Coronaviruses Induce Entry-Independent, Continuous Macropinocytosis
Open Access
- 29 August 2014
- journal article
- Published by American Society for Microbiology in mBio
- Vol. 5 (4), e01340-14-14
- https://doi.org/10.1128/mbio.01340-14
Abstract
Macropinocytosis is exploited by many pathogens for entry into cells. Coronaviruses (CoVs) such as severe acute respiratory syndrome (SARS) CoV and Middle East respiratory syndrome CoV are important human pathogens; however, macropinocytosis during CoV infection has not been investigated. We demonstrate that the CoVs SARS CoV and murine hepatitis virus (MHV) induce macropinocytosis, which occurs late during infection, is continuous, and is not associated with virus entry. MHV-induced macropinocytosis results in vesicle internalization, as well as extended filopodia capable of fusing with distant cells. MHV-induced macropinocytosis requires fusogenic spike protein on the cell surface and is dependent on epidermal growth factor receptor activation. Inhibition of macropinocytosis reduces supernatant viral titers and syncytia but not intracellular virus titers. These results indicate that macropinocytosis likely facilitates CoV infection through enhanced cell-to-cell spreading. Our studies are the first to demonstrate virus use of macropinocytosis for a role other than entry and suggest a much broader potential exploitation of macropinocytosis in virus replication and host interactions. IMPORTANCE Coronaviruses (CoVs), including severe acute respiratory syndrome (SARS) CoV and Middle East respiratory syndrome CoV, are critical emerging human pathogens. Macropinocytosis is induced by many pathogens to enter host cells, but other functions for macropinocytosis in virus replication are unknown. In this work, we show that CoVs induce a macropinocytosis late in infection that is continuous, independent from cell entry, and associated with increased virus titers and cell fusion. Murine hepatitis virus macropinocytosis requires a fusogenic virus spike protein and signals through the epidermal growth factor receptor and the classical macropinocytosis pathway. These studies demonstrate CoV induction of macropinocytosis for a purpose other than entry and indicate that viruses likely exploit macropinocytosis at multiple steps in replication and pathogenesis.Keywords
This publication has 54 references indexed in Scilit:
- Severe Acute Respiratory Syndrome Coronavirus Nonstructural Proteins 3, 4, and 6 Induce Double-Membrane VesiclesmBio, 2013
- Integrins traffic rapidly via circular dorsal ruffles and macropinocytosis during stimulated cell migrationThe Journal of cell biology, 2011
- Vaccinia virus strains use distinct forms of macropinocytosis for host-cell entryProceedings of the National Academy of Sciences of the United States of America, 2010
- Repulsion of Superinfecting Virions: A Mechanism for Rapid Virus SpreadScience, 2010
- Epidermal Growth Factor Receptor Translocation to the MitochondriaOnline Journal of Public Health Informatics, 2009
- Molecular mechanisms of clathrin-independent endocytosisJournal of Cell Science, 2009
- Coronaviruses post-SARS: update on replication and pathogenesisNature Reviews Microbiology, 2009
- Pathways of Cross-Species Transmission of Synthetically Reconstructed Zoonotic Severe Acute Respiratory Syndrome CoronavirusJournal of Virology, 2008
- Shaping cups into phagosomes and macropinosomesNature Reviews Molecular Cell Biology, 2008
- Endosomal Proteolysis by Cathepsins Is Necessary for Murine Coronavirus Mouse Hepatitis Virus Type 2 Spike-Mediated EntryJournal of Virology, 2006