Abstract
Rabies causes more than 60,000 human deaths annually in areas where the virus is endemic. Importantly, rabies is one of the few pathogens for which there is no treatment following the onset of clinical disease with the outcome of infection being death in almost 100% of cases. Whilst vaccination, and the combination of vaccine and rabies immunoglobulin treatment for post-exposure administration are available, no tools have been identified that can reduce or prevent rabies virus replication once clinical disease has initiated. The search for effective antiviral molecules to treat those that have already developed clinical disease associated with rabies virus infection is considered one of the most important goals in rabies research. The current study assesses a single chain antibody molecule (ScFv) based on a monoclonal antibody that potently neutralises rabies in vitro as a potential therapeutic candidate. The recombinant ScFv was generated in Nicotiana benthamiana by transient expression, and was chemically conjugated (ScFv/RVG) to a 29 amino acid peptide, specific for nicotinic acetylcholine receptor (nAchR) binding in the CNS. This conjugated molecule was able to bind nAchR in vitro and enter neuronal cells more efficiently than ScFv. The ability of the ScFv/RVG to neutralise virus in vivo was assessed using a staggered administration where the molecule was inoculated either four hours before, two days after or four days after infection. The ScFv/RVG conjugate was evaluated in direct comparison with HRIG and a potential antiviral molecule, Favipiravir (also known as T-705) to indicate whether there was greater bioavailability of the ScFv in the brains of treated mice. The study indicated that the approach taken with the ScFv/RVG conjugate may have utility in the design and implementation of novel tools targetting rabies virus infection in the brain.
Highlights
Rabies is a neglected disease caused by Rabies virus (RABV) that affects people in many countries, mostly in Asia and Africa
The rabies virus glycoprotein (RVG) peptide was synthesized by Pepscan (Lelystad, The Netherlands). 10 mg of the peptide (MW = 3 kDa) was dissolved in water and adjusted to pH7 with PBS
ScFv/RVG migrated slightly slower than ScFv as expected and the slight smearing of this band is consistent with variable levels of RVG peptide conjugation
Summary
Rabies is a neglected disease caused by Rabies virus (RABV) that affects people in many countries, mostly in Asia and Africa. RABV is a non-segmented negative strand RNA virus in the order Mononegavirales, family Rhabdoviridae, genus lyssavirus [1]. RABV is almost always transmitted following a bite injury from an infected animal that is excreting virus in its saliva. Lyssaviruses are strongly neurotrophic, replication in the musculature, prior to entry into the peripheral nervous system occurs, and is likely to contribute to the variation in incubation times seen following infection [2]. Whilst the prodrome generally lasts for 3–10 weeks, significantly longer incubation periods have been reported [3]. Regardless, it is during the phase between virus replication in the non-neuronal periphery and movement into the peripheral nervous system that post exposure immunoprophylaxis is hypothesised to be most effective [4]
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