Mechanisms of Foot-and-Mouth Disease virus persistence inferred from immune-related genes differentially expressed between pharyngeal epithelia of virus carriers and non-carriers

Authors: Zhu, James; STENFELDT, CAROLINA - University Of Kansas; BISHOP, ELIZABETH - US Department Of Agriculture (USDA); CANTER, JESSICA - Oak Ridge Institute For Science And Education (ORISE); ESCHBAUMER, MICHAEL - Friedrich-Loeffler-institut; Rodriguez, Luis; Arzt, Jonathan

Submitted to: Frontiers in Veterinary Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/15/2020
Publication Date: 6/19/2020
Citation: Zhu, J.J., Stenfeldt, C., Bishop, E., Canter, J.C., Eschbaumer, M., Rodriguez, L.L., Arzt, J. 2020. Mechanisms of Foot-and-Mouth Disease virus persistence inferred from immune-related genes differentially expressed between pharyngeal epithelia of virus carriers and non-carriers. Frontiers in Veterinary Science. https://doi.org/10.3389/fvets.2020.00340.
DOI: https://doi.org/10.3389/fvets.2020.00340

Interpretive Summary: Foot-and-mouth disease is one of the most contagious and economically devastating viral diseases of cloven-hoofed animals. It is caused by foot-and-mouth disease virus (FMDV). Although the mortality of this disease is very low, FMDV can persist for a long time in a high percentage of infected ruminants after they have recovered from the disease. The mechanisms involved are mostly unknown. Using micro-dissected tissues collected during the persistent infection, we identified genes that were expressed at different levels between virus carriers and non-carriers. Based on how these genes work, we found candidate immune mechanisms that can explain both why cattle cannot clear FMDV and why current vaccines cannot prevent or cure FMDV persistent infection. This study provides insightful information for further investigation of FMDV persistent infection and eventually development of a control method.

Technical Abstract: Foot-and-mouth disease virus (FMDV) causes persistent infection of nasopharyngeal epithelial cells in ~50% of infected ruminants. Currently available vaccines do not prevent or cure this persistent infection and the mechanisms involved are not clear. This current study provides continued analysis of differentially expressed genes (DEG) identified in a previously published transcriptomic study analyzing micro-dissected epithelial samples from FMDV carriers and non-carriers. Pathway analysis indicated that immune cell trafficking could be affected by the differential gene expression. Further examination of the DEG identified five downregulated (chemerin, CCL23, CXCL15, CXCL16 and CXCL17) and one upregulated (CCL2) chemokines in carriers compared to non-carriers. The differential expression could reduce the recruitment of neutrophils, antigen-experienced T cells and dendritic cells and increased the migration of macrophages and NK cells to the epithelia in carriers, which was supported by DEG expressed in these immune cells. Downregulated chemokine expression could be mainly due to the inhibition of canonical NF'B signaling based on DEG in the signaling pathways and transcription factor binding sites predicted from the proximal promoters. Additionally, the mucosal immunity in carriers could be suppressed due to significantly differential expression of immune regulator genes such as CD69, IL33 and NID1. Based on our findings, we hypothesize that (1) inadequate epithelial expression of chemokines that recruit neutrophils, antigen-experienced T cells and dendritic cells and (2) immune suppression on NK cell cytotoxicity and Th17 response compromised virus clearance and allowed FMDV to persist. The hypothesized mechanisms could explain why current vaccines cannot prevent or cure FMDV persistent infection. This study provides novel information for further investigation of persistent FMDV infection.