Glycolytic control of vacuolar-type ATPase activity: A mechanism to regulate influenza viral infection

Abstract

As new influenza virus strains emerge, finding new mechanisms to control infection is imperative. In this study, we found that we could control influenza infection of mammalian cells by altering the level of glucose given to cells. Higher glucose concentrations induced a dose-specific increase in influenza infection. Linking influenza virus infection with glycolysis, we found that viral replication was significantly reduced after cells were treated with glycolytic inhibitors. Addition of extracellular ATP after glycolytic inhibition restored influenza infection. We also determined that higher levels of glucose promoted the assembly of the vacuolar-type ATPase within cells, and increased vacuolar-type ATPase proton-transport activity. The increase of viral infection via high glucose levels could be reversed by inhibition of the proton pump, linking glucose metabolism, vacuolar-type ATPase activity, and influenza viral infection. Taken together, we propose that altering glucose metabolism may be a potential new approach to inhibit influenza viral infection.

Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Upregulates Glucose Transporter 1 Transcription via the mTORC1/NF-κB Signaling Pathways

“…STF-31, used in this study, is one of the promising Glut-1 inhibitors which have been shown to selectively kill renal carcinoma cells (25,43). Interestingly, there are reports showing that high glucose levels also enhance virus infection of host cells, supporting viral replication and maintenance of latency infection (44)(45)(46). Activation of Glut-1 transcription is a novel property of LMP1 not previously reported.…”

Lower Respiratory Tract Infection of the Ferret by 2009 H1N1 Pandemic Influenza A Virus Triggers Biphasic, Systemic, and Local Recruitment of Neutrophils

“…We previously reported greater uptake of FDG in the right caudal lung compared to that in other lobes, where we and others have found increased viral replication and neutrophil infiltration (29,30,33). Another hypothesis to explain increased FDG uptake is that IAV increases cellular glucose metabolism (99). We found that infection with IAV isolates caused an increase in FDG uptake by immortalized human epithelial cell lines (A549) in vitro but not by differentiated human bronchial epithelial cells (16HBEoϪ) (29,58; also data not shown).…”

“…We found that infection with IAV isolates caused an increase in FDG uptake by immortalized human epithelial cell lines (A549) in vitro but not by differentiated human bronchial epithelial cells (16HBEoϪ) (29,58; also data not shown). Increased glucose levels promote the acidification of cellular endosomal compartments, a step required for IAV infection of cells (99,100). In hospital clinics, FDG is used to detect metabolically active tumors throughout the body, including the lungs, as it is taken into cells through glucose transporters and accumulates (71,101,102).…”

Saccharomyces cerevisiae Vacuolar H + -ATPase Regulation by Disassembly and Reassembly: One Structure and Multiple Signals

“…Moreover, V-ATPase mutations that impair binding to phosphofructokinase-1 are associated with distal renal tubular acidosis (24), and V-ATPase regulation by glycolysis plays a role in viral infections (40) and the metabolic switch in cancers (41,42). It has been proposed that glycolytic enzymes form a supercomplex with V-ATPase that funnels ATP directly to VATPase and propels proton transport (21,24,32,34,37,43).…”