Dauletbaev Nurlan, Das Mithun, Cammisano Maria, Chen He, Singh Sareen, Kooi Cora, Leigh Richard, Beaudoin Trevor, Rousseau Simon, Lands Larry C
Research Institute of McGill University Health Centre, Montreal, Quebec, Canada.
Department of Medicine and Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
PLoS One. 2015 Nov 23;10(11):e0143129. doi: 10.1371/journal.pone.0143129. eCollection 2015.
Lung disease in cystic fibrosis (CF) is often exacerbated following acute upper respiratory tract infections caused by the human rhinovirus (HRV). Pathophysiology of these exacerbations is presently unclear and may involve deficient innate antiviral or exaggerated inflammatory responses in CF airway epithelial cells. Furthermore, responses of CF cells to HRV may be adversely affected by pre-exposure to virulence factors of Pseudomonas (P.) aeruginosa, the microorganism that frequently colonizes CF airways. Here we examined production of antiviral cytokine interferon-β and inflammatory chemokine interleukin-8, expression of the interferon-responsive antiviral gene 2'-5'-oligoadenylate synthetase 1 (OAS1), and intracellular virus RNA load in primary CF (delF508 CFTR) and healthy airway epithelial cells following inoculation with HRV16. Parallel cells were exposed to virulence factors of P. aeruginosa prior to and during HRV16 inoculation. CF cells exhibited production of interferon-β and interleukin-8, and expression of OAS1 at levels comparable to those in healthy cells, yet significantly higher HRV16 RNA load during early hours post-inoculation with HRV16. In line with this, HRV16 RNA load was higher in the CFBE41o- dF cell line overexpessing delF508 CFTR, compared with the isogenic control CFBE41o- WT (wild-type CFTR). Pre-exposure to virulence factors of P. aeruginosa did not affect OAS1 expression or HRV16 RNA load, but potentiated interleukin-8 production. In conclusion, CF cells demonstrate elevated HRV RNA load despite preserved interferon-β and OAS1 responses. High HRV load in CF airway epithelial cells appears to be due to deficiencies manifesting early during HRV infection, and may not be related to interferon-β.
囊性纤维化（CF）患者的肺部疾病常在人鼻病毒（HRV）引起的急性上呼吸道感染后加重。目前尚不清楚这些加重情况的病理生理学机制，可能涉及CF气道上皮细胞中先天性抗病毒反应不足或炎症反应过度。此外，CF细胞对HRV的反应可能会受到预先暴露于铜绿假单胞菌（P. aeruginosa）毒力因子的不利影响，铜绿假单胞菌是经常定植于CF气道的微生物。在此，我们检测了接种HRV16后原代CF（delF508 CFTR）和健康气道上皮细胞中抗病毒细胞因子干扰素-β和炎性趋化因子白细胞介素-8的产生、干扰素反应性抗病毒基因2'-5'-寡腺苷酸合成酶1（OAS1）的表达以及细胞内病毒RNA载量。在接种HRV16之前和期间，将平行的细胞暴露于铜绿假单胞菌的毒力因子。CF细胞产生的干扰素-β和白细胞介素-8以及OAS1的表达水平与健康细胞相当，但在接种HRV16后的早期，其HRV16 RNA载量显著更高。与此一致的是，与同基因对照CFBE41o-WT（野生型CFTR）相比，过表达delF508 CFTR的CFBE41o-dF细胞系中的HRV16 RNA载量更高。预先暴露于铜绿假单胞菌的毒力因子并不影响OAS1的表达或HRV16 RNA载量，但会增强白细胞介素-8的产生。总之，尽管干扰素-β和OAS1反应保持正常，但CF细胞的HRV RNA载量仍升高。CF气道上皮细胞中高HRV载量似乎是由于HRV感染早期出现的缺陷所致，可能与干扰素-β无关。
