Biology subjects

Melchor, S. J.

Publications and source records attributed to Melchor, S. J..

3 recordsLinked to original sources

bioRxiv2022

Tricarboxylic acid (TCA) cycle, sphingolipid, phosphatidylcholine metabolism is dysregulated in T. gondii infection-induced cachexia

Cachexia is a life-threatening disease characterized by chronic, inflammatory muscle wasting and systemic metabolic impairment. Despite its high prevalence, there are no efficacious therapies for cachexia. Mice chronically infected with the protozoan parasite Toxoplasma gondii represent a novel animal model recapitulating the chronic kinetics of cachexia. To understand how perturbations to metabolic tissue homeostasis influence circulating metabolite availability we used mass spectrometry analysis. Despite the significant reduction in circulating triacylglycerides, non-esterified fatty acids, and glycerol, sphingolipid long-chain bases and a subset of phosphatidylcholines (PCs) were significantly increased in the sera of mice with T. gondii infection-induced cachexia. In addition, the TCA cycle intermediates -ketoglutarate, 2-hydroxyglutarate, succinate, fumarate, and malate were highly depleted in cachectic mouse sera. Sphingolipids and their de novo synthesis precursors PCs are the major components of the mitochondrial membrane and regulate mitochondrial function consistent with a causal relationship in the energy imbalance driving T. gondii-induced chronic cachexia.

immunology↗

bioRxiv2019

Acute lymph node slices are a functional model system to study immunity ex vivo

The lymph node is a highly organized and dynamic structure that is critical for facilitating the intercellular interactions that constitute adaptive immunity. Most ex vivo studies of the lymph node begin by reducing it to a cell suspension, thus losing the spatial organization, or fixing it, thus losing the ability to make repeated measurements. Live murine lymph node tissue slices offer the potential to retain spatial complexity and dynamic accessibility, but their viability, level of immune activation, and retention of antigen-specific functions have not been validated. Here we systematically characterized live murine lymph node slices as a platform to study immunity. Live lymph node slices maintained the expected spatial organization and cell populations while reflecting the 3D spatial complexity of the organ. Slices collected under optimized conditions were comparable to cell suspensions in terms of both 24-hr viability and inflammation. Slices responded to T cell receptor cross-linking with increased surface marker expression and cytokine secretion, in some cases more strongly than matched lymphocyte cultures. Furthermore, slices processed protein antigens, and slices from vaccinated animals responded to ex vivo challenge with antigen-specific cytokine secretion. In summary, lymph node slices provide a versatile platform to investigate immune functions in spatially organized tissue, enabling well-defined stimulation, time-course analysis, and parallel read-outs.

immunology↗

bioRxiv2019

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. T. gondii is a protozoan parasite that causes lifelong infection in many warm-blooded organisms, including humans and mice. Here we show that mice infected with T. gondii 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.\n\nSummaryIL-1R signaling drives a disease tolerance program that protects mice from tissue pathology during acute Toxoplasma gondii infection. However, extended IL-1R signaling drives chronic cachexia and perivascular fibrosis in the liver and skeletal muscle.

immunology↗