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Inoculation of swine with foot-and-mouth disease SAP-mutant virus induces early protection against disease

Diaz-San Segundo, Fayna, Weiss, Marcelo, Perez-Martin, Eva, Dias, Camila C., Grubman, Marvin J., de los Santos, Teresa
Journal of virology 2012 v.86 no.3 pp. 1316
Foot-and-mouth disease virus, T-lymphocytes, antibodies, cytokines, disease prevention, foot-and-mouth disease, hosts, immune response, live vaccines, mutants, mutation, neutralization, sap, structure-activity relationships, swine, swine diseases, vaccine development, viral proteins, viremia, viruses
Foot-and-mouth disease virus (FMDV) leader proteinase (L(pro)) cleaves itself from the viral polyprotein and cleaves the translation initiation factor eIF4G. As a result, host cell translation is inhibited, affecting the host innate immune response. We have demonstrated that L(pro) is also associated with degradation of nuclear factor κB (NF-κB), a process that requires L(pro) nuclear localization. Additionally, we reported that disruption of a conserved protein domain within the Lpro coding sequence, SAP mutation, prevented Lpro nuclear retention and degradation of NF-κB, resulting in in vitro attenuation. Here we report that inoculation of swine with this SAP mutant virus does not cause clinical signs of disease, viremia or virus shedding even when inoculated at doses 100-fold higher than those required to cause disease with wild type (WT) virus. Remarkably, SAP mutant virus inoculated animals developed a strong neutralizing antibody response and were completely protected against challenge with WT FMDV as early as 2 and for at least 21 days post inoculation. Early protection correlated with a distinct pattern in the serum levels of pro-inflammatory cytokines in comparison to animals inoculated with WT FMDV that developed disease. In addition, animals inoculated with the FMDV SAP mutant displayed a memory T cell response that resembled infection with WT virus. Our results suggest that L(pro) plays a pivotal role in modulating several pathways of the immune response. Furthermore, manipulation of the L(pro) coding region may serve as a viable strategy to derive live attenuated strains with potential for development as effective vaccines against FMD.