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Title: Mechanisms of foot-and-mouth disease virus tropism inferred from differential tissue gene expression

Author
item Zhu, James
item Arzt, Jonathan
item Puckette, Michael
item Smoliga, George
item Pacheco Tobin, Juan
item Rodriguez, Luis

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/11/2013
Publication Date: 5/28/2013
Citation: Zhu, J.J., Arzt, J., Puckette, M.C., Smoliga, G.R., Pacheco Tobin, J., Rodriguez, L.L. 2013. Mechanisms of foot-and-mouth disease virus tropism inferred from differential tissue gene expression. PLoS One. 8(5):e64119. DOI:10.1371/journal.pone.0064119.

Interpretive Summary: Foot-and-mouth disease is a devastating disease of livestock caused by a virus (FMDV). In cattle, the virus targets specific sites to start the infection (primary sites) and then it spreads throughout the body via the bloodstream causing lesions at specific sites i.e. feet and mouth. After lesions heal, the virus can persist at the same sites where infection started. Why the virus targets these sites remains unknown. We utilized gene expression profiling to identify genes differentially expressed between FMDV-targeted and not targeted tissues and applied bioinformatics and statistical analyses to identify biological pathways\networks that could explain FMDV tissue tropism. Based on the knowledge in antiviral innate immunity and FMDV receptors, our results indicate that FMDV tissue tropism is strongly associated with differential expression of genes involved in non-specific (innate) immune responses, cell attachments, cell apoptosis, and cytokine signaling. Therefore, we hypothesize based our results that differences in the accessibility of cell receptors to FMDV, permissiveness for virus replication, and effectiveness in the clearance of infected cells play roles in determining FMDV tissue tropism. Understanding the mechanisms of disease will help design better vaccines.

Technical Abstract: Foot-and-Mouth Disease virus (FMDV) has a characteristic tropism in terms of primary, secondary, and persistent infection and vesicular lesion sites. The virus targets specific tissues for primary replication. From these tissues, the virus spreads via the blood stream to a few preferred secondary infection sites (e.g. foot and mouth) where it replicates to high titers and causes typical vesicular lesions. In some animals, the virus establishes long-term persistence at some primary replication sites. Although integrins have been identified as FMDV receptors, their tissue distribution does not explain the highly selective tissue tropism; thus, other unknown molecular mechanisms must play roles in determining the tropism. We utilized whole genome gene expression profiling to identify genes differentially expressed between FMDV-targeted and not targeted tissues and applied bioinformatic and statistical analysis using a functional genomics approach to identify biological pathways\networks that could explain FMDV tissue tropism. Based on the knowledge in antiviral innate immunity and FMDV receptors, our results indicate that FMDV tissue tropism is strongly associated with differential expression of genes involved in (1) Toll-like receptor, interferon, and IL-1 family signaling, (2) cell attachments, (3) apoptosis and TNF-mediated cell death, and (4) cytokine-receptor kinase signaling. Therefore, we hypothesize that differences in the accessibility of cell receptors to FMDV, permissiveness for virus replication, and effectiveness in the clearance of infected cells play roles in determining FMDV tissue tropism.