Rapidly progressive course of Trypanosoma cruzi infection in mice heterozygous for hexamethylene bis-acetamide inducible 1 (Hexim1) gene

Eduardo Mascareno, Raavi Gupta, Laura A. Martello, Manya Dhar-Mascareno, Louis Salciccioli, Daniel Beckles, Michael G. Walsh, Fabiana S. Machado, Herbert B. Tanowitz, M. A. Haseeb

Research output: Contribution to journalArticle

Abstract

Infection with Trypanosoma cruzi causes Chagas disease and results in myocardial inflammation and cardiomyopathy. Downregulated Hexim1 expression, as in Hexim1+/− mice, reduces cardiac inflammation and fibrosis following ischemic stress. We asked whether reduced expression of Hexim1 would also afford protection against T. cruzi-induced cardiomyopathy. C57BL/6J (wild type – WT) and Hexim1+/− mice were infected with sub-lethal doses of T. cruzi (Brazil strain), and cardiac function, serologic markers of inflammation and tissue pathology were examined. Infected Hexim1+/− mice had compromised cardiac function, altered expression of both pro- and anti-inflammatory cytokines, and increased inflammation and fibrosis. Cardiac failure was evidenced by severely diminished heart rate, compensatory increase in respiratory rate, and abnormally high left ventricular mass with severe transmural inflammation. Lungs displayed intense peribronchial inflammation and fibrosis extending into the parenchyma. We also observed Smad3-serine208 phosphorylation in hearts and lungs of infected mice, suggesting increased TGF-β signaling pathway activity. This was more pronounced in Hexim1+/− mice and correlated with increased fibrosis in these tissues. Conspicuous splenomegaly in the Hexim1+/− mice most likely resulted from the observed extensive white pulp expansion. T. cruzi infection induced colonic dilatation and marked villous atrophy in both the WT and Hexim1+/− mice but more so in the latter. The profound exacerbation of pathologic findings suggests a protective role for Hexim1 in T. cruzi infection.

Original languageEnglish (US)
Pages (from-to)25-36
Number of pages12
JournalMicrobes and Infection
Volume20
Issue number1
DOIs
StatePublished - Jan 2018

Keywords

  • Cardiomyopathy
  • Chagas disease
  • Hexim1
  • Inflammation
  • Smad3-serine phosphorylation
  • Trypanosoma cruzi

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Infectious Diseases

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  • Cite this

    Mascareno, E., Gupta, R., Martello, L. A., Dhar-Mascareno, M., Salciccioli, L., Beckles, D., Walsh, M. G., Machado, F. S., Tanowitz, H. B., & Haseeb, M. A. (2018). Rapidly progressive course of Trypanosoma cruzi infection in mice heterozygous for hexamethylene bis-acetamide inducible 1 (Hexim1) gene. Microbes and Infection, 20(1), 25-36. https://doi.org/10.1016/j.micinf.2017.09.001