T. gondii infection induces IL-1R dependent chronic cachexia and perivascular fibrosis in the liver and skeletal muscle.

Cachexia is a progressive muscle wasting disease that contributes to death in a wide range of chronic diseases. Currently, the cachexia field lacks animal models that recapitulate the long-term kinetics of clinical disease, which would provide insight into the pathophysiology of chronic cachexia and a tool to test therapeutics for disease reversal. Toxoplasma gondii (T. gondii) is a protozoan parasite that uses conserved mechanisms to infect rodents and human hosts. Infection is lifelong and has been associated with chronic weight loss and muscle atrophy in mice. We have recently shown that T. gondii-induced muscle atrophy meets the clinical definition of cachexia. Here, the longevity of the T. gondii-induced chronic cachexia model revealed that cachectic mice develop perivascular fibrosis in major metabolic organs, including the adipose tissue, skeletal muscle, and liver by 9 weeks post-infection. Development of cachexia, as well as liver and skeletal muscle fibrosis, is dependent on intact signaling through the type I IL-1R receptor. IL-1α is sufficient to activate cultured fibroblasts and primary hepatic stellate cells (myofibroblast precursors in the liver) in vitro, and IL-1α is elevated in the sera and liver of cachectic, suggesting a mechanism by which chronic IL-1R signaling could be leading to cachexia-associated fibrosis.

IL-1R Regulates Disease Tolerance and Cachexia in Toxoplasma gondii Infection.

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.

Hyperlipidaemia in trypanosomiasis of naturally infected horses: possible cachexia-anorexia syndrome?

Trypanosomiasis caused by Trypanosoma evansi commonly produces wasting disease with signs of emaciation and cachexia mainly at the end stage. The present study was conducted to explore the possible hyperlipaemia or hyperlipidaemia and its association with cachexia-anorexia in equine trypanosomiasis. Out of the fifteen confirmed animals, none of the plasma sample was opaque. There was a significant increase in plasma triglyceride, total cholesterol and blood urea nitrogen and a highly significant increase in low-density lipoprotein (LDL) levels. A mild increase in high-density lipoprotein (HDL) and very low-density lipoprotein levels were observed, while the relative percentage of HDL and LDL was altered with high significance. A moderate increase in triglyceride and highly significant increase in LDL might be the reasons for retention of appetite and lipolysis. Possible protein breakdown and presence of lipolysis might be the reasons for cachexia in equine trypanosomiasis.

Effect of progressive cachectic parasitism and growth hormone treatment on hepatic 5'-deiodinase activity in calves.

Thyroid status is compromised in a variety of acute and chronic infections. Conversion of thyroxine (T(4)) into the metabolically active hormone, triiodothyronine (T(3)), is catalyzed by 5'-deiodinase (5'D) mainly in extrathyroidal tissues. The objective of this study was to examine the effect of protozoan parasitic infection (Sarcocystis cruzi) on hepatic 5'D (type I) activity and plasma concentrations of T(3) and T(4) in placebo- or bovine GH (bGH)-injected calves. Holstein bull calves (127.5+/-2.0 kg BW) were assigned to control (C, ad libitum fed), infected (I, 250,000 S. cruzi sporocysts per os, ad libitum fed), and pair-fed (PF, non-infected, fed to intake of I treatment) groups placebo-injected, and three similar groups injected daily with pituitary-derived bGH (USDA-B-1, 0.1mg/kg, i.m.) designated as C(GH), I(GH) and PF(GH). GH injections were initiated on day 20 post-infection (PI), 3-4 days prior to the onset of clinical signs of the acute phase response (APR), and were continued to day 56 PI at which time calves were euthanized for liver collection. Blood samples were collected on day 0, 28, and 55 PI. Alterations in nutritional intake did not affect type I 5'D in liver. Treatment with bGH increased (P<0.05) 5'D activity in C (24.6%) and PF (25.5%) but not in I calves. Compared to PF calves, infection with S. cruzi reduced 5'D activity 25% (P<0.05) and 47.8% (P<0.01) in placebo- and bGH-injected calves, respectively. Neither nutrition nor bGH treatment significantly affected plasma concentrations of T(4) and T(3) on day 28 and 55 PI. However, plasma thyroid hormones were reduced by infection. On day 28 PI, the average plasma concentrations of T(3) and T(4) were reduced in infected calves (I and I(GH)) 36.4% (P<0.01) and 29.4% (P<0.05), respectively, compared to pair-fed calves (PF and PF(GH)). On day 55 PI, plasma T(3) still remained lower (23.7%, P<0.01 versus PF) in infected calves while plasma T(4) returned to control values. The data suggest that parasitic infection in growing calves inhibits both thyroidal secretion and extrathyroidal T(4) to T(3) conversion during the APR. After recovery from the APR, thyroidal secretion returns to normal but basal and bGH-stimulated generation of T(3) in liver remains impaired.

[Cryptosporidium in veal calves affected with cachexia]. / Cryptosporidium bij cachectische mestkalveren.

Coccidia of the genus Cryptosporidium were detected in histological sections of the small intestine of three veal calves. Autopsy was performed on these calves as part of a study of the aetiology of the syndrome "cachexia" in veal calves. In addition, typical 4 mu cryptosporidium oocysts were observed in the bowel contents of one of two histologically positive calves examined and seven out of eight other cachectic calves in which coccidia had not been detected on histological examination. The changes of the mucosa of the small intestine observed are described and the possible role of cryptosporidiosis in the pathogenesis of these lesions is discussed.