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

View ORCID ProfileDanya A. Dean, View ORCID ProfileGautham, Jair L. Siqueira-Neto, James H. McKerrow, Pieter C. Dorrestein, View ORCID ProfileLaura-Isobel McCall
doi: https://doi.org/10.1101/2020.06.29.178038
Danya A. Dean
1Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, United States of America
2Laboratories of Molecular Anthropology and Microbiome Research, University of Oklahoma, Norman, Oklahoma, United States of America
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  • ORCID record for Danya A. Dean
Gautham
2Laboratories of Molecular Anthropology and Microbiome Research, University of Oklahoma, Norman, Oklahoma, United States of America
3Department of Biology, University of Oklahoma, Norman, Oklahoma, United States of America
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Jair L. Siqueira-Neto
4Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America
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James H. McKerrow
4Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America
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Pieter C. Dorrestein
4Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America
5Center for Microbiome Innovation, University of California San Diego, La Jolla, California, United States of America
6Collaborative Mass Spectrometry Innovation Center, University of California San Diego, La Jolla, California, United States of America
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Laura-Isobel McCall
1Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, United States of America
2Laboratories of Molecular Anthropology and Microbiome Research, University of Oklahoma, Norman, Oklahoma, United States of America
7Department of Microbiology and Plant Biology, University of Oklahoma, Norman, Oklahoma, United States of America
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  • For correspondence: lmccall@ou.edu
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Abstract

Chagas disease (CD) is one of thirteen neglected tropical diseases caused by the parasite Trypanosoma cruzi. CD is a vector-borne disease transmitted by triatomines but CD can also be transmitted through blood transfusions, organ transplants and congenital transmission. While endemic to Latin America, 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 disease pathogenesis are not fully understood. Using spatial metabolomics (chemical cartography), we sought to understand the localized impact of infection on the cardiac metabolome of mice chronically 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 select sites in chronic CD. These sites were distinct from the sites of highest parasite burden. In addition, we identified acylcarnitines and phosphocholines as discriminatory chemical families within each heart region, comparing infected and uninfected samples. Overall, our study indicated overall 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 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 South America; however, there are now 7-8 million people infected worldwide due to population movements. CD is transmitted through a triatomine vector, organ transplants, blood transfusions and congenital transmission. It occurs in two stages, an acute stage (usually asymptomatic) and the chronic stage. Chronic stage CD presents with 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. We also 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 why localized cardiac symptoms occur in CD. Overall, our work gives insight to chronic cardiac CD symptom development and shapes a framework for novel treatment and biomarker development.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=f16bc44c3d5040d098c978823f50c68f

  • https://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=5f8af6d62d8549358966f3896a81063a

  • ftp://massive.ucsd.edu/MSV000080450/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Spatial metabolomics identifies localized chemical changes in heart tissue during chronic cardiac Chagas disease
Danya A. Dean, Gautham, Jair L. Siqueira-Neto, James H. McKerrow, Pieter C. Dorrestein, Laura-Isobel McCall
bioRxiv 2020.06.29.178038; doi: https://doi.org/10.1101/2020.06.29.178038
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Spatial metabolomics identifies localized chemical changes in heart tissue during chronic cardiac Chagas disease
Danya A. Dean, Gautham, Jair L. Siqueira-Neto, James H. McKerrow, Pieter C. Dorrestein, Laura-Isobel McCall
bioRxiv 2020.06.29.178038; doi: https://doi.org/10.1101/2020.06.29.178038

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