Mass Spectrometry-Based Chemical Cartography of a Cardiac Parasitic Infection

Abstract

Trypanosoma cruzi parasites are the causative agents of Chagas disease, a leading infectious form of heart failure whose pathogenesis is still not fully characterized. In this work, we applied untargeted liquid chromatography-tandem mass spectrometry to heart sections from T. cruzi-infected and uninfected mice. We combined molecular networking and three-dimensional modeling to generate chemical cartographical heart models. This approach revealed for the first time preferential parasite localization to the base of the heart and regiospecific distributions of nucleoside derivatives and eicosanoids, which we correlated to tissue-damaging immune responses. We further detected novel cardiac chemical signatures related to the severity and ultimate outcome of the infection. These signatures included differential representation of higher- vs lower-molecular-weight carnitine and phosphatidylcholine family members in specific cardiac regions of mice infected with lethal or nonlethal T. cruzi strains and doses. Overall, this work provides new insights into Chagas disease pathogenesis and presents an analytical chemistry approach that can be broadly applied to the study of host-microbe interactions.

3D mapping of host-parasite-microbiome interactions reveals metabolic determinants of tissue tropism and disease tolerance in Chagas disease

“…Translating ‘omics findings into novel therapeutic approaches is one of the major challenges of this post-genome era. Because we observed larger metabolome than microbiome infection-associated perturbations, and based on our current observations of infection-induced elevation in specific acylcarnitine family members, and our prior findings of differential cardiac acylcarnitine distribution and mass range in mild vs severe acute T. cruzi infection 13 , we focused here on acylcarnitines and the potential of acylcarnitine modulation for CD treatment. The acylcarnitine sub-network ( Fig.…”

“…GI CD is still poorly understood. In our prior work, we identified specific small molecules correlated with cardiac parasite tropism 13 . Here, we sought to identify the locoregional chemical changes associated with parasite GI colonization.…”

“…Samples from both biological replicate experiments were analyzed jointly. Metabolites were extracted from the collected tissue samples using a two-step process as implemented in our prior work 13 , normalizing to tissue weight. Tissue samples were homogenized in LC-MS grade water (50 mg tissue in 125 μL water) using a 5 mm steel ball in Qiagen TissueLyzer at 25 Hz for 3 min.…”

Venomous Arachnid Diagnostic Assays, Lessons from Past Attempts

“…Using high-throughput methodologies, a transcriptomic signature of these specific gene expression alterations (either from mRNA or miRNA) can be defined in the victim’s biological samples and used as a biomarker for developing diagnostic tools. Another approach using chemical signatures instead of RNAs [ 80 , 81 ] can also be applied, using mass spectrometry (MS) for detecting small-molecule metabolites or other biomarkers produced by envenomings [ 82 ]. Establishing and validating molecular profiles or biomarker cartography for envenomations can be challenging, and the fast dynamics of the onset of envenoming symptoms can hamper the clinical relevance of this type of test.…”

Metabolomics: Eavesdropping on silent conversations between hosts and their unwelcome guests

“…tuberculosis –infected macrophages [ 7 ]. (B) Trypanosoma cruzi tropism correlated with host metabolite distribution [ 9 ]. (C) Multi-omics approach to study host–pathogen interactions in a diseased human lung [ 10 ].…”