Sarco/Endoplasmic Reticulum Ca2+-Transporting ATPase (SERCA) Modulates Autophagic, Inflammatory, and Mitochondrial Responses during Influenza A Virus Infection in Human Lung Cells
Sarco/Endoplasmic Reticulum Ca2+-Transporting ATPase (SERCA) Modulates Autophagic, Inflammatory, and Mitochondrial Responses during Influenza A Virus Infection in Human Lung Cells
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肉质/内质网 Ca2 转运 ATP 酶 (SERCA) 调节人肺细胞甲型流感病毒感染期间的自噬、炎症和线粒体反应
DOI：
10.1128/jvi.00217-21
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发表时间：
2021-05-01
影响因子：
5.4
通讯作者：
Ling，Chen
中科院分区：
文献类型：
--
作者：
Peng，Jiaojiao;Ran，Yeqian;Ling，Chen
IAV是传染性呼吸道疾病的主要原因，其特征在于显著的呼吸道炎症反应，其在季节性流行病或大流行病爆发中引起发病率和死亡率。SERCA是维持细胞钙水平的关键成分，与自噬通量呈正相关。甲型流感病毒是一种重要的人类病原体，可导致严重的发病率和死亡率。在甲型流感病毒（IAV）感染期间，许多宿主因子和细胞反应失调。这包括依赖于流感M2离子通道的自噬通量的停滞，但关于哪些宿主因素参与这种自噬功能障碍知之甚少。肌浆网/内质网钙ATP酶（SERCA）是调节钙离子在细胞质和肌浆网/内质网之间转运的重要酶，与自噬通量呈正相关。在这里，我们发现SERCA活性在甲型流感病毒感染的人肺细胞（H1395）中被抑制，并且SERCA的激活剂CDN1163恢复自噬通量，从而减少由甲型流感病毒引起的自噬体积累。用CDN1163激活SERCA活性还降低了IAV感染的H1395细胞中炎性细胞因子和趋化因子的表达，并减弱了线粒体功能障碍。相反，SERCA抑制或基因消融加重了感染甲型流感病毒的细胞中的自噬功能障碍、线粒体和炎症反应。进一步的研究表明，SERCA可能通过调节MAPK-JNK通路的磷酸化来调节炎症反应。这些发现表明，甲型流感病毒通过抑制SERCA活性诱导自噬通量阻断、炎症反应和线粒体功能障碍。这项研究提供了流感病毒，SERCA活性，自噬，炎症反应和线粒体功能之间的宿主-病毒相互作用的进一步理解。SERCA可能是减轻甲型流感病毒感染过程中炎症和超氧化物损伤的宿主靶点。重要性IAV是传染性呼吸道疾病的主要原因，其特征是显著的呼吸道炎症反应，在季节性流行病或大流行病爆发中引起发病率和死亡率。SERCA是维持细胞钙水平的关键成分，与自噬通量呈正相关。在这里，我们发现SERCA在IAV感染的人肺细胞中被抑制，并且甲型流感病毒通过抑制SERCA诱导自噬通量、炎症反应和线粒体功能障碍的阻断。我们认为，药理学激活SERCA可以是一个强大的干预策略，以防止自噬停滞，炎症反应，和IAV感染的细胞线粒体功能障碍。因此，SERCA活性调节可能是控制严重流感疾病临床症状的治疗策略。
IAV is a major cause of infectious respiratory diseases, characterized by a marked respiratory tract inflammatory response that causes morbidity and mortality in seasonal epidemics or pandemic outbreaks. SERCA is a critical component in maintaining cellular calcium levels and is positively correlated with autophagic flux. ABSTRACT Influenza A virus is an important human pathogen, causing significant morbidity and mortality. Numerous host factors and cellular responses are dysregulated during influenza A virus (IAV) infection. This includes the arrest of autophagic flux dependent on the influenza M2 ion channel, but little is known about which host factors participate in this autophagic dysfunction. Sarco/endoplasmic reticulum calcium ATPase (SERCA) is known to regulate the transport of calcium ions between the cytoplasm and the sarco/endoplasmic reticulum and has been positively correlated with autophagic flux. Here, we found that SERCA activity was suppressed in influenza A virus-infected human lung cells (H1395) and that CDN1163, an activator of SERCA, restored autophagic flux and, thus, reduced autophagosome accumulation caused by the influenza A virus. Activating SERCA activity with CDN1163 also decreased expression of inflammatory cytokines and chemokines and attenuated mitochondrial dysfunction in IAV-infected H1395 cells. Conversely, SERCA inhibition or genetic ablation aggravated the autophagy dysfunction, mitochondria, and inflammatory responses in the cells infected with influenza A virus. Further study showed that SERCA might regulate the inflammatory response by modulating phosphorylation of the MAPK-JNK pathway. These findings showed that the influenza A virus induced autophagic flux blocking, inflammatory response, and mitochondrial dysfunction by inhibiting SERCA activity. This study provides further understanding of the host-virus interactions between the influenza virus, SERCA activity, autophagy, inflammatory response, and mitochondrial function. SERCA may be a host target for decreasing inflammatory and superoxide injury during influenza A virus infection. IMPORTANCE IAV is a major cause of infectious respiratory diseases, characterized by a marked respiratory tract inflammatory response that causes morbidity and mortality in seasonal epidemics or pandemic outbreaks. SERCA is a critical component in maintaining cellular calcium levels and is positively correlated with autophagic flux. Here, we discovered that SERCA is suppressed in IAV-infected human lung cells, and influenza A virus induces blocking of autophagic flux, inflammatory response, and mitochondrial dysfunction by inhibiting SERCA. We posit that the pharmacological activation of SERCA can be a powerful intervention strategy to prevent autophagy arrest, inflammatory response, and mitochondrial dysfunction in IAV-infected cells. Therefore, SERCA activity modulation could be a therapeutic strategy for managing clinical symptoms of severe influenza disease.