1 Department of Pharmacology and Toxicology, School of Pharmacy, University of Arizona, Tucson, Arizona; and.
Am J Respir Cell Mol Biol. 2014 Jun;50(6):1136-43. doi: 10.1165/rcmb.2013-0357OC.
Multiple pathogens, such as bacteria, fungi, and viruses, have been frequently found in asthmatic airways and are associated with the pathogenesis and exacerbation of asthma. Among these pathogens, Alternaria alternata (Alt), a universally present fungus, and human rhinovirus have been extensively studied. However, their interactions have not been investigated. In the present study, we tested the effect of Alt exposure on virus-induced airway epithelial immunity using live virus and a synthetic viral mimicker, double-stranded RNA (dsRNA). Alt treatment was found to significantly enhance the production of proinflammatory cytokines (e.g., IL-6 and IL-8) induced by virus infection or dsRNA treatment. In contrast to this synergistic effect, Alt significantly repressed type I and type III IFN production, and this impairment led to elevated viral replication. Mechanistic studies suggested the positive role of NF-κB and mitogen-activated protein kinase pathways in the synergism and the attenuation of the TBK1-IRF3 pathway in the inhibition of IFN production. These opposite effects are caused by separate fungal components. Protease-dependent and -independent mechanisms appear to be involved. Thus, Alt exposure alters the airway epithelial immunity to viral infection by shifting toward more inflammatory but less antiviral responses.
多种病原体，如细菌、真菌和病毒，已在哮喘气道中频繁发现，并与哮喘的发病机制和加重有关。在这些病原体中，广泛存在的真菌链格孢菌（Alternaria alternata，Alt）和人类鼻病毒已被广泛研究。然而，它们之间的相互作用尚未得到研究。在本研究中，我们使用活病毒和合成病毒模拟物双链 RNA（dsRNA）测试了 Alt 暴露对病毒诱导的气道上皮免疫的影响。发现 Alt 处理显著增强了病毒感染或 dsRNA 处理诱导的促炎细胞因子（如 IL-6 和 IL-8）的产生。与这种协同作用相反，Alt 显著抑制 I 型和 III 型 IFN 的产生，这种抑制导致病毒复制增加。机制研究表明，NF-κB 和丝裂原活化蛋白激酶途径在协同作用中起积极作用，而 TBK1-IRF3 途径在 IFN 产生的抑制中起衰减作用。这些相反的效应是由真菌的不同成分引起的。似乎涉及到依赖和不依赖蛋白酶的机制。因此，Alt 暴露通过向更具炎症性但抗病毒性较低的反应转变，改变了气道上皮对病毒感染的免疫反应。
