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

item Arzt, Jonathan
item Pacheco Tobin, Juan
item Tucker, Meghan
item Smoliga, George
item Bishop, Elizabeth
item Pauszek, Steven
item Hartwig, Ethan
item De Los Santos, Teresa
item Rodriguez, Luis

Submitted to: Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/2/2014
Publication Date: 3/1/2014
Publication URL:
Citation: Arzt, J., Pacheco Tobin, J., Tucker, M.T., Smoliga, G.R., Bishop, E.A., Pauszek, S.J., Hartwig, E.J., De Los Santos, T.B., Rodriguez, L.L. 2014. Foot and mouth disease virus virulence in cattle is co-determined by viral replication dynamics and route of infection. Virology. 452-453:12-22.

Interpretive Summary: Foot-and-mouth disease (FMD) has been intensively studied for over 100 years, yet many basic mechanisms that enable FMD virus (FMDV) to attack and infect a host are still not understood. The goal of the current work was to dissect and elucidate the early events in the virus-host interaction when FMDV infects cattle by the aerosol route. In previous work from our laboratory we constructed and characterized an attenuated FMDV mutant virus that successfully infected cattle but did not cause disease. In the current study we compared various aspects of infection with this mutant virus to the parental virus, capable of causing severe disease in cattle, from which it was derived. The most important disease-defining factor identified herein was the prolific growth of the parental virus compared to relative incapacity of the mutant. Another important aspect of the study was investigation of the early immune response to the viruses. Specifically, we tested the hypothesis that the mutant virus failed to cause disease because it failed to inactivate the host innate immune system (predominantly interferons). We disproved this hypothesis by showing that there was less interferon activity associated with the mutant virus compared to the parent. Thus, the overall conclusion was that the speed and efficiency of virus reproduction was the primary defining factor that allowed the parental virus to cause severe disease.

Technical 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). 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.