Genetic hallmark of susceptible cows through macrophage profiling of MAP infected cows: Johne's-disease-associated SNPs impair macrophage function

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Johne's disease (JD) is a debilitating and chronic enteritis in ruminants caused by an intracellular pathogen called Mycobacterium avium ssp. paratuberculosis (MAP). JD causes significant economic losses in the Canadian dairy industry, estimated at $15-$90 million annually. Research is ongoing to identify early and more accurate markers; improvement of host disease resistance using a judicious genetic selection strategy is also an important strategy of the dairy industry. In the present research proposal, we will study cow's macrophages which are a type of specialized antigen presenting immune cells responsible for the engulfment of pathogens. There is evidence that MAP requires macrophages for its survival and dissemination. We hypothesize that macrophage is genetically altered in susceptible cows which allows MAP to proliferate and escape the normal mycobacterial killing process. With the use of next-generation RNA sequencing technology, we will study the functional properties of macrophages challenged with MAP. RNA-Seq is an effective way of identifying expression quantitative trait loci (eQTL) and those causative DNA polymorphisms associated with candidate gene transcripts and their types of isoforms. The specific objectives are: (1) to identify eQTL which define the genetic differences that discriminate MAP infected from healthy/resistant cows; (2) to identify the genes (and their isoforms) and the regulatory pathways involved in MAP requisitioning of macrophage; (3) to identify functional genetic variations that delineate susceptible from non-susceptible cows; and (4) to confirm the influence of beneficial or dysfunctional allele (s) on the capacity of the bovine macrophage to process intracellular pathogens. This information is relevant in genetic selection, as they preclude disease susceptibility. An integration of the findings of this research (genomic information), into the conventional young sire selection and progeny testing program could yield a better, more accurate and rapid genetic improvement of resistance to bovine paratuberculosis in Canadian dairy herds.