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

Arzt, Jonathan, Pacheco, Juan M., Smoliga, George R., Tucker, Meghan T., Bishop, Elizabeth, Pauszek, Steven J., Hartwig, Ethan J., de los Santos, Teresa, Rodriguez, Luis L.
Virology 2014 v.452-453 pp. 12-22
Foot-and-mouth disease virus, RNA, aerosols, antiviral properties, avirulent strains, blood, cattle diseases, disease severity, drug delivery systems, epithelial cells, foot-and-mouth disease, immune response, interferons, mutants, pathogenesis, phenotype, steers, virulence, virus replication, viruses
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). We had previously shown that after aerosolization, FMDV-Mut replicated at primary infection sites, but unlike FMDV-WT was unable to generalize and cause disease. In the current study we confirmed this finding and explored the virulence/attenuation continuum of FMDV infection. Several important differences were identified between infection of steers with FMDV-WT and FMDV-Mut. Tissues collected postmortem from primary infection sites of FMDV-WT-aerosolized cattle had substantially greater quantities of infectious FMDV, viral RNA, and type I/III interferon (IFN) activity compared to corresponding tissues from cattle infected with FMDV-Mut. Substantial quantities of IFN-ß were microscopically localized to FMDV-WT-infected epithelial cells at lesion sites indicating these tissues as important sites of antiviral activity. FMDV-WT-infected cattle additionally had marked induction of systemic IFN activity in serum, whereas FMDV-Mut infected cattle did not. The presence of viral RNA in the blood was consistently associated with the systemic induction of IFN response. Interestingly, IEL inoculation of FMDV-Mut in cattle restored virulent phenotype and systemic IFN response. These data indicate that the attenuated FMDV-Mut phenotype in cattle is associated with decreased replicative efficiency at primary infection sites, which is reflected by decreased systemic and local innate response. However, this attenuation is abrogated by bypassing the natural path of infection resulting in accelerated viral replication at the inoculation site.