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 inoculation

- Knockdown of JMJD6 was demonstrated to impede the progression of infection in cell culture with a JMJD6-targeted mutant FMDV.
- Post-attachment entry pathway for JMJD6-targeted mutant FMDV was determined to be through clathrin-coated pit mediated endocytosis.
- JMJD6-targeted mutant FMDV exhibited similar pathogenesis as the parental virus by both aerosol and intraepithelial lingual inoculation.
- JMJD6-targeted mutant FMDV was detected exclusively in JMJD6-positive cells by immunohistochemistry while the parental virus was only seen partially localizing with JMJD6-positive cells.

A companion study reported Jumonji-C domain containing protein 6 (JMJD6) is involved in an integrin- and HS-independent pathway of FMDV infection in CHO cells. JMJD6 localization was investigated in animal tissues from cattle infected with either wild type A24-FMDV (A24-WT) or mutant FMDV (JMJD6-FMDV) carrying E95K/S96L and RGD to KGE mutations in VP1. Additionally, pathogenesis of mutant JMJD6-FMDV was investigated in cattle through aerosol and intraepithelial lingual (IEL) inoculation. Interestingly, JMJD6-FMDV pathogenesis was equivalent to A24-WT administered by IEL route. In contrast, JMJD6-FMDV aerosol-infected cattle did not manifest signs of FMD and animals showed no detectable viremia. Immunofluorescent microscopy of post-mortem tissue revealed JMJD6-FMDV exclusively co-localized with JMJD6+ cells while A24-WT was occasionally found in JMJD6+ cells. In vitro, chemical uptake inhibitors demonstrated JMJD6-FMDV entered cells via clathrin-coated pit endocytosis. In vivo, JMJD6-FMDV exhibited preference for JMJD6+ cells, but availability of this alternative receptor likely depends on route of inoculation.