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Title: Transcriptomic analysis of persistent infection with foot-and-mouth disease virus in cattle suggests impairment of cell-mediated immunity in the nasopharynx

item ESCHBAUMER, MICHAEL - Oak Ridge Institute For Science And Education (ORISE)
item STENFELDT, CAROLINA - Oak Ridge Institute For Science And Education (ORISE)
item Smoliga, George
item PACHECO, JUAN - Us Deparment Of Homeland Security
item Rodriguez, Luis
item Li, Robert
item Zhu, James
item Arzt, Jonathan

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/2/2016
Publication Date: 9/19/2016
Citation: Eschbaumer, M., Stenfeldt, C., Smoliga, G.R., Pacheco, J., Rodriguez, L.L., Li, R.W., Zhu, J.J., Arzt, J. 2016. Transcriptomic analysis of persistent infection with foot-and-mouth disease virus in cattle suggests impairment of cell-mediated immunity in the nasopharynx. PLoS One. 11:e0162750.

Interpretive Summary: One of the reasons that foot-and-mouth disease virus (FMDV) is a great concern for the international trade in livestock and animal products is its ability to cause chronic infections in cattle. After an acute FMDV infection, some cattle recover completely, while others go on to become “silent carriers” of the virus. It has been confirmed that FMDV carriers harbor the virus in the mucosal lining of their upper respiratory tract, particularly the nasopharynx, but it is not known what allows the virus to survive there. In this study, we attempted to answer this question by comparing the gene expression in tissues of FMDV carriers to animals that had been infected, but cleared the virus from their tissues, the so-called “non-carriers”. This comparison revealed a number of interesting differences. Carriers more strongly expressed some genes that interfere with programmed cell death that is important for the elimination of virus-infected cells from the body. Among the other genes that were expressed more strongly in carriers, we identified groups of genes related to immunosuppression and cell signaling that could explain why the immune system of carrier cattle cannot remove FMDV from their nasopharyngeal tissues. Similar processes are involved in the maintenance of other persistent viral infections like hepatitis B, hepatitis C and HIV in humans. These novel findings will provide a guide towards the development of vaccines and biotherapeutics that prevent or terminate the carrier state of FMD.

Technical Abstract: 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. Differential gene expression was strongly correlated between non-vaccinated and vaccinated animals (biological correlation +0.97). 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 – including lymphocyte chemotaxis, cytokine production and chemokine-mediated signaling – were significantly overrepresented. 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 tissues of carrier animals. In contrast, tissues from non-carrier animals expressed higher levels of pro-apoptotic genes that could promote virus clearance. Based on these findings, we hypothesize that FMDV persistence in nasopharyngeal tissues of cattle may be maintained by a local suppression of cell-mediated antiviral immunity by regulatory T cells, their inhibitory signals and the functional exhaustion of effector T cells.