哮喘患者鼻上皮细胞中CC16介导的宿主对鼻病毒的反应受损
2026/07/31
摘要
背景：鼻病毒（RV）感染会增加哮喘发病风险，是疾病加重的主要诱因。Club细胞分泌蛋白16（CC16）水平在哮喘患者中降低，且与炎症和加重频率呈负相关。
目的：本研究旨在确定CC16对哮喘状态下气道鼻上皮细胞中鼻病毒A型1B亚型（RV-A1B）感染的影响。
方法：来自哮喘和非哮喘受试者在气液界面培养的人鼻上皮细胞（HNECs），用有无重组CC16（rCC16）处理的RV-A1B感染处理。通过逆转录定量聚合酶链反应（RT-qPCR）来定量病毒RNA及先前与CC16水平相关的宿主因子（包括溶菌酶、SPLUNC1、乳铁蛋白和表面活性蛋白-D）的表达。为验证研究结果，对CC16充足和缺乏的动物模型及小鼠气管上皮细胞（MTECs）分别用RV-A1B感染，同时在有无重组CC16（rCC16）的情况下进行处理。
结果：与非哮喘HNECs相比，哮喘个体（n=7）在基线条件下CC16和相关宿主防御因子的基因表达较低（n=7）。虽然RV感染增加了非哮喘性HNECs的宿主因子，但来自哮喘个体的HNECs对RV的反应没有上调宿主因子。rCC16诱导了非哮喘和哮喘参与者的宿主防御因子的表达并降低了HNECs的病毒负担，这部分依赖于整合素α2β1、vas -2的相互作用。CC16缺失小鼠与野生型小鼠相比，RV感染更严重，炎症更多，肺部宿主防御因子基因表达更低。从CC16-/-的MTECs根尖洗涤中验证了分泌蛋白水平，与WT MTECs相比，分泌蛋白水平显著降低。在RV感染期间，在CC16-/-小鼠中通过递送rCC16进行的救援研究导致炎症细胞募集和感染减少。
结论：结果表明，CC16通过介导宿主防御因子的上调来减少上皮细胞中的鼻病毒感染，而哮喘患者由于CC16水平低，此机制可能受损。
Impaired CC16-mediated host responses to rhinovirus in nasal epithelial cells from asthma patients
Sasipa Tanyaratsrisakul, Natalie Iannuzo, Laurie M Ellerman, Paul R Langlais, Fernando D Martinez, Stefano Guerra, Julie G Ledford
Abstract
Background:Rhinovirus (RV) infections increase the risk for developing asthma and are the major trigger for disease exacerbations. Club cell secretory protein 16 (CC16) levels are decreased in asthma patients and inversely associated with inflammation and exacerbation frequency.
Objective:This study aims to determine the impact of CC16 on rhinovirus A, type 1B (RV-A1B) infection in airway nasal epithelial cells in the context of asthma status.
Methods:Human nasal epithelial cells (HNECs) from asthma and non-asthma participants in air-liquid interface culture were infected with RV-A1B, with and without rCC16. Viral RNA and the expression of host factors previously identified as associated with CC16 levels, including lysozyme, SPLUNC1, lactotransferrin and surfactant protein-D were quantified by RT-qPCR. Animal models and mouse tracheal epithelial cells (MTECs) sufficient and deficient in CC16 were infected with RV-A1B, with and without rCC16, to verify findings.
Results:HNECs from asthmatic individuals (n=7) had lower gene expression of CC16 and associated host defense factors under baseline conditions compared to non-asthmatic HNECs (n=7). While RV infection increased host factors in non-asthmatic HNECs, HNECs derived from asthmatic individuals failed to upregulate host factors in response to RV. rCC16 induced the expression of the host defense factors and reduced viral burden in HNECs from both non-asthma and asthma participants, which was in part dependent on integrin α2β1, VLA-2, interactions. Mice deficient in CC16 had worse RV infection, more inflammation and lower gene expression of host defense factors in their lungs compared to wild type mice. Secreted protein levels were verified from apical washings of MTECs from CC16-/- mice, which were significantly decreased compared to WT MTECs. Rescue studies in CC16-/-mice by delivery of rCC16 during RV infection resulted in decreased inflammatory cell recruitment and infection.
Conclusions:Results suggest that CC16 reduces rhinovirus infection in epithelial cells by mediating the upregulation of host defense factors and that this mechanism may be defective in asthma patients who have low levels of CC16.
