DENDRITIC CELL INTERNALISATION OF FOOT-AND-MOUTH DISEASE VIRUS: INFLUENCE OF HEPARAN SULPHATE BINDING ON VIRUS UPTAKE AND IMMUNE RESPONSE INDUCTION

Institute of Virology and Immunoprophylaxis, 3147 Mittelhäusern, Switzerland; Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM) 28049 Cantoblanco, Madrid, Spain; Centro de Investigación en Sanidad Animal, INIA, 28130 Valdeolmos, Madrid, Spain

^* To whom correspondence should be addressed. Email: Lisa.Harwood{at}ivi.admin.ch.

	Abstract

Dendritic cells (DC), essential for inducing and regulating immune defences and responses, represent the critical target for vaccines against pathogens such as foot-and-mouth disease (FMDV). Although it is clear that FMDV enters epithelial cells via integrins, little is known about FMDV interaction with DC. Accordingly, DC internalisation of FMDV antigen was analysed by comparing vaccine virus dominated by heparan sulphate (HS) binding variants with FMDV lacking HS-binding capacity. The internalisation was most efficient with the HS-binding virus, employing diverse endocytic pathways. Moreover, this relied primarily on HS-binding. Uptake of non-HS binding virus by DC was considerably less efficient, so much so that it was often difficult to detect virus interacting with the DC. The HS-binding FMDV replicated in DC, albeit transiently - demonstrable by its sensitivity to cycloheximide treatment and the short duration of infectious virus production. There was no evidence that the non-HS binding virus replicated in the DC. These events could be related to the activity of viral RNA - when DC were transfected with infectious RNA, only 1% translated viral proteins were detected. Nevertheless, the transfected cells – and DC which had internalised live virus - did present antigen to lymphocytes, inducing an FMDV-specific IgG response. These results demonstrate that DC internalisation of FMDV is most efficient for vaccine virus with HS-binding capacity, but HS-binding is not an exclusive requirement. Both non-HS binding virus and infectious RNA interacting with DC will induce specific immune responses, albeit less efficiently compared with HS-binding virus.