Innate Inflammatory Control of Cachexia

University Of Virginia, Charlottesville VA

Investigators

Linked publications & trials

Abstract

Project Summary Inflammation is a common driver of chronic disease. These inflammatory pathways evolved to relay damage caused by foreign invaders to upregulate defense mechanisms. However, in chronic disease, aberrant activation of inflammation shifts metabolic homeostasis and tissue function leading to pathology. To understand this biology my lab uses the protozoan parasite Toxoplasma gondii, which naturally infects humans and mice for life, using conserved interactions with the immune system. T. gondii is genetically tractable, interacts with most tissues, and infects hosts for life making it an ideal tool to probe chronic inflammatory networks. My long-term goal is to identify the inflammatory pathways driving chronic disease progression that can be inhibited without increasing susceptibility to pathobiont infection. In the next 5 years, my research will focus on 3 areas: My lab has shown that T. gondii infection is a robust and reproducible model of chronic cachexia. Cachexia, or the inflammatory loss of lean body mass, is a predictor of morbidity across chronic diseases. The molecular mechanisms controlling cachexia onset, persistence, and pathology is poorly understood and we lack efficacious interventions to reverse cachexia. In the previous funding period, we determined that inhibiting the IL-1R/NF-κβ signaling axis is sufficient to reverse cachexia progression without increasing susceptibility to T. gondii infection. Oxidative stress metabolites were highly dysregulated in cachexia, to the greatest degree, in the colon. Our work during this funding period will test the model that commensal dysbiosis initiated during acute cachexia, sustains NF-κβ signaling, leading to the metabolic perturbation driving chronic cachexia. Recognizing that parasite load may not be a reliable readout for unique infection and clearance events we developed a T. gondii barcoding method to evaluate population dynamics in vivo. This tool revealed that the blood-brain barrier is not a major limitation to brain colonization by T. gondii, however, the gut may be a stringent bottleneck to infection. Here, barcoded T. gondii will be applied to differentiate the inflammatory pathways regulating gut pathobiont invasiveness from signals regulating pathology, tolerance, and resilience. Our studies have clarified a need for better tools to understand tissue cell types and signaling environments that regulate inflammation in solid tissues. To address this, we developed a protein discovery tool called Automated Spatially Targeted Optical Micro Proteomics. AutoSTOMP uses a confocal microscope to identify cell types or structures of interest and photo-biotinylate proteins in those structures for identification by LC-MS. We have applied this technique to the T. gondii vacuole membrane, fibroblast and macrophage in cardiac infarcts, as well as inflammatory cell types and dietary allergens driving eosinophilic esophagitis in patient biopsies. Currently, the resolution of this technique is limited by the sensitivity of LC-MS, not the precision of the microscope. Thus, we will combine state-of-the-art advances in single-cell proteomics with autoSTOMP to generate a high- sensitivity tool with the precision to perform discovery proteomics on rare cell types at the biopsy scale.