Sarco/Endoplasmic Reticulum Ca

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.