HIF-1α Modulates Core Metabolism and Virus Replication in Primary Airway Epithelial Cells Infected with Respiratory Syncytial Virus

Abstract

Metabolic reprogramming of host cells is key to the foundation of a successful viral infection. Hypoxia inducible factors (HIFs) mediate oxygen utilization by regulating cellular metabolism and redox homeostasis. Under normoxic conditions, HIF proteins are synthesized and subsequently degraded following ubiquitination to allow for normal metabolic activities. Recent studies suggest that respiratory syncytial virus (RSV) has the ability to induce HIF-1α stabilization and accumulation through non-hypoxic mechanisms. This makes the HIF pathway a potential avenue of approach for RSV therapeutic development. Using a model of primary human small alveolar epithelial cells, we demonstrate RSV infections to greatly alter cellular metabolism in favor of the glycolytic and pentose phosphate pathways. Additionally, we show RSV infections to stabilize HIF-1α and HIF-2α expression in these cells. Inhibition of HIF-1α, but not HIF-2α, was found to significantly reduce RSV replication as well as the glycolytic pathway, as measured by the expression of hexokinase II. Our study contributes to the understanding of RSV-mediated changes to cellular metabolism and supports further investigation into anti-HIF-1α therapeutics for RSV infections.

Metabolic Reprogramming of Nasal Airway Epithelial Cells Following Infant Respiratory Syncytial Virus Infection

“…RSV infection is certainly sufficient to induce changes in metabolism. This is supported by studies showing increased glycolysis, pentose phosphate pathway activity, and mitochondrial respiration in RSV-infected airway epithelial cells in vitro [19][20][21] and in vivo [22]. These metabolic phenotypes largely agree with our findings of increased central energy and anabolic metabolism in primary airway cells from children with a history of RSV infection in infancy.…”

“…Several studies have documented that human RSV infection in vivo and bronchiolitis are accompanied by systemic changes in metabolism [14][15][16][17][18]. Metabolic changes resulting from RSV infection of epithelial cells in vitro have also been previously documented [19][20][21]. Active infection with in vitro RSV increases cellular energetic demands and results in increased activity of mitochondrial and cellular metabolism pathways.…”

“…Active infection with in vitro RSV increases cellular energetic demands and results in increased activity of mitochondrial and cellular metabolism pathways. These changes largely favor the activity of glycolytic and pentose phosphate pathways [21]. However, despite growing interest in targeting metabolic reprogramming of RSV and influenza infection for therapeutic intervention [20,22], virtually nothing is known about in-vivo metabolic reprogramming of epithelial cells from children with history of RSV infection in infancy (less than one year of age).…”

Impact of Hypoxia over Human Viral Infections and Key Cellular Processes

“…Furthermore, mRNA expression of hexokinase 2 (HK II), which catalyzes the phosphorylation of glucose to glucose-6-P, corelates with HIF-1α protein in hepatocellular carcinoma cells and metastatic liver cancer, and HK II and HIF-1α protein expression co-localized in these cancer cells [ 35 , 36 ]. Furthermore, during viral infections, such as those produced by the hepatitis C virus (HCV), HK II is overexpressed and in cells infected with the human respiratory syncytial virus (hRSV) HIF-1α suppression induced a decrease in HK II protein levels [ 37 , 38 ]. Moreover, PFK-1, which phosphorylates fructose-6-P to fructose-1,6 bisphosphate (FBP), is also activated under hypoxic conditions by HIF-1-induced PFK-2/F-2,6-BPase, and the downregulation of the latter in cancer cells has been reported to inhibit tumor growth [ 39 , 40 ].…”

Respiratory syncytial virus: from pathogenesis to potential therapeutic strategies

“…These changes lead to impairment of mitochondrial respiratory function, loss of mitochondrial membrane potential and elevation of mitochondrial reactive oxygen species (ROS), which in turn increase the replication and titer of RSV. In addition, RSV infection can stabilize the expression of hypoxia-inducible factor-1α (HIF-1α) in infected cells, which profoundly changes cell metabolism to facilitate glycolysis and the pentose phosphate pathway activation and further enhance the replication ability of RSV [53].…”