Abstract
Toxoplasma gondii is a protozoan parasite with a predation-mediated transmission cycle between rodents and felines. Intermediate hosts acquire Toxoplasma by eating parasite cysts which invade the small intestine, disseminate systemically and finally establish host life-long chronic infection in brain and muscles. Here we show that Toxoplasma infection can trigger a severe form of sustained cachexia: a disease of progressive lean weight loss that is a causal predictor of mortality in cancer, chronic disease and many infections. Toxoplasma cachexia is characterized by acute anorexia, systemic inflammation and loss of 20% body mass. Although mice recover from symptoms of peak sickness, they fail to regain muscle mass or visceral adipose depots. We asked whether the damage to the intestinal microenvironment observed at acute time points was sustained in chronic infection and could thereby play a role in sustaining cachexia. We found that parasites replicate in the same region of the distal jejunum/proximal ileum throughout acute infection, inducing the development of secondary lymphoid structures and severe, regional inflammation. Small intestine pathology was resolved by 5 weeks post-infection. However, changes in the commensal populations, notably an outgrowth of Clostridia spp., were sustained in chronic infection. Importantly, uninfected animals co-housed with infected mice display similar changes in commensal microflora but never display symptoms of cachexia, indicating that altered commensals are not sufficient to explain the cachexia phenotype alone. These studies indicate that Toxoplasma infection is a novel and robust model to study the immune-metabolic interactions that contribute to chronic cachexia development, pathology and potential reversal.
Highlights
Chronic diseases account for over 85% of deaths in the first world and 70% of deaths globally [1]
Toxoplasma was no longer observed in the Peyer’s patch-containing segments of the small intestine by 5 weeks post infection by Q PCR (Fig 2H). These results indicate that acute inflammation in the small intestine is resolved by chronic infection and is unlikely to drive the sustained cachexia in these animals
Toxoplasma cachexia is characterized by a loss of 20% in body mass, including fat and muscle, transient anorexia and an acute elevation in the hallmark cachexia cytokines IL-1, TNF and IL-6
Summary
Chronic diseases account for over 85% of deaths in the first world and 70% of deaths globally [1]. Therapeutic interventions including nutritional supplementation, appetite stimulants, steroid treatment and TNF-α inhibitors have not proven widely successful to block or reverse cachexia[3] This may be linked to limitation of current animal models of cachexia which fail to recapitulate the chronic nature of clinical disease. The importance of this relationship is evident in the sophisticated mechanisms the parasite has evolved to intersect host signaling pathways[14], promoting intracellular survival; as well as the observation that Toxoplasma infected rodents lose their aversion to cat urine, a putative means to facilitate transmission[15,16]. We propose that promoting muscle and fat wasting may be a means of enhancing the opportunity for rodent predation and transmission of this parasite to definitive feline hosts
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