Human cathelicidin peptide LL-37 as a therapeutic antiviral targeting Venezuelan equine encephalitis virus infections

Aslaa Ahmed; Gavriella Siman-Tov; Forrest Keck; Stephanie Kortchak; Allison Bakovic; Kenneth Risner; Timothy K Lu; Nishank Bhalla; Cesar de la Fuente-Nunez; Aarthi Narayanan

doi:10.1016/j.antiviral.2019.02.002

Human cathelicidin peptide LL-37 as a therapeutic antiviral targeting Venezuelan equine encephalitis virus infections

Antiviral Res. 2019 Apr:164:61-69. doi: 10.1016/j.antiviral.2019.02.002. Epub 2019 Feb 8.

Affiliations

¹ National Center for Biodefense and Infectious Disease, School of Systems Biology, George Mason University, Manassas, VA, USA.
² 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.
³ 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.

PMID: 30738837
DOI: 10.1016/j.antiviral.2019.02.002

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.

Keywords: Antimicrobial peptides; Antivirals; Cathelicidins; IFN- β; LL-37; Venezuelan equine encephalitis virus.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antimicrobial Cationic Peptides / pharmacology*
Antiviral Agents / pharmacology*
Cathelicidins
Cell Line
Encephalitis Virus, Venezuelan Equine / drug effects*
Encephalitis Virus, Venezuelan Equine / physiology
Humans
Viral Load
Virus Replication / drug effects*

Substances

Antimicrobial Cationic Peptides
Antiviral Agents
Cathelicidins