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Title: Pathogenesis and micro-anatomic characterization of a cell-adapted mutant foot-and-mouth disease virus in cattle: impact of the Jumonji C-domain containing protein 6 (JMJD6) and route of innoculation

Author
item Lawrence, Paul
item Pacheco Tobin, Juan
item STENFELDT, CAROLINA - Oak Ridge Institute For Science And Education (ORISE)
item Arzt, Jonathan
item RAI, DEVENDRA - University Of Connecticut
item Rieder, Aida - Elizabeth

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/11/2016
Publication Date: 2/4/2016
Citation: Lawrence, P.J., Pacheco Tobin, J., Stenfeldt, C., Arzt, J., Rai, D., Rieder, A.E. 2016. Pathogenesis and micro-anatomic characterization of a cell-adapted mutant foot-and-mouth disease virus in cattle: impact of the Jumonji C-domain containing protein 6 (JMJD6) and route of innoculation. Journal of Virology. 492:108-117. doi: 10.1016/j.virol.2016.02.004.

Interpretive Summary: Foot and mouth disease (FMD) is a devastating disease of livestock caused by a virus (FMDV). Understanding how the virus infects the animal cells is critical to develop better methods to prevent infection. In this study, we examined the pathogenesis of mutant FMDV that uses an alternative receptor to enter cells and showed similar virulence as the wild-type virus A24-WT when administered orally via the tongue. In contrast, when a more natural method of inoculation was used (aerosol), the mutant virus was unable to cause disease or replicate in the infected cattle. This new information contributes to the knowledge of virus-host interaction and has potential for the development of antiviral disease intervention strategies.

Technical Abstract: In a companion study, we reported that the cellular Jumonji-C Domain containing Protein 6 (JMJD6) protein is involved in an alternate integrin- and HS-independent pathway of FMDV infection in CHO cells. Here, we investigated the JMJD6 localization in animal tissues from cattle infected with either wild type A24-FMDV (A24-WT) or the mutant FMDV (JMJD6-FMDV) carrying an E95K/S96L and a RGD to KGE mutations in VP1. In addition we investigated the pathogenesis of mutant JMJD6-FMDV virus in cattle through aerosol and intraepithelial lingual (IEL) inoculation. Interestingly, the pathogenesis of JMJD6-FMDV was equivalent to A24-WT when administered by the IEL route. In contrast, JMJD6-FMDV aerosol-infected cattle did not manifest signs of FMD neither the animals showed detectable viremia. Immunofluorescent microscopy of post-mortem tissue revealed that JMJD6-FMDV exclusively co-localized with JMJD6+ cells while A24-WT was occasionally found in JMJD6+ cells. In vitro, chemical uptake inhibitors demonstrated that JMJD6-FMDV entered host cells via clathrin-coated pit endocytosis. In vivo mutant JMJD6-FMDV exhibit preference for JMJD6+ cells, but the availability of this alternative receptor likely depends on the route of inoculation.