Mechanisms of Maintenance of Foot-and-Mouth Disease Virus Persistence Inferred From Genes Differentially Expressed in Nasopharyngeal Epithelia of Virus Carriers and Non-carriers.

James J Zhu,Jessica A Canter,Michael Eschbaumer,Jonathan Arzt,Carolina Stenfeldt,Luis L Rodriguez,Elizabeth A Bishop

doi:10.3389/fvets.2020.00340

Abstract

Foot-and-mouth disease virus (FMDV) causes persistent infection of nasopharyngeal epithelial cells in ~50% of infected ruminants. The mechanisms involved are not clear. This study provides a continued investigation 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 of DEG indicated that immune cell trafficking, cell death and hematological system 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 increase 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 NFκB signaling based on DEG in the signaling pathways and transcription factor binding sites predicted from the proximal promoters. Additionally, upregulated CD69, IL33, and NID1 and downregulated CASP3, IL17RA, NCR3LG1, TP53BP1, TRAF3, and TRAF6 in carriers could inhibit the Th17 response, NK cell cytotoxicity and apoptosis. Based on our findings, we hypothesize that (1) under-expression of chemokines that recruit neutrophils, antigen-experienced T cells and dendritic cells, (2) blocking NK cell binding to target cells and (3) suppression of apoptosis induced by death receptor signaling, viral RNA, and cell-mediated cytotoxicity in the epithelia compromised virus clearance and allowed FMDV to persist. These hypothesized mechanisms provide novel information for further investigation of persistent FMDV infection.

Highlights

Foot-and-mouth disease (FMD) is one of the most contagious and economically devastating animal viral diseases
Among the genes associated with these probes, there were 1,281 downregulated and 951 upregulated genes that could be mapped to human or mouse genes. This gene set including both up- and down-regulated genes was used in the NCBI DAVID and Ingenuity Pathway Analysis (IPA) pathway analyses
These findings suggest that the interferon, IRF3, MAPK and especially canonical NFκB signaling pathways could be negatively impacted by the differential gene expression during persistent Foot-and-mouth disease virus (FMDV) infection

Summary

Introduction

Foot-and-mouth disease (FMD) is one of the most contagious and economically devastating animal viral diseases. The virus replicates locally in the nasopharynx or lungs depending on exposure conditions [1,2,3]. Mortality is generally low in adults, but persistent infection can occur for long periods (30 days−5 years) with virus persisting at the primary infection sites (e.g., nasopharynx) in a high percentage (∼50%) of infected cattle, buffalo and sheep [4,5,6,7,8]. FMDV persistent replication sites in cattle were localized to the epithelial cells of the dorsal soft palate and pharynx [9] and, more precisely, the follicle-associated epithelia of the nasopharyngeal mucosa [7, 10]. Various studies have failed to demonstrate natural transmission from FMDV carrier cattle [8], it has been demonstrated that oropharyngeal fluid from carrier cattle is infectious to naïve cattle [11]

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Conclusion