Transcriptional Analyses Identify Genes That Modulate Bovine Macrophage Response to Infection and Immune Stimulation.

The obligate intracellular parasite, , is highly prevalent among livestock species. Although cattle are generally resistant to strains circulating in Europe and North America, the underlying mechanisms are largely unknown. Here, we report that bovine bone marrow-derived macrophage (BMDM) pre-stimulated with interferon gamma (IFNγ) restricts intracellular growth independently of nitric oxide. While promoted the expression of genes associated with alternative macrophage activation and lipid metabolism, IFNγ abrogated parasite-induced transcriptional responses and promoted the expression of genes linked to the classical macrophage activation phenotype. Additionally, several chemokines, including , that are linked to parasite-induced activation of the /β-catenin signaling were highly expressed in -exposed naïve BMDMs. A chemical /β-catenin signaling pathway antagonist (IWR-1-endo) significantly reduced intracellular parasite burden in naïve BMDMs, suggesting that activates this pathway to evade bovine macrophage anti-parasitic responses. Congruently, intracellular burden of a mutant strain (RHΔ) that does not secrete dense granule proteins into the host cell, which is an essential requirement for parasite-induced activation of the /β-catenin pathway, was significantly reduced in naïve BMDMs. However, both the /β-catenin antagonist and RHΔ5 did not abolish parasite burden differences in naïve and IFNγ-stimulated BMDMs. Finally, we observed that parasites infecting IFNγ-stimulated BMDMs largely express genes associated with the slow dividing bradyzoite stage. Overall, this study provides novel insights into bovine macrophage transcriptional response to . It establishes a foundation for a mechanistic analysis IFNγ-induced bovine anti- responses and the counteracting survival strategies.