Mechanisms of Foot-and-Mouth Disease Virus Tropism Inferred from Differential Tissue Gene Expression

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.

Persistent Foot-and-Mouth Disease Virus Infection in the Nasopharynx of Cattle; Tissue-Specific Distribution and Local Cytokine Expression

“…This lack of evidence of cellular degeneration of FMDV-infected cells in carriers suggests a distinct mechanism in which infected cells survive and remain within the carrier's epithelium. These findings are consistent with previously published suggestion that in the carrier state, FMDV employs a distinct, non-cytolytic infection process which may be driven by alterations in cytokine signaling cascades and/or tissue specific decreased cell death mechanisms [3,53].…”

“…However, the causality of this association remains undermined; specifically, one might consider whether 1) FMDV dysregulated the expression of these genes thus enabling the carrier state or 2) a subset of cattle are intrinsically poor producers of IFN and it is these animals that ultimately become carriers. Previous work describing gene expression in tissues with different FMDV tropism from non-infected cattle suggested that pharyngeal tissues are intrinsically poor type I and III IFN inducers and responders, and this might explain their susceptibility to both primary and persistent infection (Zhu et al 2013). The results of the current study are consistent with those findings.…”

“…Recent reports from our laboratory describing the acute phase of FMD in cattle demonstrated modest induction of some of the same cytokine genes at these same tissues [26] and tissue-specific induction of IFN signaling pathways [53]. In the acute phase of infection, FMDV is largely similar to several other viral infections that generally induce proinflammatory and antiviral innate immune responses [13,26,28,[53][54][55][56]. By contrast, there are examples wherein the persistent phase of FMDV and other viral infections have been shown to be associated with suppression or modulation the host immune response [13,57,58].…”

“…The current data suggest that in the persistent phase of FMDV infection in cattle there is a clear lack of stimulation and a trend towards suppression of transcription of various host cytokine genes at the sites of virus persistence. Recent reports from our laboratory describing the acute phase of FMD in cattle demonstrated modest induction of some of the same cytokine genes at these same tissues [26] and tissue-specific induction of IFN signaling pathways [53]. In the acute phase of infection, FMDV is largely similar to several other viral infections that generally induce proinflammatory and antiviral innate immune responses [13,26,28,[53][54][55][56].…”

“…Indeed, two studies have demonstrated upregulation of TNF-α in tissues of cattle persistently infected with FMDV [13,34]. Additionally, decreased detection of IFN-β and lower IFN signaling capacity have been demonstrated during the acute phase of FMDV infection of cattle [13,53].…”