Viral RNA Degradation and Diffusion Act as a Bottleneck for the Influenza A Virus Infection Efficiency
| Autor: | Andreas Herrmann, Max Flöttmann, Christian Sieben, Edda Klipp, Fabian Jolmes, Max Schelker, Robert-William Welke, Caroline M. Mair |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
RNA viruses
0301 basic medicine viruses Cell Membranes Endocytic cycle Artificial Gene Amplification and Extension medicine.disease_cause Membrane Fusion Polymerase Chain Reaction Cell Fusion Diffusion Influenza A virus lcsh:QH301-705.5 Pathology and laboratory medicine Viral Genomics Cell fusion Ecology Genomics Medical microbiology Endocytosis Hemagglutinins Computational Theory and Mathematics Modeling and Simulation Viruses RNA Viral Pathogens Cellular Structures and Organelles Network Analysis Research Article Cell Physiology Computer and Information Sciences Endosome Microbial Genomics Endosomes Biology Research and Analysis Methods Genome Complexity Microbiology Models Biological Virus 03 medical and health sciences Cellular and Molecular Neuroscience Viral entry Virology Influenza Human Genetics medicine Influenza viruses Humans Computer Simulation Vesicles Molecular Biology Techniques Molecular Biology Ecology Evolution Behavior and Systematics Medicine and health sciences Biology and life sciences 030102 biochemistry & molecular biology Organisms Viral pathogens Computational Biology Lipid bilayer fusion Cell Biology Virus Internalization Viral membrane Microbial pathogens Signaling Networks 030104 developmental biology lcsh:Biology (General) Wireless Sensor Networks Orthomyxoviruses |
| Zdroj: | PLoS Computational Biology, Vol 12, Iss 10, p e1005075 (2016) PLoS Computational Biology |
| ISSN: | 1553-7358 |
| Popis: | After endocytic uptake, influenza viruses transit early endosomal compartments and eventually reach late endosomes. There, the viral glycoprotein hemagglutinin (HA) triggers fusion between endosomal and viral membrane, a critical step that leads to release of the viral segmented genome destined to reach the cell nucleus. Endosomal maturation is a complex process involving acidification of the endosomal lumen as well as endosome motility along microtubules. While the pH drop is clearly critical for the conformational change and membrane fusion activity of HA, the effect of intracellular transport dynamics on the progress of infection remains largely unclear. In this study, we developed a comprehensive mathematical model accounting for the first steps of influenza virus infection. We calibrated our model with experimental data and challenged its predictions using recombinant viruses with altered pH sensitivity of HA. We identified the time point of virus-endosome fusion and thereby the diffusion distance of the released viral genome to the nucleus as a critical bottleneck for efficient virus infection. Further, we concluded and supported experimentally that the viral RNA is subjected to cytosolic degradation strongly limiting the probability of a successful genome import into the nucleus. Author Summary Influenza A virus carries its segmented genome inside a lipid envelope. Since genome replication occurs inside the nucleus, the main goal of virus infection is to deliver all genome segments through the cytoplasm into the nucleus. After endocytic uptake, influenza viruses transit early endosomal compartments and eventually reach late endosomes. Within a complex maturation process, the endosomal lumen acidifies while the vesicles are transported trough the cytosol. If and how these early processes affect virus infection remained mostly speculative. To reach a better understanding and to quantify the physical interplay between membrane fusion, genome diffusion and infection, we developed a mathematical model that comprises all initial steps of virus infection until genome delivery. We calibrated our model using experimental data and challenged its predictions using recombinant viruses to introduce perturbations. Our results provide a theoretical framework to understand the importance of the endosomal virus passage before membrane fusion and genome release. We further unraveled RNA degradation as a previously unknown limiting factor for virus infection. Our work will help to make predictions and evaluate newly occurring virus strains, regarding their infection efficiency in a given host cell, by simply considering their pH sensitivity. |
| Databáze: | OpenAIRE |
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