Year: 2023
Type: preprint
Abstract: The cell entry mechanism of SARS-CoV-2, the causative agent of the COVID-19 pandemic, is not fully understood. Most animal viruses hijack cellular endocytic pathways as an entry route into the cell. Here, we show that in cells that do not express serine proteases such as TMPRSS2, genetic depletion of all dynamin isoforms blocked the uptake and strongly reduced infection with SARS-CoV-2 and its variant Delta. However, increasing the viral loads partially and dose-dependently restored infection via a thus far uncharacterized entry mechanism. Ultrastructural analysis by electron microscopy showed that this dynamin-independent endocytic processes appeared as 150-200 nm non-coated invaginations and was efficiently used by numerous mammalian viruses, including alphaviruses, influenza, vesicular stomatitis, bunya, adeno, vaccinia, and rhinovirus. Both the dynamin-dependent and dynamin-independent infection of SARS-CoV-2 required a functional actin cytoskeleton. In contrast, the alphavirus Semliki Forest virus, which is smaller in diameter, required actin only for the dynamin-independent entry. The presence of TMPRSS2 protease rescued SARS-CoV-2 infection in the absence of dynamins. Collectively, these results indicate that some viruses such as canine parvovirus and SARS-CoV-2 mainly rely on dynamin for endocytosis-dependent infection, while other viruses can efficiently bypass this requirement harnessing an alternative infection entry route dependent on actin.
Authors: Ravi Ojha, Anmin Jiang, Elina Mäntylä, Naphak Modhira, Robert Witte, Arnaud Gaudin, Lisa De Zanetti, Rachel Gormal, Maija Vihinen-Ranta, Jason Mercer, Maarit Suomalainen, Urs F. Greber, Yohei Yamauchi, Pierre Yves-Lozach, Ari Helenius, Olli Vapalahti, Paul Young, Daniel Watterson, Frédéric A. Meunier, Merja Joensuu, Giuseppe Balistreri
Institutions: University of Helsinki, The University of Queensland, Tampere University, University of Tampere, University of Zurich, Ghent University, University of Jyväskylä, University of Birmingham, ETH Zurich, Institute of Pharmaceutical Sciences, École Pratique des Hautes Études, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Helsinki University Hospital
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
Funders: Helsingin Yliopisto, European Commission, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, University of Queensland, Academy of Finland, Jane ja Aatos Erkon Säätiö, HORIZON EUROPE Framework Programme, Medical Research Council, Australian Research Council, National Health and Medical Research Council
Awards: Live molecular imaging using super resolution microscopy, two photon and spinning disk confocal microscopy, G2426164892, A novel role for saturated fatty acids in learning and memory, Targeting neuropilin in SARS-Cov-2 neuronal uptake and transport, Special funding for research on COVID-19 epidemic and the mitigation of its effects, G5704780687, Decision support for prediction and management of Long Covid Syndrome (LCS), Mechanisms of Infection Variability in Virus Entry, Persistence and Egress, Viral offense meets cellular defense – From virus entry to egress, G8690818240
OpenAlex ID: W4383106116