Clearance of a persistent picornavirus infection is associated with enhanced pro-apoptotic and cellular immune responses

Carolina Stenfeldt,Jonathan Arzt,Michael Eschbaumer,James Zhu,Luis L Rodriguez,George R Smoliga

doi:10.1038/s41598-017-18112-4

Abstract

Long-term persistent viral infections cause substantial morbidity and associated economic losses in human and veterinary contexts. Yet, the mechanisms associated with establishment of persistent infections are poorly elucidated. We investigated immunomodulatory mechanisms associated with clearance versus persistence of foot-and-mouth disease virus (FMDV) in micro-dissected compartments of the bovine nasopharynx by microarray. The use of laser-capture microdissection allowed elucidation of differential gene regulation within distinct anatomic compartments critical to FMDV infection. Analysis of samples from transitional and persistent phases of infection demonstrated significant differences in transcriptome profiles of animals that cleared infection versus those that became persistently infected carriers. Specifically, it was demonstrated that clearance of FMDV from the nasopharyngeal mucosa was associated with upregulation of targets associated with activation of T cell-mediated immunity. Contrastingly, gene regulation in FMDV carriers suggested inhibition of T cell activation and promotion of Th2 polarization. These findings were corroborated by immunofluorescence microscopy which demonstrated relative abundance of CD8+ T cells in the nasopharyngeal mucosa in association with clearance of FMDV. The findings presented herein emphasize that a critical balance between Th1 and Th2 -mediated immunity is essential for successful clearance of FMDV infection and should be considered for development of next-generation vaccines and antiviral products.

Highlights

Foot-and-mouth disease virus (FMDV), the prototype Aphthovirus within the Picornaviridae family, is the causal agent of foot-and-mouth disease (FMD), a highly contagious disease of cloven-hoofed animals[1]
An extensive analysis of gene expression in nasopharyngeal tissue samples using whole tissue macerates from FMDV carriers and a bovine whole transcriptome microarray suggested that the FMDV carrier state was associated with impairment of apoptotic pathways and overexpression of genes associated with induction of regulatory T cells and T cell exhaustion[21]
A previous investigation has suggested that regulation of the early immune response to FMDV infection by high systemic levels of IL-10 may predispose to establishment of persistent infection[22]

Summary

Introduction

Foot-and-mouth disease virus (FMDV), the prototype Aphthovirus within the Picornaviridae family, is the causal agent of foot-and-mouth disease (FMD), a highly contagious disease of cloven-hoofed animals[1]. There were significant negative correlations in FMDV carriers between the quantity of FMDV RNA and the relative expression levels of interferon (IFN)-λ, IFN-γ, IFN regulatory factor (IRF)-7, and CXCL10 in micro-dissected samples of nasopharyngeal FAE11 This finding distinctly contrasts the significant induction of inflammatory cytokines and anti-viral host factors that occurs during acute FMDV infection in cattle[18,19,20]. Isolation of distinct microanatomic regions of the highly heterogeneous bovine nasopharynx, by use of laser-capture microdissection (LCM), enabled precise characterization of transcriptome profiles associated with defined stages of FMDV infection This was based upon previous works which had enabled determination of the temporal window during which FMDV is cleared from the nasopharyngeal mucosa in animals that do not develop persistent infection[11]

Methods

Results

Discussion

Conclusion