Interferons: Reprogramming the Metabolic Network against Viral Infection

Abstract

Viruses exploit the host and induce drastic metabolic changes to ensure an optimal environment for replication and the production of viral progenies. In response, the host has developed diverse countermeasures to sense and limit these alterations to combat viral infection. One such host mechanism is through interferon signaling. Interferons are cytokines that enhances the transcription of hundreds of interferon-stimulated genes (ISGs) whose products are key players in the innate immune response to viral infection. In addition to their direct targeting of viral components, interferons and ISGs exert profound effects on cellular metabolism. Recent studies have started to illuminate on the specific role of interferon in rewiring cellular metabolism to activate immune cells and limit viral infection. This review reflects on our current understanding of the complex networking that occurs between the virus and host at the interface of cellular metabolism, with a focus on the ISGs in particular, cholesterol-25-hydroxylase (CH25H), spermidine/spermine acetyltransferase 1 (SAT1), indoleamine-2,3-dioxygenase (IDO1) and sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1), which were recently discovered to modulate specific metabolic events and consequently deter viral infection.

Keywords: 25HC; IDO1; ISGs; SAMHD1; SAT1; interferons; metabolism; viruses.

Figure 1

Host Cell Metabolism. Glucose is taken up by specific transporters (GLUT family), where it is converted to pyruvate in the cytoplasm, generating two ATP molecules (glycolysis). In the presence of oxygen, pyruvate is transported into the mitochondria and oxidized into acetyl coenzyme A (acetyl-CoA), which enters the tricarboxylic acid (TCA) cycle. Intermediates of the TCA cycle feed off for fatty acid and cholesterol synthesis. Viruses are known to alter these key cellular metabolic pathways (highlighted in yellow). Further details are outlined in the text.

Figure 2

An overview of the antiviral activities of 25-HC. Interferon signaling leads to the expression of CH25H (cholesterol 25-hydroxylase) which catalyzes the formation of 25 hydroxycholesterol (25-HC) from cholesterol. Multiple studies have elucidated into the antiviral effects of 25-HC including, altering lipid membrane content to restrict viral fusion and entry, altering the distribution of cholesterol in internal membranes which hinders viral replication and, antagonizing endogenous protein prenylation (attachment of an isoprenoid e.g., farnesyl) thereby restricting viral replication and assembly. Yellow boxes indicate membrane alterations induced by 25-HC. Blue boxes indicate the effect of 25-HC on different viruses. T bar in red indicates inhibition. ER, endoplasmic reticulum.

Figure 3

Polyamine Biosynthesis. Upregulation of SAT1 by Type 1 IFNs results in polyamine depletion (red arrow). Enzymes are shown between each reaction (ODC, orthinine decarboxylase; SRM, spermidine synthase; SMS, spermine synthase; SMO, spermine oxidase; SAT1, Spermidine/spermine N(1)-acetyltransferase). Ornithine decarboxylase antizyme (OAZ), the first rate-limiting step in polyamine synthesis, binds and inhibits ODC. Difluoromethylornithine (DFMO), currently in clinical trials for cancer treatment, is an irreversible inhibitor of ornithine decarboxylase. T bar indicates inhibition. Blue dotted circle, nucleus. Consult text for more detail.

Figure 4

IDO1-mediated Tryptophan Depletion. Tryptophan is metabolized by the serotonin and kynurenine pathway. Iindole-2,3-dioxygenase 1 (IDO1) converts tryptophan into kynurenine. IFN-induced IDO1 gene expression decreases tryptophan availability for viral replication as well as reducing melatonin/serotonin synthesis and T cell proliferation. 1-methyl-d-tryptophan (I-MT) inhibits IDO1 and may have applications as a facilitator to enhance the immune response. Red arrows, downregulation; green arrows, upregulation. T bar, inhibition.