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Coxsackievirus B Exits the Host Cell in Shed Microvesicles Displaying Autophagosomal Markers
Open accessAbstract
Coxsackievirus B3 (CVB3), a member of the picornavirus family and enterovirus genus, causes viral myocarditis, aseptic meningitis, and pancreatitis in humans. We genetically engineered a unique molecular marker, "fluorescent timer" protein, within our infectious CVB3 clone and isolated a high-titer recombinant viral stock (Timer-CVB3) following transfection in HeLa cells. "Fluorescent timer" protein undergoes slow conversion of fluorescence from green to red over time, and Timer-CVB3 can be utilized to track virus infection and dissemination in real time. Upon infection with Timer-CVB3, HeLa cells, neural progenitor and stem cells (NPSCs), and C2C12 myoblast cells slowly changed fluorescence from green to red over 72 hours as determined by fluorescence microscopy or flow cytometric analysis. The conversion of "fluorescent timer" protein in HeLa cells infected with Timer-CVB3 could be interrupted by fixation, suggesting that the fluorophore was stabilized by formaldehyde cross-linking reactions. Induction of a type I interferon response or ribavirin treatment reduced the progression of cell-to-cell virus spread in HeLa cells or NPSCs infected with Timer-CVB3. Time lapse photography of partially differentiated NPSCs infected with Timer-CVB3 revealed substantial intracellular membrane remodeling and the assembly of discrete virus replication organelles which changed fluorescence color in an asynchronous fashion within the cell. "Fluorescent timer" protein colocalized closely with viral 3A protein within virus replication organelles. Intriguingly, infection of partially differentiated NPSCs or C2C12 myoblast cells induced the release of abundant extracellular microvesicles (EMVs) containing matured "fluorescent timer" protein and infectious virus representing a novel route of virus dissemination. CVB3 virions were readily observed within purified EMVs by transmission electron microscopy, and infectious virus was identified within low-density isopycnic iodixanol gradient fractions consistent with membrane association. The preferential detection of the lipidated form of LC3 protein (LC3 II) in released EMVs harboring infectious virus suggests that the autophagy pathway plays a crucial role in microvesicle shedding and virus release, similar to a process previously described as autophagosome-mediated exit without lysis (AWOL) observed during poliovirus replication. Through the use of this novel recombinant virus which provides more dynamic information from static fluorescent images, we hope to gain a better understanding of CVB3 tropism, intracellular membrane reorganization, and virus-associated microvesicle dissemination within the host.
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“Many viruses such as HIV, coxsackievirus, hepatitis B and C, influenza, Epstein-Barr virus, and SARS-CoV-2 highjack cellular and mitochondrial programs to enhance viral replication, package virus into EVs, and use EVs containing virus or viral components to subvert the immune response to obtain a replicative advantage in the host (Figure 1).”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [45]
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Research works printed but not linked: 2
- G Tsueng, 2014, Unique 2C and 3A viral protein mutations identified in hypervirulent and attenuated coxsackievirus strains isolated from persistently-infected neural progenitor cell cultures, Manuscript In Preparation
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Metadata
- Authors
- Robinson, S. M., Tsueng, G., Sin, J., Mangale, V., Rahawi, S., McIntyre, L. L., Williams, W., Kha, N., Cruz, C., Hancock, B. M., Nguyen, D. P., Sayen, M. R., Hilton, B. J., Doran, K. S., Segall, A. M., Wolkowicz, R., Cornell, C. T., Whitton, J. L., Gottlieb, R. A., & Feuer, R.
- Affiliations
- San Diego State University (US)
- Scripps Research Institute (US)
- Corresponding author
- Feuer, Ralph
- ORCID
- Venue
- PLoS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-04-10
- Volume
- 10
- Issue
- 4
- Pages
- e1004045
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC3983045
- OpenAlex
- W1994527574
- Cited by
- 322
- References
- 66
- Citations by year
- 2026: 11 · 2025: 21 · 2024: 26 · 2023: 29 · 2022: 25 · 2021: 32 · 2020: 43 · 2019: 29 · 2018: 27 · 2017: 20 · 2016: 19 · 2015: 29 · 2014: 11
- FWCI
- 18.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Science Foundation (1046413, DBI-030829)
- San Diego State University
- National Institutes of Health (NIH-R01, HL093177, AI042314, NS054108)
- National Heart, Lung, and Blood Institute (R01HL092136, R01HL093177, T32HL116273)
- National Institute of Mental Health (R24MH065515, MH065515)
- National Institute of Allergy and Infectious Diseases (F32AI065095, R01AI042314)
- National Institute of Neurological Disorders and Stroke (R01NS054108)
- Division of Environmental Biology (1046413)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Viral Infections and Immunology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- coxsackievirus B3, extracellular microvesicles, autophagy, viral dissemination, myoblasts, LC3, 3A protein, type I interferon, ribavirin, viral myocarditis, poliovirus
- MeSH terms
- Animals, Enterovirus Infections, HeLa Cells, Humans, Microtubule-Associated Proteins, Phagosomes, Viral Proteins, Virus Shedding, Enterovirus B, Human, Mice, Cell-Derived Microparticles
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