School of Medicine, South China University of Technology, Guangzhou, China.
Department of Respiration, Guangzhou Women and Children's Medical Centre, Guangzhou, China.
Front Immunol. 2023 Apr 18;14:1169968. doi: 10.3389/fimmu.2023.1169968. eCollection 2023.
Human adenovirus (HAdV) is a common respiratory virus, which can lead to severe pneumonia in children and immunocompromised persons, and canonical inflammasomes are reported to be involved in anti-HAdV defense. However, whether HAdV induced noncanonical inflammasome activation has not been explored. This study aims to explore the broad roles of noncanonical inflammasomes during HAdV infection to investigate the regulatory mechanism of HAdV-induced pulmonary inflammatory damage.
We mined available data on GEO database and collected clinical samples from adenovirus pneumonia pediatric patients to investigate the expression of noncanonical inflammasome and its clinical relevance. An cell model was employed to investigate the roles of noncanonical inflammasomes in macrophages in response to HAdV infection.
Bioinformatics analysis showed that inflammasome-related genes, including caspase-4 and caspase-5, were enriched in adenovirus pneumonia. Moreover, caspase-4 and caspase-5 expression levels were significantly increased in the cells isolated from peripheral blood and broncho-alveolar lavage fluid (BALF) of pediatric patients with adenovirus pneumonia, and positively correlated with clinical parameters of inflammatory damage. experiments revealed that HAdV infection promoted caspase-4/5 expression, activation and pyroptosis in differentiated THP-1 (dTHP-1) human macrophages via NF-κB, rather than STING signaling pathway. Interestingly, silencing of caspase-4 and caspase-5 in dTHP-1 cells suppressed HAdV-induced noncanonical inflammasome activation and macrophage pyroptosis, and dramatically decreased the HAdV titer in cell supernatants, by influencing virus release rather than other stages of virus life cycle.
In conclusion, our study demonstrated that HAdV infection induced macrophage pyroptosis by triggering noncanonical inflammasome activation via a NF-kB-dependent manner, which may explore new perspectives on the pathogenesis of HAdV-induced inflammatory damage. And high expression levels of caspase-4 and caspase-5 may be a biomarker for predicting the severity of adenovirus pneumonia.
人腺病毒（HAdV）是一种常见的呼吸道病毒，可导致儿童和免疫功能低下者发生严重肺炎，已有报道称经典炎性小体参与抗 HAdV 防御。然而，HAdV 是否诱导非经典炎性小体激活尚未得到探索。本研究旨在探讨非经典炎性小体在 HAdV 感染过程中的广泛作用，以研究 HAdV 诱导的肺炎症性损伤的调控机制。
我们从 GEO 数据库中挖掘了可用数据，并从腺病毒肺炎儿科患者中收集了临床样本，以研究非经典炎性小体的表达及其与临床的相关性。采用细胞模型研究非经典炎性小体在巨噬细胞应对 HAdV 感染中的作用。
生物信息学分析显示，炎性小体相关基因，包括 caspase-4 和 caspase-5，在腺病毒肺炎中富集。此外，在儿科腺病毒肺炎患者外周血和支气管肺泡灌洗液（BALF）分离的细胞中，caspase-4 和 caspase-5 的表达水平显著增加，且与炎症损伤的临床参数呈正相关。实验发现，HAdV 感染通过 NF-κB 而非 STING 信号通路促进分化的 THP-1（dTHP-1）人巨噬细胞中 caspase-4/5 的表达、激活和细胞焦亡。有趣的是，在 dTHP-1 细胞中沉默 caspase-4 和 caspase-5 抑制了 HAdV 诱导的非经典炎性小体激活和巨噬细胞细胞焦亡，并通过影响病毒释放而不是病毒生命周期的其他阶段，显著降低细胞上清液中的 HAdV 滴度。
总之，本研究表明，HAdV 感染通过 NF-κB 依赖性方式触发非经典炎性小体激活，导致巨噬细胞细胞焦亡，这可能为 HAdV 诱导的炎症损伤发病机制提供新视角。高表达水平的 caspase-4 和 caspase-5 可能是预测腺病毒肺炎严重程度的生物标志物。
