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Proteogenomics uncovers critical elements of host response in bovine soft palate epithelial cells following in vitro infection with foot-and-mouth disease virus (FMDV)

ABSTRACT: Proteogenomics uncovers critical elements of host response in bovine soft palate epithelial cells following in vitro infection with foot-and-mouth disease virus (FMDV)

PROVIDER: PRJEB30839 | ENA |

REPOSITORIES: ENA

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Proteogenomics uncovers critical elements of host response in bovine soft palate epithelial cells following in vitro infection with foot-and-mouth disease virus (FMDV)

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Project description:: Foot-and-mouth disease (FMD) is the most devastating disease of cloven-hoofed livestock, with a crippling economic burden in endemic areas and immense costs associated with outbreaks in free countries. Foot-and-mouth disease virus (FMDV), a picornavirus, will spread rapidly in naïve populations, reaching morbidity rates of up to 100% in cattle. Even after recovery, over 50% of cattle remain subclinically infected and infectious virus can be recovered from the nasopharynx. The pathogen and host factors that contribute to FMDV persistence are currently not understood. Using for the first time primary bovine soft palate multilayers in combination with proteogenomics, we analyzed the transcriptional responses during acute and persistent FMDV infection. During the acute phase viral RNA and protein was detectable in large quantities and in response hundreds of interferon-stimulated genes (ISG) were overexpressed, mediating antiviral activity and apoptosis. Although the number of pro-apoptotic ISGs and the extent of their regulation decreased during persistence, some ISGs with antiviral activity were still highly expressed at that stage. This indicates a long-lasting but ultimately ineffective stimulation of ISGs during FMDV persistence. Furthermore, downregulation of relevant genes suggests an interference with the extracellular matrix that may contribute to the skewed virus-host equilibrium in soft palate epithelial cells.

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Project description:In order to investigate the mechanisms of persistent foot-and-mouth disease virus (FMDV) infection in cattle, transcriptome alterations associated with the FMDV carrier state were characterized using a bovine whole-transcriptome microarray. Eighteen cattle (8 vaccinated with a recombinant FMDV A vaccine, 10 non-vaccinated) were challenged with FMDV A24 Cruzeiro, and the gene expression profiles of nasopharyngeal tissues collected between 21 and 35 days after challenge were compared between 11 persistently infected carriers and 7 non-carriers. Carriers and non-carriers were further compared to 2 naïve animals that had been neither vaccinated nor challenged. At a controlled false-discovery rate of 10% and a minimum difference in expression of 50%, 648 genes were differentially expressed between FMDV carriers and non-carriers, and most (467) had higher expression in carriers. Among these, genes associated with cellular proliferation and the immune response – such as chemokines, cytokines and genes regulating T and B cells – were significantly overrepresented. Differential gene expression was significantly correlated between non-vaccinated and vaccinated animals (biological correlation +0.97), indicating a similar transcriptome profile across these groups. Genes related to prostaglandin E2 production and type 2 immune polarization, as well as to the induction of regulatory T cells and T-cell exhaustion were overexpressed in carriers. In contrast, tissues from non-carrier animals expressed higher levels of complement regulators and pro-apoptotic genes that could promote virus clearance. Based on these findings, we propose that FMDV persistence in nasopharyngeal tissues of cattle is maintained by an impairment of apoptosis and the local suppression of cell-mediated antiviral immunity by inducible regulatory T cells.

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