Correlates of vaccine protection against Mycobacterium avium sub-species paratuberculosis infection revealed in a transcriptomic study of responses in Gudair® vaccinated sheep

Abstract

A critical hindrance in the development of effective vaccine strategies to combat infectious disease is lack of knowledge about correlates of protection and of the host responses necessary for successful adaptive immunity. Often vaccine formulations are developed by stepwise experimentation, with incomplete investigation of the fundamental mechanisms of protection. Gudair^® is a commercially available vaccine registered for use in sheep and goats for controlling spread of Mycobacterium avium sub-species paratuberculosis (MAP) infections and reduces mortality by up to 90%. Here, using an experimental infection model in sheep, we have utilized a transcriptomics approach to identify white blood cell gene expression changes in vaccinated, MAP-exposed Merino sheep with a protective response in comparison to those vaccinated animals that failed to develop immunity to MAP infection. This methodology facilitated an overview of gene-associated functional pathway adaptations using an in-silico analysis approach. We identified a group of genes that were activated in the vaccine-protected animals and confirmed stability of expression in samples obtained from naturally exposed commercially maintained sheep. We propose these genes as correlates of vaccine induced protection.

Keywords: Gudair® vaccine; Johne's disease; Mycobacterium avium subsp. paratuberculosis; correlates of protection; pathways analysis; sheep; transcriptomics; vaccination.

Figure 1

Variation of gene ontological (GO) functions associated to a protective vaccine profile. The cartoons illustrate expression changes in genes or functions associated to Non-Infected in comparison to Infected sheep. Genes and the predicted downstream response are highlighted in color. Color intensity indicates the degree of increased (red) or decreased (green) relative expression of the individual gene expression and predicted activation (orange) or suppression (blue) of downstream function as a consequence of the measured gene expression. Expression of the selected genes (S100B, TET2, CXCL10, TNFRSF21, NRP1, and APP) are predicted to activate generation of cells and cellular infiltration but suppress differentiation of phagocytes in vaccinated sheep that show no sign of MAP infection. *Indicates that multiple identifiers in the dataset file mapped to a sing gene identifier within the Global Molecular Network.

Figure 2

Genes associated to the antigen presenting canonical pathway are associated to a protective vaccine profile. The cartoons illustrate expression changes in genes associated to Non-Infected Gudair^® treated and MAP exposed sheep in comparison to similarly treated Infected sheep. Genes and the predicted downstream response are highlighted in color. Color intensity indicates the degree of increased (red) or decreased (green) relative expression and suggest a suppression of antigen presentation to CD4⁺ T cell lymphocytes but enhanced presentation to CD8⁺ T cell lymphocytes. Detailed explanation for figure notations is located at https://qiagen.my.salesforce-sites.com/KnowledgeBase/articles/Knowledge/Legend.