Cachexia and fibrosis are costs of chronic IL-1R-mediated disease tolerance in T. gondii infection

Cachexia is an immune-metabolic disease of progressive muscle wasting that impairs patient survival and quality of life across a range of chronic diseases. is a protozoan parasite that causes lifelong infection in many warm-blooded organisms, including humans and mice. Here we show that mice infected with develop robust, sustained cachexia and perivascular fibrosis in metabolic tissues. Consistent with an emerging role for the IL-1 axis in disease tolerance, we show that mice deficient in the Type 1 IL-1 receptor (IL-1R) have more severe acute muscle wasting, adipocyte and hepatocyte necrosis, independent of parasite burden. Unexpectedly, IL-1R mice rapidly recover from acute disease, despite sustained parasite infection, and are protected from chronic cachexia as well as perivascular liver and muscle fibrosis. These data are consistent with a model where IL-1R signaling benefits cell survival and tissue integrity over short periods of inflammation, but sustained reliance on IL-1 mediated tolerance programs come at the cost of fibrosis and cachexia.