IL-1R Regulates Disease Tolerance and Cachexia in <i>Toxoplasma gondii</i> Infection
Stephanie Melchor, Claire M. Saunders, Imani Sanders, Jessica A. Hatter, Kari A. Byrnes, Sheryl Coutermarsh‐Ott, Sarah E. Ewald
Abstract
Abstract Toxoplasma gondii 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 Salmonella infection. However, the role of the IL-1 axis in T. gondii infection is unclear. In this study we show that IL-1R−/− mice can control T. gondii 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.