Laboratory animal models to study foot-and-mouth disease: a review with emphasis on natural and vaccine-induced immunity

Abstract

Laboratory animal models have provided valuable insight into foot-and-mouth disease virus (FMDV) pathogenesis in epidemiologically important target species. While not perfect, these models have delivered an accelerated time frame to characterize the immune responses in natural hosts and a platform to evaluate therapeutics and vaccine candidates at a reduced cost. Further expansion of these models in mice has allowed access to genetic mutations not available for target species, providing a powerful and versatile experimental system to interrogate the immune response to FMDV and to target more expensive studies in natural hosts. The purpose of this review is to describe commonly used FMDV infection models in laboratory animals and to cite examples of when these models have failed or successfully provided insight relevant for target species, with an emphasis on natural and vaccine-induced immunity. IntroductionFoot-and-mouth disease virus (FMDV: family Picornaviridae; genus Aphthovirus) is known to naturally infect a wide variety of cloven-hoofed domesticated and wild animal species, causing an acute disease characterized by vesicular lesions of the tongue, snout, buccal cavity, feet and teats (Grubman & Baxt, 2004). Despite causing extensive lesions, the cycle of infection in the individual animal is short, and foot-and-mouth disease (FMD) usually resolves without the need for treatment and is seldom lethal in adults (Arzt et al., 2011b). However, the highly contagious nature, wide dissemination and significant economic impact of FMD have made it one of the most feared livestock diseases and a major research focus for more than a century. Progress towards the development of effective tools for FMD control has been hampered by several factors including the cost and logistics of largeanimal experimentation in specialized high-containment facilities, incomplete knowledge of the host's immune systems and lack of immunological reagents compared to biomedical rodent species and humans. These factors delayed the production of vaccines on an industrial scale and this major research goal was subsequently only achieved in the 1950s (Lombard et al., 2007). In a review, Brown (2003) highlighted that this milestone could not have been achieved without certain significant advances in our knowledge of FMD. The first significant advance was the demonstration by Loeffler & Frosch (1897) that the disease was caused by a virus and the second was the establishment of FMD laboratory animal models, including the guinea-pig model (Waldman & Pape, 1920) followed by the suckling mouse model (Skinner, 1951). Although not without their flaws, these FMD laboratory animal models have helped elucidate several mechanisms of FMD pathogenesis, which would have been difficult to achieve directly in target species. These models have provided an accelerated time frame at significantly reduced costs to develop and test vaccine candidates and continue to be a useful tool for interrogating FMDV immune responses. However, we now know that porcine and ru...

Application of mouse model for effective evaluation of foot-and-mouth disease vaccine

“…However, when mice were inoculated IP with an FMDV, viremia and an increase of the serum neutralizing titer as a result of viral replication were reported [21]. The acute symptoms of cardiomyopathy are the characteristics of FMDV infection in mice which is in accordance with FMDV replication sites in these animals [13,22].…”

“…Injection of 10 7.0 plaque forming units (PFU) of the A/Arg/00 virus had no pathogenic effect in C57BL/6 mice, whereas 10 7.0 PFU of the A/Arg/01 FMDV caused severe disease in the mice [20]. Since most FMDVs do not greatly affect the mortality of adult C57BL/6 mice, except for a few that have been studied [13], adult mice have been shown to have no sensitivity to natural infection. However, when mice were inoculated IP with an FMDV, viremia and an increase of the serum neutralizing titer as a result of viral replication were reported [21].…”

“…What is more, the study findings obtained from mouse experiments can often be harmonized with the results obtained from experiments on the target species. Therefore, the mouse model can help to successfully predict the immune response to FMDVs in cows and pigs [13]. In the future, if the serotypes and subtypes of FMDVs are certified as challenge viruses through the method devised for C57BL/6 mice, it is expected that they could help to cut cost and time in the efficacy and dosage evaluations of new vaccines and commercial vaccines with epidemic viruses.…”

“…The pathogenesis of FMDV in mice depends on the animal strain, the route of virus challenge, and the features of the virus [13]. According to recent studies [13], C57BL/6 mice are sensitive to artificial FMDV infection and only a few FMDVs, such as C1 C-S8c1, SAT1, Asia1 Shamir, and A/Arg/01, can cause 100% fatality in the mice.…”

Foot-and-mouth disease virus infection of dendritic cells triggers phosphorylation of ERK1/2 inducing class I presentation and apoptosis

“…Therefore, FMDV-specific MHC class I-restricted CD8+ lymphocytes were reported after infection and vaccination [8]. While, the CD4+ response does not appear to play a central role in the resolution of acute infection by FMDV [9].…”