Interferon-Stimulated Genes and Immune Metabolites as Broad-Spectrum Biomarkers for Viral Infections

Abstract

The type I interferon (IFN-I) response is a critical component of the immune defense against various viral pathogens, triggering the expression of hundreds of interferon-stimulated genes (ISGs). These ISGs encode proteins with diverse antiviral functions, targeting various stages of viral replication and restricting infection spread. Beyond their antiviral functions, ISGs and associated immune metabolites have emerged as promising broad-spectrum biomarkers that can differentiate viral infections from other conditions. This review provides an overview of the diagnostic potential of ISGs at transcript and protein levels, as well as their immune metabolites. We focus on their clinical applications and the sensitivity and specificity of these biomarkers through receiver operating characteristic (ROC) analysis. We highlight the need for further research to facilitate the effective translation of these biomarkers into clinical practice.

Keywords: Biomarker; CXCL10; IFI27; IFI44L; ISG15; ISGs; MxA; ddhC; type I Interferon.

Figure 1

The IFN-I response and IFN-I-derived biomarkers. During viral infections, host cells recognize viral components through pattern recognition receptors, including toll-like receptors (TLRs) on the cell surface or in the endosomes. Additionally, viral DNA or RNA in the cytoplasm can be detected by nucleic acid sensors, such as RIG-I, MDA5, and cGAS. These sensors activate the induction and secretion of IFN-I (IFNα and IFNβ). The binding of IFNα and IFNβ to the type I interferon receptor (IFNAR) triggers the expression of interferon-stimulated genes (ISGs) driven by the interferon-stimulated response element (ISRE). Several ISGs, along with their protein products and small-molecule immune metabolites, have been identified as promising biomarkers for viral infections.

Figure 2

CMPK2, viperin, and the synthesis of ddhCTP-derived nucleoside analogs. The antiviral ISG protein UMP-CMP kinase 2 (CMPK2) catalyzes the phosphorylation of cytidine diphosphate (CDP) to produce cytidine triphosphate (CTP), which is then converted into 3′-deoxy-3′,4′-didehydro-CTP (ddhCTP) by the ISG protein viperin [65]. ddhCTP can be further converted into several ddhCTP-derived nucleoside analogs, including ddhC, ddh-uridine (ddhU), ddhC-5′-carboxylic acid (ddhC-5′CA), and ddhC-5′homocysteine (ddhC-5′Hcy). These four metabolites are the most highly induced nucleoside analogs in the urine and serum of patients with acute COVID-19 [22]. C, cytosine (in blue); U, uracil (in yellow).