Influenza A Virus (H1N1) Infection Induces Glycolysis to Facilitate Viral Replication

Lehao Ren,Huiying Zhang,Ruilan Wang,Jiaxiang Zhang,Yong Zhu,Wanju Zhang,Jing Zhang,Zhigang Yi,Xiaoxiao Meng

doi:10.1007/s12250-021-00433-4

Abstract

Viruses depend on host cellular metabolism to provide the energy and biosynthetic building blocks required for their replication. In this study, we observed that influenza A virus (H1N1), a single-stranded, negative-sense RNA virus with an eight-segmented genome, enhanced glycolysis both in mouse lung tissues and in human lung epithelial (A549) cells. In detail, the expression of hexokinase 2 (HK2), the first enzyme in glycolysis, was upregulated in H1N1-infected A549 cells, and the expression of pyruvate kinase M2 (PKM2) and pyruvate dehydrogenase kinase 3 (PDK3) was upregulated in H1N1-infected mouse lung tissues. Pharmacologically inhibiting the glycolytic pathway or targeting hypoxia-inducible factor 1 (HIF-1), the central transcriptional factor critical for glycolysis, significantly reduced H1N1 replication, revealing a requirement for glycolysis during H1N1 infection. In addition, pharmacologically enhancing the glycolytic pathway further promoted H1N1 replication. Furthermore, the change of H1N1 replication upon glycolysis inhibition or enhancement was independent of interferon signaling. Taken together, these findings suggest that influenza A virus induces the glycolytic pathway and thus facilitates efficient viral replication. This study raises the possibility that metabolic inhibitors, such as those that target glycolysis, could be used to treat influenza A virus infection in the future.

Highlights

Viruses are obligate intracellular parasites that depend on host cellular metabolism to accomplish their replication
To identify the changes in glucose metabolism after H1N1 infection, we conducted a screen of key glycolytic enzymes in mock infected and H1N1 (A/PR/8/34) infected human lung epithelial (A549) cells, and we found that hexokinase 2 (HK2) was significantly upregulated after H1N1 infection at 16 h and 24 h post-infection (p.i.) (Fig. 1A)
It is known that less ATP is produced when the same amount of glucose is oxidized by glycolysis than by tricarboxylic acid (TCA) cycle, so we observed intracellular ATP levels in mock and H1N1-infected A549 cells at 24 h p.i

Summary

Introduction

Viruses are obligate intracellular parasites that depend on host cellular metabolism to accomplish their replication. An array of diverse viruses induces dramatic alterations in host cellular metabolic pathways including glycolysis, fatty acid synthesis, and glutaminolysis for their benefits (Sanchez and Lagunoff 2015). There are similarities among virus-induced metabolic modifications to some extent, each virus species may require unique metabolic alterations to complete its life cycle (Sanchez and Lagunoff 2015). White spot syndrome virus, dengue virus, norovirus, and Kaposi’s sarcoma herpesvirus (KSHV) induce glycolysis (Chen et al 2011; Yogev et al 2014; Fontaine et al 2015; Passalacqua et al 2019), whereas hepatitis C virus and vaccinia virus activate glutamine catabolism (Fontaine et al 2014; Thai et al 2015; Asim et al 2017; Levy et al 2017). Tomato bushy stunt virus (TBSV) recruits pyruvate kinase into its replicase complex to generate ATP to fuel its own replication (Chuang et al 2017).

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Conclusion