Identification of interferon stimulated genes that control Toxoplasma in pig macrophages

Toxoplasma gondii, the principal cause of abortion in livestock, cost the UK livestock industry about $15 million per year. Acute infection in pigs can cause fever and respiratory distress, and over 50% mortality rates in infected pigs. Piglets infected in utero may be born premature, dead, weak, or die within three weeks of birth. Toxoplasma in pigs is also important for human health, who often get infected by consuming pork from chronically infected pigs. In humans, Toxoplasma is the main cause of childhood blindness and early death in HIV/AIDS patients. No drugs or approved vaccines exists for Toxoplasma in pigs, making the development of new anti-Toxoplasma tools for pigs an import biomedical priority. Interferon gamma (IFNg) cytokine is required to control acute and chronic infections. However, we know relatively little about how IFNg control Toxoplasma in the pig. including which interferon-stimulated gene (ISGs) directly inhibit Toxoplasma in pig cells. In preliminary experiments, we have observed that Toxoplasma induce differential expression of over 1000 ISGs, and recombinant IFNg inhibits Toxoplasma, in pig macrophages. Guided by these and other preliminary data, this project will address the gap in our current knowledge of how ISGs control Toxoplasma in pig cells by systematically identifying which and how the differentially expressed ISGs directly control Toxoplasma in pig macrophages using pig pluripotent stem cell-derived macrophages and high throughput ISG functional screening tools that we have recently developed. The fundamental insights that we will obtain will provide a deeper understanding ISG-Toxoplasma interactions in pig macrophages, which in the long-term, may prime one health strategies reduce the disease burden and zoonotic potential of Toxoplasma in pigs. The tools and data from this work will also have broad relevance to other pig pathogens controlled by IFNs such as African swine fever.