Acute effects of interferon-alpha on cellular anabolic and catabolic processes are associated with the development of fatigue during Interferon-alpha-based therapy for Hepatitis-C: A preliminary study

Periche Tomas, Eva, Cattamep, Annamaria, Cattane, Nadia, Bone, Claudia, Tibble, Jeremy, Bullmore, Edward T., Pariante, Carmine and Harrison, Neil A. ORCID: https://orcid.org/0000-0002-9584-3769 2025. Acute effects of interferon-alpha on cellular anabolic and catabolic processes are associated with the development of fatigue during Interferon-alpha-based therapy for Hepatitis-C: A preliminary study. Brain, Behavior, and Immunity 123 , pp. 717-724. 10.1016/j.bbi.2024.09.038

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Abstract

Introduction Interferon-alpha (IFN-α) is a key mediator of antiviral immune responses used to treat Hepatitis-C virus (HCV) infection. Though clinically effective, IFN-α frequently induces functionally impairing mood and motivation symptoms, particularly fatigue. Unlike mood impairment, which typically emerges after weeks of treatment, fatigue tends to emerge and evolve rapidly, typically within hours of the first IFN-α injection. Despite being a major source of functional impairment during IFN-α and other immune-based therapies, the biological mechanisms underlying fatigue remain poorly understood. Here, we aimed to identify acute immune-response signatures to IFN-α that could predict the later development of fatigue. Methods In this exploratory study, we analyzed whole blood transcriptomics in a longitudinal sample of 27 HCV patients initiating IFN-α and Ribavirin therapy. Blood samples were obtained at baseline and 4½ hours after the first IFN-α dose and transcriptomic data was obtained using Affymetrix Human Gene 1.1 ST Array Strips. Gene expression data visualization and quality control were assessed using Partek Genomics Suite V6.6 and protein–protein interaction networks using STRING and Ingenuity Pathway Analysis (IPA). A Fatigue Visual Analogue Scale (fVAS) was utilized to record fatigue symptoms at baseline, 4½ hours and 4 weeks after initiation of treatment. Results IFN-α was associated with an upregulation of 526 transcripts and a downregulation of 228 genes, indicating a rapid transcriptomic response in whole blood within 4½ hours of injection. 93 genes were significantly positively correlated with changes in fatigue, with gene expression changes measured from baseline to 4.5 h and increases in fatigue assessed from baseline to week 4 on the fVAS. We identified a novel network of predominantly cytosolic ribosomal units and ubiquitin proteins implicated in modulating mTOR signaling that was associated with the development of fatigue 4 weeks after initiation of IFN-α treatment (p = 0.0078). Conclusion Our findings suggest that acute activation of this anabolic/catabolic network by IFN-α may predispose to the experience of fatigue similar to evidence found in cancer-related fatigue. Further investigation is warranted to confirm the exploratory nature of these observations.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Psychology Cardiff University Brain Research Imaging Centre (CUBRIC)
Publisher:	Elsevier
ISSN:	0889-1591
Funders:	MRC
Date of First Compliant Deposit:	28 October 2024
Date of Acceptance:	24 September 2024
Last Modified:	25 Nov 2024 16:53
URI:	https://orca.cardiff.ac.uk/id/eprint/173247

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