Human cathelicidin peptide LL-37 as a therapeutic antiviral targeting Venezuelan equine encephalitis virus infections.
Abstract: Venezuelan equine encephalitis virus (VEEV), a new world alphavirus belonging to the Togaviridae family, causes periodic disease outbreaks in humans and equines with high associated mortality and morbidity. VEEV is highly infectious via the aerosol route and so has been developed as a biological weapon (Hawley and Eitzen, 2001). Despite its current classification as a category B select agent, there are no FDA approved vaccines or therapeutics to counter VEEV infections. Here we utilize a naturally occurring host defense peptide, LL-37, as a therapeutic strategy to inhibit VEEV multiplication in infected cells. LL-37 has previously demonstrated activity against several viruses by directly interacting with viral particles and indirectly by establishing an antiviral state in the host cell. We show that LL-37 exhibited potent antiviral activity against VEEV by inhibiting viral replication. Genomic RNA copies of the TC-83 strain of VEEV and viral titers were significantly reduced compared to non-treated controls. LL-37 also inhibited the virulent Trinidad Donkey (TrD) strain of VEEV. Entry assays revealed a robust reduction of viral RNA copies at the early stages of TC-83 infection. Pre-incubation of cells with LL-37 and TC-83 resulted in a strong inhibitory response, indicating that LL-37 impacts early stages of the infectious process. Confocal and electron microscopy images confirmed the aggregation of viral particles, which potentially accounts for entry prevention and hence reduced viral infection. LL-37 treatment also modulated type I interferon (IFN) expression in infected cells. LL-37 treatment dramatically increased IFNβ1 expression in treated cells in a time-dependent manner. Our results establish LL-37 as a relevant and novel potential therapeutic strategy for the treatment of VEEV infections.
Copyright © 2019. Published by Elsevier B.V.
Publication Date: 2019-02-08 PubMed ID: 30738837DOI: 10.1016/j.antiviral.2019.02.002Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
- Research Support
- U.S. Gov't
- Non-P.H.S.
Summary
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The research investigates the use of a naturally occurring peptide, LL-37, as a potential treatment strategy for Venezuelan equine encephalitis virus (VEEV), an infectious disease causing high mortality and morbidity in humans and equines.
Background on VEEV and LL-37
- The Venezuelan equine encephalitis virus (VEEV) is a highly infectious virus causing severe disease outbreaks in humans and equines. Due to its nature, it has even been developed as a biological weapon.
- Currently, there are no FDA approved treatments or vaccines for VEEV infections, emphasizing the need for effective treatments.
- The peptide LL-37 is a naturally occurring host defense peptide that has previously demonstrated antiviral activity against multiple viruses. When it interacts with viral particles, it establishes an antiviral environment in the host cell.
Experiment Results
- The study showed that LL-37 exhibits robust antiviral activity against VEEV by inhibiting the replication of the virus. This was apparent in significantly reduced genomic RNA copies of the TC-83 strain of VEEV and lower viral titers compared to untreated controls.
- This inhibition also occurred with the Trinidad Donkey (TrD) strain of VEEV showing the wide applicability of this peptide.
LL-37’s Influence on Viral Entry
- During the experimentation, a substantial reduction of viral RNA copies was observed with LL-37 at the early stages of TC-83 infection.
- Pre-incubation of cells with LL-37 and TC-83 led to a significant inhibitory response, suggesting that LL-37 impacts the early stages of the infectious process.
- Images from confocal and electron microscopy further confirmed the aggregation (clustering) of viral particles, restricting their entry and subsequently lowering the rate of infection.
LL-37’s Effects on Type I Interferon (IFN) Expression
- LL-37 treatment was found to modulate the expression of type I interferon (IFN) in infected cells, a group of proteins that help regulate the immune system’s response to viruses.
- Specifically, there was a dramatic increase in IFNβ1 expression in treated cells, occurring in a time-dependent manner. This finding suggests that LL-37 can stimulate the cells’ own defenses to help combat the virus.
Conclusion
- The results of this study highlight the potential of LL-37 as a promising therapeutic strategy to treat VEEV infections.
- This research opens up new avenues of investigation into potential treatments for other viral infections as well.
Cite This Article
APA
Ahmed A, Siman-Tov G, Keck F, Kortchak S, Bakovic A, Risner K, Lu TK, Bhalla N, de la Fuente-Nunez C, Narayanan A.
(2019).
Human cathelicidin peptide LL-37 as a therapeutic antiviral targeting Venezuelan equine encephalitis virus infections.
Antiviral Res, 164, 61-69.
https://doi.org/10.1016/j.antiviral.2019.02.002 Publication
Researcher Affiliations
- National Center for Biodefense and Infectious Disease, School of Systems Biology, George Mason University, Manassas, VA, USA.
- National Center for Biodefense and Infectious Disease, School of Systems Biology, George Mason University, Manassas, VA, USA.
- National Center for Biodefense and Infectious Disease, School of Systems Biology, George Mason University, Manassas, VA, USA.
- National Center for Biodefense and Infectious Disease, School of Systems Biology, George Mason University, Manassas, VA, USA.
- National Center for Biodefense and Infectious Disease, School of Systems Biology, George Mason University, Manassas, VA, USA.
- National Center for Biodefense and Infectious Disease, School of Systems Biology, George Mason University, Manassas, VA, USA.
- Synthetic Biology Group, MIT Synthetic Biology Center; The Center for Microbiome Informatics and Therapeutics; Research Laboratory of Electronics, Department of Biological Engineering, Cambridge, MA, USA; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- National Center for Biodefense and Infectious Disease, School of Systems Biology, George Mason University, Manassas, VA, USA.
- Synthetic Biology Group, MIT Synthetic Biology Center; The Center for Microbiome Informatics and Therapeutics; Research Laboratory of Electronics, Department of Biological Engineering, Cambridge, MA, USA; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: cfuente@mit.edu.
- National Center for Biodefense and Infectious Disease, School of Systems Biology, George Mason University, Manassas, VA, USA.
MeSH Terms
- Antimicrobial Cationic Peptides / pharmacology
- Antiviral Agents / pharmacology
- Cell Line
- Encephalitis Virus, Venezuelan Equine / drug effects
- Encephalitis Virus, Venezuelan Equine / physiology
- Humans
- Viral Load
- Virus Replication / drug effects
- Cathelicidins
Citations
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