IL-1R drives acute disease tolerance, liver and skeletal muscle fibrosis, and sustained cachexia during T. gondii infection

Toxoplasma gondii (T. gondii) is a protozoan parasite that chronically infects a wide range of warm-blooded hosts, including humans and mice. After an acute phase of infection, when the parasite is replicating quickly and inducing rampant inflammation and tissue damage throughout the body, T. gondii transitions to a chronic stage where it remains in a protective cyst for the rest of the host’s life. It has been known in the T. gondii field for decades that infection in rodents leads to prolonged wasting; however, the mechanism of this wasting has not been probed in the modern molecular era. Here we characterize T. gondii-induced wasting as cachexia, a deadly muscle wasting disease associated with most chronic human illness. The discovery that T. gondii causes cachexia is a critical tool for the cachexia field, as it introduces a natural infection model that allows for mechanisms of wasting to be studied over the course of months rather than days to weeks (the span of most popular experimental models of cachexia today). T. gondii-induced cachexia occurs independently of intestinal inflammation and sustained dysbiosis, but does require signaling through the type I interleukin-1 receptor (IL-1R), as IL-1R-/- are protected from cachexia while maintaining a comparable parasite burden as wildtype mice. Importantly, while IL-1R signaling remains dispensable for control of the parasite during the acute period as well, it promotes pathways of tissue tolerance to infection and inflammation. IL-1R-/- have significantly worse tissue damage in the liver and adipose tissue than wildtype mice, despite having the same number of parasites. Together these observations suggest a paradigm that while pathways controlling disease tolerance pathways may be beneficial in the short-term (for example, protection from acute liver and adipose tissue damage), unchecked activation of them can lead to pathology, like cachexia. In addition to cachexia, IL-1R is also necessary for the perivascular fibrosis that arises in the skeletal muscle and liver of cachectic mice, a heretofore unobserved phenomenon in experimental cachexia models, despite being seen in clinical cachexia.