpressing cells infection was unaffected. Nasal epithelial PAFR expression may be used as a biomarker of susceptibility to pneumococcal infection in order to target individuals, particularly those at high risk such as welders, for the pneumococcal vaccine. Expression of HIF-1α in unexposed respiratory cells inhibits basal pneumococcal infection via PAFR-independent mechanisms.
焊工更容易感染肺炎球菌性肺炎。其机制尚不清楚。肺炎球菌利用血小板活化因子受体（PAFR）感染呼吸道上皮细胞。我们之前报道过，呼吸道细胞暴露于焊接烟尘（WF）中会上调PAFR依赖性肺炎球菌感染。然而，这种反应的信号通路尚不清楚，在肠道细胞中，据报道缺氧诱导因子-1α（HIF 1α）介导PAFR依赖性感染。我们试图评估氧化应激是否通过血小板活化因子受体在肺炎球菌感染易感性中起作用。我们还试图评估焊工鼻腔上皮PAFR表达作为感染易感性生物标志物的适用性。最后，我们使用各种不同的焊接烟尘样本研究了焊接烟尘对肺炎球菌感染和生长影响的普遍性。通过流式细胞术分析焊工和对照组的鼻腔上皮PAFR表达。使用标准方法收集WF。使用流式细胞术、HIF-1α敲低和过表达以及肺炎球菌感染试验确定WF对呼吸道细胞活性氧产生、HIF-1α表达和肺炎球菌感染的影响。我们发现，与对照组相比，焊工的鼻腔PAFR表达显著增加，并且WF显著增加活性氧产生、HIF-1α和PAFR表达以及呼吸道细胞的肺炎球菌感染。在未受刺激的细胞中，HIF-1α敲低降低PAFR表达，HIF-1α过表达增加PAFR表达。然而，在敲低细胞中肺炎球菌感染反而增加，而过表达细胞中的感染不受影响。鼻腔上皮PAFR表达可作为肺炎球菌感染易感性的生物标志物，以便针对个体，特别是像焊工这样的高危人群接种肺炎球菌疫苗。未暴露的呼吸道细胞中HIF-1α的表达通过不依赖PAFR的机制抑制基础肺炎球菌感染。
