First Genome-Scale Metabolic Model for Understanding HMPV-Host Interaction

Abstract

BackgroundHuman Metapneumovirus (HMPV) is a major contributor to acute respiratory tract infections. Currently, no approved vaccines or specific antiviral therapies are available worldwide. Genome-scale metabolic models (GEMs), when integrated with Viral Biomass Objective Functions (VBOFs), provide a robust computational framework for identifying host metabolic dependencies essential for viral replication. This approach enables systematic prioritization of potential antiviral drug targets. ResultsThe first comprehensive VBOF for HMPV was constructed by integrating stoichiometric data from the viral genome, including structural proteins with defined copy numbers, amino acid residues per virion, envelope lipids, and glycan modifications. The reconstructed VBOF was incorporated into the human bronchial epithelial cell model, iHBEC1, to analyze metabolic changes between uninfected and infected host cells. Knockout analysis identified two selective antiviral gene targets: PGM3 (phosphoacetylglucosamine mutase) and GNPNAT1 (N-acetylglucosamine-6-phosphate acetyltransferase), as well as seven selective reaction targets primarily within the hexosamine biosynthesis and nucleotide sugar pathways. Knockout of PGM3 or GNPNAT1 completely abolished viral production while preserving complete host cell viability. Additionally, guanylate kinase (GUK1/GK1) emerged as a highly selective target for HMPV, confirming findings from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) studies and suggesting a conserved vulnerability across respiratory viruses. ConclusionsUDP-GlcNAc, the vital end-product of the hexosamine biosynthesis pathway (HBP), is computationally predicted as a critical metabolic hub. This pathway represents the primary metabolic vulnerability of HMPV, due to the extensive glycosylation requirements of the HMPV attachment protein. The host-directed antiviral targets PGM3 and GNPNAT1 are high-priority candidates for experimental validation and may provide novel strategies to combat this respiratory infection.