IL-1R Regulates Disease Tolerance and Cachexia in <i>Toxoplasma gondii</i> Infection

Abstract

<i>Toxoplasma gondii</i> is an obligate intracellular parasite that establishes life-long infection in a wide range of hosts, including humans and rodents. To establish a chronic infection, pathogens often exploit the trade-off between resistance mechanisms, which promote inflammation and kill microbes, and tolerance mechanisms, which mitigate inflammatory stress. Signaling through the type I IL-1R has recently been shown to control disease tolerance pathways in endotoxemia and <i>Salmonella</i> infection. However, the role of the IL-1 axis in <i>T. gondii</i> infection is unclear. In this study we show that IL-1R^-/- mice can control <i>T. gondii</i> burden throughout infection. Compared with wild-type mice, IL-1R^-/- mice have more severe liver and adipose tissue pathology during acute infection, consistent with a role in acute disease tolerance. Surprisingly, IL-1R^-/- mice had better long-term survival than wild-type mice during chronic infection. This was due to the ability of IL-1R^-/- mice to recover from cachexia, an immune-metabolic disease of muscle wasting that impairs fitness of wild-type mice. Together, our data indicate a role for IL-1R as a regulator of host homeostasis and point to cachexia as a cost of long-term reliance on IL-1-mediated tolerance mechanisms.