Sarco/Endoplasmic Reticulum Ca2+-Transporting ATPase (SERCA) Modulates Autophagic, Inflammatory, and Mitochondrial Responses during Influenza A Virus Infection in Human Lung Cells

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 dysfunctio