IFN-γ control of metabolic stress response during T. gondii infection

Abstract

Abstract IFN-γ is essential for host resistance against Toxoplasma gondii infection; however, overproduction of IFN-γ systemically results in increased host morbidity. During acute infection, mice lose weight due to anorexia and hypermetabolism and exhibit high levels of circulating IFN-γ. We wish to understand the role of IFN-γ in the host stress response during infection. We focused on two peptide stress hormones: GDF15 and FGF21. Growth differentiation factor 15, a member of the TGF-β family, is an anorexic agent while fibroblast growth factor 21 is a hormone that upregulates energy expenditure. Indeed, we observed increased levels of serum GDF15 and FGF21 during acute infection preceding weight loss. To investigate the contribution of IFN-γ in the regulation of GDF15 and FGF21, we transiently neutralized IFN-γ in T. gondii infected mice. We observed a decrease in serum GDF15 and FGF21 levels following IFN-γ blockade. Moreover, IFN-γ neutralization not only prevented further weight loss but also led to weight gain. However, there was no difference between control and treated mice in the tissue levels of GDF15. Altogether, these data suggest that IFN-γ contributes to the sickness response during infection by regulating the systemic levels of GDF15 and FGF21. Ongoing studies are focused on the role of IFN-γ in promoting the maturation and release to the circulation of these metabolism-regulating stress hormones during infection.