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Transcriptome analysis of mouse hearts infected with Trypanosoma cruzi: Differential modulation of gene expression by two strains

ABSTRACT: Purpose: One important challenge in the field of Chagas disease research is to determine the main factors leading to the establishment of the parasite in some organs in the chronic stage, mainly the heart and/or digestive system. Our group previously showed that distinct strains of T. cruzi (JG and Col1.7G2) presented differential tissue distribution in the chronic stage in double-infected BALB/c mice. To investigate changes in the host triggered by the two distinct T. cruzi strains, we assessed the gene expression profile of BALB/c mouse hearts infected with either JG, Col1.7G2 or an equivalent mixture of both parasites during the initial phase of infection. Results: We demonstrate a clear distinction in host gene expression modulation by both parasites. Col1.7G2 strongly activated Th1-polarized immune response genes, whereas JG showed minor immune response activation. Moreover, JG strongly impaired the expression of genes for ribosomal proteins and mitochondrial proteins related to the electron transport chain and the citric acid cycle. Interestingly, evaluation of gene expression in mice inoculated with the mixture of parasites showed expression profiles for both up- and downregulated genes, indicating the coexistence of both parasite strains in the heart during the acute phase. Conclusions: We suggest that different strains of T. cruzi may be distinguished by their efficiency in activating the immune system, modulating host energy and reactive oxygen species production and impairing protein synthesis during early infection, which may be decisive in defining parasite persistence in specific organs.

ORGANISM(S): Mus musculus

PROVIDER: GSE132132 | GEO | 2020/08/19

REPOSITORIES: GEO

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Project description:To investigate the early host response triggered by three different strains of Trypanosoma cruzi at a local infection site, changes in host gene expression were monitored in a murine intradermal infection model using Affymetrix oligonucleotide arrays. Robust induction of IFN-stimulated genes (ISGs) was observed in excised skin 24 hours post-infection where the level of ISG induction was parasite strain-dependent with the least virulent strain triggering a muted IFN response. Infection of mice immunodepleted of IFNÎ³-producing cells or infection of IFNÎ³-deficient mice had minimal impact on the IFN response generated in T. cruzi infected mice. In contrast, infection of mice lacking the type I IFN receptor demonstrated that type I IFNs are largely responsible for the IFN response generated at the site of infection. These data highlight type I IFNs as important components of the innate immune response to T. cruzi the site of inoculation and their role in shaping the early transcriptional response to this pathogen. We used microarrays to detail the local host transcriptional response to intradermal T. cruzi infection in WT mice and mice depleted of NK cells, or deficient in IFN-gamma or type I IFN responses. Additionally we compared the local host-transcriptional response generated to infection with 3 different strains of Trypanosoma cruzi (Y, Brazil, and G). Experiment Overall Design: Mice were infected by intradermal injection of 10^6 T. cruzi trypomastigotes in 100uL of saline split between 2 adjacent sites on the shaved side flank. Control mice were injected with an equal volume of saline. 24 hours post-injection approximately 75mm^2 of skin immediately surrounding the injection site was excised and RNA was isolated from the tissue. Balb/c mice were used for most experiments and IFN-gamma KO mice were on the Balb/c background. WT 129 mice were also used as IFNAR-/- mice were on the 129 background. In total 33 arrays were performed. 7 WT (Balb/c) control, 3 Y strain infected, 3 Brazil strain infected, 3 G strain infected, 2 IFN-gamma KO control, 2 IFN-gamma KO infected, 1 NK cell depleted control, 1 NK cell depleted infected, 3 WT (129) control, 3 WT (129) infected, 3 IFNAR KO control, 3 IFNAR KO infected

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Transcriptome analysis of mouse hearts infected with Trypanosoma cruzi: Differential modulation of gene expression by two strains

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