Abstract
Foot-and-mouth disease virus (FMDV) targets specific tissues for primary infection, secondary high-titer replication (e.g. foot and mouth where it causes typical vesicular lesions) and long-term persistence at some primary replication sites. Although integrin αVβ6 receptor has been identified as primary FMDV receptors in animals, their tissue distribution alone fails to explain these highly selective tropism-driven events. Thus, other molecular mechanisms must play roles in determining this tissue specificity. We hypothesized that differences in certain biological activities due to differential gene expression determine FMDV tropism and applied whole genome gene expression profiling to identify genes differentially expressed between FMDV-targeted and non-targeted tissues in terms of supporting primary infection, secondary replication including vesicular lesions, and persistence. Using statistical and bioinformatic tools to analyze the differential gene expression, we identified mechanisms that could explain FMDV tissue tropism based on its association with differential expression of integrin αVβ6 heterodimeric receptor (FMDV receptor), fibronectin (ligand of the receptor), IL-1 cytokines, death receptors and the ligands, and multiple genes in the biological pathways involved in extracellular matrix turnover and interferon signaling found in this study. Our results together with reported findings indicate that differences in (1) FMDV receptor availability and accessibility, (2) type I interferon-inducible immune response, and (3) ability to clear virus infected cells via death receptor signaling play roles in determining FMDV tissue tropism and the additional increase of high extracellular matrix turnover induced by FMDV infection, likely via triggering the signaling of highly expressed IL-1 cytokines, play a key role in the pathogenesis of vesicular lesions.
Highlights
Foot and mouth disease (FMD) is one of the most contagious and economically devastating viral animal diseases
Based on the expression of the genes involved in these biological processes and on relevant findings from the literature, we propose molecular bases that help explain the mechanisms of FMD virus (FMDV) tissue tropism
V$STAT1_01 and V$STAT_Q6 were over-represented in the primary replication sites (PRS)-up gene set. These results indicate that transcription factors binding to these binding sites may play roles in differential gene expression; pathways such as interferons and IL-1 cytokines that activate these transcription factors may be involved in determining FMDV tropism
Summary
Foot and mouth disease (FMD) is one of the most contagious and economically devastating viral animal diseases. The mechanisms that determine FMDV tissue tropism including target sites for primary, secondary, and persistent infection remain undetermined despite extensive research on this virus discovered over 100 years ago. Swine vesicular disease virus, and vesicular exanthema of swine virus have nearly identical lesion sites and clinical signs as FMD in cattle and swine, suggesting that these targeted tissues possess certain biological characteristics rendering them susceptible to a common pathway associated with these viral vesicular diseases. There are several reports showing that altering some host cellular factors such as Rab and RNA helicase A can inhibit FMDV replication [23], [24] These findings indicate that host factors other than the virus receptors may be contributing to FMDV tissue tropism. Based on the expression of the genes involved in these biological processes and on relevant findings from the literature, we propose molecular bases that help explain the mechanisms of FMDV tissue tropism
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