The Use of Antimicrobial Peptides, LL-37 and Derivatives, to Target Rift Valley Fever Virus Infection
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Anjorin, Monisola
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Abstract
Rift Valley Fever Virus (RVFV) is an enveloped negative and ambisense, single-stranded RNA phlebovirus of the family Phenuiviridae that primarily infects domestic livestock, but can be transmitted to, and infect, humans. Disease following RVFV infection causes near 100% abortion in pregnant livestock, dramatically affecting economic livelihoods in RVFV endemic areas. In humans, RVFV infection results in a mild febrile illness; however, in a small number of cases, a severe form of the disease may develop which manifests as meningoencephalitis and hemorrhagic fever that is occasionally fatal. Additionally, RVFV is highly infectious in aerosol form solidifying its potential as a biological weapon. In 2015, RVFV was added to the World Health Organization’s list of “World’s Most Dangerous Emerging Pathogens.” There are currently no approved vaccines or therapeutics available for the treatment of RVFV infection. We propose the use of antimicrobial peptides (AMP), both naturally occurring and synthetic, as a therapeutic strategy against RVFV infection. AMPs are broad-spectrum oligopeptides that are produced as a first line of defense by the innate immune response. The AMP LL-37, the sole member of the human cathelicidin family of AMPs, has demonstrated antiviral activity against a number of viruses. LL-37 inhibits viral infections through several mechanisms including: directly binding to and disrupting viral envelopes, an activity facilitated by its amphipathic structure; inhibiting the upregulation and production of inflammatory mediators; and modulating host signaling pathways. In this study, we assessed the efficacy of LL-37 against RVFV in Human Small Airway Epithelial Cells (HSAECs), using plaque assays and polymerase chain reaction (PCR) techniques, and found that LL-37 significantly reduced RVFV titers. In addition, a library of synthetic peptides was screened against RVFV, which resulted in the identification of several LL-37 derivative peptides with potent anti-RVFV activity. As such, LL-37 and derivative peptides offer an intriguing therapeutic strategy for the treatment of RVFV infections.
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This thesis has been embargoed for 2 years and will not be available until June 2021 at the earliest.
Keywords
Antimicrobial peptide, LL-37, Rift Valley Fever Virus, Infection, Rift, Virus