A quantitative model for virus uncoating predicts influenza A infectivity
Alina Artcibasova,
Longlong Wang,
Stephanie Anchisi,
Yohei Yamauchi,
Mirco Schmolke,
Patrick Matthias,
Jörg Stelling
Affiliations
Alina Artcibasova
Department of Biosystems Science and Engineering and SIB Swiss Institute of Bioinformatics, ETH Zurich, 4058 Basel, Switzerland
Longlong Wang
Friedrich Miescher Institute for Biomedical Research (FMI), 4058 Basel, Switzerland; Faculty of Sciences, University of Basel, 4031 Basel, Switzerland
Stephanie Anchisi
Department of Microbiology and Molecular Medicine and Geneva Center of Inflammation Research, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
Yohei Yamauchi
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
Mirco Schmolke
Department of Microbiology and Molecular Medicine and Geneva Center of Inflammation Research, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
Patrick Matthias
Friedrich Miescher Institute for Biomedical Research (FMI), 4058 Basel, Switzerland; Faculty of Sciences, University of Basel, 4031 Basel, Switzerland; Corresponding author
Jörg Stelling
Department of Biosystems Science and Engineering and SIB Swiss Institute of Bioinformatics, ETH Zurich, 4058 Basel, Switzerland; Corresponding author
Summary: For virus infection of new host cells, the disassembly of the protective outer protein shell (capsid) is a critical step, but the mechanisms and host-virus interactions underlying the dynamic, active, and regulated uncoating process are largely unknown. Here, we develop an experimentally supported, multiscale kinetics model that elucidates mechanisms of influenza A virus (IAV) uncoating in cells. Biophysical modeling demonstrates that interactions between capsid M1 proteins, host histone deacetylase 6 (HDAC6), and molecular motors can physically break the capsid in a tug-of-war mechanism. Biochemical analysis and biochemical-biophysical modeling identify unanchored ubiquitin chains as essential and allow robust prediction of uncoating efficiency in cells. Remarkably, the different infectivity of two clinical strains can be ascribed to a single amino acid variation in M1 that affects binding to HDAC6. By identifying crucial modules of viral infection kinetics, the mechanisms and models presented here could help formulate novel strategies for broad-range antiviral treatment.
