Proof of Concept for the Inhibition of Foot-and-Mouth Disease Virus Replication by the Anti-Viral Drug 2′-C-Methylcytidine in Severe Combined Immunodeficient Mice

Abstract

Recent European contingency plans envisage emergency vaccination as an animal-friendly control strategy for foot-and-mouth disease (FMD). Anti-viral drugs may be used as an alternative or complementary measure. We here demonstrate that the nucleoside analogue 2'-C-methylcytidine (2'CMC) protects severe combined immunodeficient (SCID) mice against lethal FMD virus infection. In brief, SCID mice were inoculated with serotype A FMD virus and treated for five consecutive days with 2'CMC. All 15 treated mice remained healthy until the end of the study at 14 days post-infection (dpi). At that time, viral RNA was no longer detected in 13 of 15 treated mice. All eight untreated mice suffered from an acute generalized disease and were euthanized for ethical reasons on average at 4 dpi. These results illustrate the potential of small molecules to control FMD.

A Refined Guinea Pig Model of Foot-and-Mouth Disease Virus Infection for Assessing the Efficacy of Antiviral Compounds

“…The treatment of GP with the pyrazinecarboxamide derivative T‐1105 as a reference molecule offered substantial clinical and virological protection against O 1 Manisa infection, similar to the protection offered by vaccination with a high‐potency homologous vaccine. The present data provide further evidence for the potential of antiviral treatment to reduce FMDV replication in vivo , in accordance with previous findings in SCID mice (Lefebvre et al., ).…”

“…From the perspective of animal welfare and biosecurity, small‐animal models are preferable over FMDV target species for exploratory in vivo assessment of antivirals. An FMDV serotype A infection model in severe combined immunodeficient (SCID) mice was established (Lefebvre et al., ) and validated for antiviral research using the ribonucleoside analogue 2′‐ C ‐methylcytidine (Lefebvre et al., ), a known FMDV inhibitor in vitro (Goris et al., ). Besides mice, guinea pigs (GP) are susceptible to experimental FMDV infection, and they embody the preferential laboratory species for FMDV research because, contrary to mice, the clinical outcome particularly resembles that observed in natural FMDV hosts (Terpstra et al., ; Brown, ).…”

In vitro surrogate models to aid in the development of antivirals for the containment of foot-and-mouth disease outbreaks

“…Only a few FMDV inhibitors have been reported in literature, most (if not all) of which demonstrate broad-spectrum activity (Goris et al, 2008). Ribavirin and 2 0 -C-methylcytidine [2CMC, which was originally developed as an HCV inhibitor (Sommadossi and La Colla, 2001)] have been previously reported as replication inhibitors of FMDV in vitro and also in severe combined immunodeficient mice for 2CMC (Goris et al, 2007;Lefebvre et al, 2013). Both compounds are known to exhibit pan-serotype FMDV activity, but ribavirin is less potent than 2CMC (Goris et al, 2007).…”

Foot-and-Mouth Disease, an Economically Important Disease of Animals

“…Washing of the wounds with soda ash solution and topical application of honey and finger millet is found suitable in foot lesions (Gakuya et al, 2011). Antiviral approaches including 2'-C-Methylcytidine (Meyer et al, 1997;Lefebvre et al, 2013), ribavirin ; cytokine therapy inclusive of IFN-α/β as an anti-FMD agent is useful for the purpose of prophylaxis in susceptible animals. Development of antiviral drug therapy targeting specific viral protein is limited.…”