Foot-and-mouth disease virus virulence in cattle is co-determined by viral replication dynamics and route of infection

Abstract

Early events in the pathogenesis of foot-and-mouth disease virus (FMDV) infection in cattle were investigated through aerosol and intraepithelial lingual (IEL) inoculations of a cDNA-derived FMDV-A24 wild type virus (FMDV-WT) or a mutant derived from the same clone (FMDV-Mut). After aerosolization of FMDV-WT, primary infection sites had significantly greater quantities of FMDV, viral RNA, and type I/III interferon (IFN) activity compared to corresponding tissues from cattle infected with FMDV-Mut. Additionally, FMDV-WT-infected cattle had marked induction of systemic IFN activity in serum. In contrast, FMDV-Mut aerosol-infected cattle did not manifest systemic IFN response nor had viremia. Interestingly, IEL inoculation of FMDV-Mut in cattle restored the virulent phenotype and systemic IFN response. These data indicate that the attenuated phenotype in cattle is associated with decreased replicative efficiency, reflected by decreased innate response. However, attenuation is abrogated by bypassing the common primary infection sites, inducing accelerated viral replication at the inoculation site.

Synonymous Deoptimization of Foot-and-Mouth Disease Virus Causes Attenuation In Vivo while Inducing a Strong Neutralizing Antibody Response

“…These results indicate that the attenuated phenotype observed in the natural host is directly associated with the changes introduced during the deoptimization process that can determine reduced viral pathogenesis. Likewise, Arzt et al (31) have proposed that FMDV virulence in another livestock species (cattle) is determined by replication dynamics and the complex interactions between the virus and host innate immune factors at the initial site of infection. However, further studies are required to determine how stable the A12-P1 deopt virus is after repeated passage in primary cell lines and different hosts.…”

“…The detection level of this assay is 5 PFU/ml. In addition, FMDV RNA was detected by real-time RT-PCR (rRT-PCR) as previously described (31). Forty-five amplification cycles were run, and samples were considered positive when threshold cycle (C T ) values were Ͻ40.…”

Pathogenesis of virulent and attenuated foot-and-mouth disease virus in cattle

“…These investigations have included viruses with deletions within the 3A coding region [6] or the VP1 GH-loop [5] as well as variable deletions or substitutions within the L pro region [20, 21]. However, only two studies have directly compared the tissue-specificity of early pathogenesis events between a mutant FMDV and the virulent parental virus during the early stages of infection [1, 2]. …”

“…Recent investigations from our laboratory have sought to elucidate mechanisms associated with host response to virulent and mutant-attenuated strains of FMDV-A24-Cruzeiro in cattle [2]. The overall conclusion based upon macroscopic analyses, was that the mutant virus was capable of establishing infection at similar primary sites as the parental virus; however, infection with the mutant was arrested at the primary infection sites by incompletely elucidated mechanisms which prevented dissemination and systemic disease.…”

Clinical and virological dynamics of a serotype O 2010 South East Asia lineage foot-and-mouth disease virus in sheep using natural and simulated natural inoculation and exposure systems

“…The outcome of experimental FMDV studies can vary considerably depending on the system used for virus exposure (Arzt et al, 2014;Fowler et al, 2014;Stenfeldt et al, 2014b). Although injection-based (intra-epithelial) inoculation systems are highly efficient in generating consistent and synchronous clinical FMD, these systems have the disadvantage of utilizing an unnatural manner of virus delivery that bypasses the natural barriers of the mucosal immune system, thereby providing an inaccurate simulation of the initial events of FMDV pathogenesis.…”