背景：鼻病毒（RV）感染会增加哮喘发病风险，是疾病加重的主要诱因。Club细胞分泌蛋白16（CC16）水平在哮喘患者中降低，且与炎症和加重频率呈负相关。
目的：本研究旨在确定CC16对哮喘状态下气道鼻上皮细胞中鼻病毒A型1B亚型（RV-A1B）感染的影响。
方法：来自哮喘和非哮喘受试者在气液界面培养的人鼻上皮细胞（HNECs），用有无重组CC16（rCC16）处理的RV-A1B感染处理。通过逆转录定量聚合酶链反应（RT-qPCR）来定量病毒RNA及先前与CC16水平相关的宿主因子（包括溶菌酶、SPLUNC1、乳铁蛋白和表面活性蛋白-D）的表达。为验证研究结果，对CC16充足和缺乏的动物模型及小鼠气管上皮细胞（MTECs）分别用RV-A1B感染，同时在有无重组CC16（rCC16）的情况下进行处理。
结果：与非哮喘HNECs相比，哮喘个体（n=7）在基线条件下CC16和相关宿主防御因子的基因表达较低（n=7）。虽然RV感染增加了非哮喘性HNECs的宿主因子，但来自哮喘个体的HNECs对RV的反应没有上调宿主因子。rCC16诱导了非哮喘和哮喘参与者的宿主防御因子的表达并降低了HNECs的病毒负担，这部分依赖于整合素α2β1、vas -2的相互作用。CC16缺失小鼠与野生型小鼠相比，RV感染更严重，炎症更多，肺部宿主防御因子基因表达更低。从CC16-/-的MTECs根尖洗涤中验证了分泌蛋白水平，与WT MTECs相比，分泌蛋白水平显著降低。在RV感染期间，在CC16-/-小鼠中通过递送rCC16进行的救援研究导致炎症细胞募集和感染减少。
结论：结果表明，CC16通过介导宿主防御因子的上调来减少上皮细胞中的鼻病毒感染，而哮喘患者由于CC16水平低，此机制可能受损。
（北京朝阳医院呼吸与危重症医学科 顾宪民 摘译）
（中日友好医院呼吸与危重症医学科 林江涛 审校）
（J Allergy Clin Immunol. 2026 Jul 20:S0091-6749(26)00489-6. doi:10.1016/j.jaci.2026.06.021.）
（中日友好医院呼吸与危重症医学科 林江涛 审校）
（J Allergy Clin Immunol. 2026 Jul 20:S0091-6749(26)00489-6. doi:10.1016/j.jaci.2026.06.021.）
Impaired CC16-mediated host responses to rhinovirus in nasal epithelial cells from asthma patients
Sasipa Tanyaratsrisakul, Natalie Iannuzo, Laurie M Ellerman, Paul R Langlais, Fernando D Martinez, Stefano Guerra, Julie G Ledford
Abstract
Background:Rhinovirus (RV) infections increase the risk for developing asthma and are the major trigger for disease exacerbations. Club cell secretory protein 16 (CC16) levels are decreased in asthma patients and inversely associated with inflammation and exacerbation frequency.
Objective:This study aims to determine the impact of CC16 on rhinovirus A, type 1B (RV-A1B) infection in airway nasal epithelial cells in the context of asthma status.
Methods:Human nasal epithelial cells (HNECs) from asthma and non-asthma participants in air-liquid interface culture were infected with RV-A1B, with and without rCC16. Viral RNA and the expression of host factors previously identified as associated with CC16 levels, including lysozyme, SPLUNC1, lactotransferrin and surfactant protein-D were quantified by RT-qPCR. Animal models and mouse tracheal epithelial cells (MTECs) sufficient and deficient in CC16 were infected with RV-A1B, with and without rCC16, to verify findings.
Results:HNECs from asthmatic individuals (n=7) had lower gene expression of CC16 and associated host defense factors under baseline conditions compared to non-asthmatic HNECs (n=7). While RV infection increased host factors in non-asthmatic HNECs, HNECs derived from asthmatic individuals failed to upregulate host factors in response to RV. rCC16 induced the expression of the host defense factors and reduced viral burden in HNECs from both non-asthma and asthma participants, which was in part dependent on integrin α2β1, VLA-2, interactions. Mice deficient in CC16 had worse RV infection, more inflammation and lower gene expression of host defense factors in their lungs compared to wild type mice. Secreted protein levels were verified from apical washings of MTECs from CC16-/- mice, which were significantly decreased compared to WT MTECs. Rescue studies in CC16-/-mice by delivery of rCC16 during RV infection resulted in decreased inflammatory cell recruitment and infection.
Conclusions:Results suggest that CC16 reduces rhinovirus infection in epithelial cells by mediating the upregulation of host defense factors and that this mechanism may be defective in asthma patients who have low levels of CC16.
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严重哮喘中细胞衰老通路的临床特征
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