Spatial metabolomics identifies localized chemical changes in heart tissue during chronic cardiac Chagas Disease

Chagas disease (CD), caused by the parasite Trypanosoma cruzi, is one of nineteen neglected tropical diseases. CD is a vector-borne disease transmitted by triatomines, but CD can also be transmitted through blood transfusions, organ transplants, T. cruzi-contaminated food and drinks, and congenital transmission. While endemic to the Americas, T. cruzi infects 7-8 million people worldwide and can induce severe cardiac symptoms including apical aneurysms, thromboembolisms and arrhythmias during the chronic stage of CD. However, these cardiac clinical manifestations and CD pathogenesis are not fully understood. Using spatial metabolomics (chemical cartography), we sought to understand the localized impact of chronic CD on the cardiac metabolome of mice infected with two divergent T. cruzi strains. Our data showed chemical differences in localized cardiac regions upon chronic T. cruzi infection, indicating that parasite infection changes the host metabolome at specific sites in chronic CD. These sites were distinct from the sites of highest parasite burden. In addition, we identified acylcarnitines and glycerophosphocholines as discriminatory chemical families within each heart region, comparing infected and uninfected samples. Overall, our study indicated global and positional metabolic differences common to infection with different T. cruzi strains and identified select infection-modulated pathways. These results provide further insight into CD pathogenesis and demonstrate the advantage of a systematic spatial perspective to understand infectious disease tropism. Author summary Chagas disease (CD) is a tropical disease caused by the parasite Trypanosoma cruzi. CD originated in the Americas but is now found globally due to population movements. CD is transmitted through a triatomine vector, organ transplants, blood transfusions, T. cruzi-contaminated food and drinks, and congenitally. It occurs in two stages, an acute stage (usually asymptomatic) and a chronic stage. Twenty to thirty percent of chronic stage cases present severe cardiac symptoms such as heart failure, localized aneurysms and cardiomyopathy. Unfortunately, what causes severe cardiac symptoms in some individuals in chronic CD is not fully understood. Therefore, we used liquid chromatography-tandem mass spectrometry to analyze the heart tissue of chronically T. cruzi-infected and uninfected mice, to understand the impact of infection on the tissue metabolome. We identified discriminatory small molecules related to T. cruzi infection and determined that regions with the highest parasite burden are distinct from the regions with the largest changes in overall metabolite profile. These locations of high metabolic perturbation provide a molecular mechanism to explain why localized cardiac symptoms occur in CD, particularly at the heart apex. Overall, our work gives insight into chronic cardiac CD symptom development and shapes a framework for novel CD treatment.

Automated summary

Chagas disease, caused by Trypanosoma cruzi, affects millions of people worldwide and can induce severe cardiac symptoms during the chronic stage. By analyzing the heart tissue metabolome of mice infected with T. cruzi, researchers identified specific metabolic changes in localized cardiac regions, highlighting the impact of parasite infection on host metabolism. Furthermore, discriminatory small molecules related to infection were identified, providing insight into the development of chronic cardiac symptoms in CD.