Sarco/Endoplasmic Reticulum Ca2+ Transporting ATPase (SERCA) Modulates Autophagic, Inflammatory, and Mitochondrial Responses during Influenza A Virus Infection in Human Lung Cells.
J Virol
; 95(10)2021 04 26.
Article
em En
| MEDLINE
| ID: mdl-33692207
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 infection. This includes arrest of autophagic flux dependent on the influenza M2 ion channel, but little is known which host factors participate in this autophagic dysfunction. Sarco/endoplasmic reticulum calcium ATPase (SERCA) is known to regulate transport of calcium ions between the cytoplasm and the sarco/endoplasmic reticulum, and has been positively correlated with autophagic flux. Herein, 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 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-viral interactions between the influenza virus, SERCA activity, autophagy, inflammatory response, and mitochondrial function. SERCA may be a potential host target for decreasing inflammatory and superoxide injury during influenza A virus infection.IMPORTANCEIAV 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 potential therapeutic strategy for managing clinical symptoms of severe influenza disease.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
J Virol
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
China