Differential modulation of mouse heart gene expression by infection with twoTrypanosoma cruzistrains: a transcriptome analysis

Abstract

The protozoan Trypanosoma cruzi (T. cruzi) is a well-adapted parasite to mammalian hosts and 11 the pathogen of Chagas disease in humans. As both host and T. cruzi are highly genetically diverse, 12 many variables come into play during infection, making disease outcomes difficult to predict. One 13 important challenge in the field of Chagas disease research is determining the main factors leading 14 to parasite establishment in the chronic stage in some organs, mainly the heart and/or digestive 15 system. Our group previously showed that distinct strains of T. cruzi (JG and Col1.7G2) acquired 16 differential tissue distribution in the chronic stage in dually-infected BALB/c mice. To investigate 17 changes in the host triggered by the two distinct T. cruzi strains, we assessed the gene expression 18 profile of BALB/c mouse hearts infected with either JG, Col1.7G2 or an equivalent mixture of 19 both parasites during the initial phase of infection. This study demonstrates a clear distinction in 20 host gene expression modulation by both parasites. Col1.7G2 strongly activated Th1-polarized 21 immune signature genes, whereas JG showed only minor activation of the host immune response. 22 Moreover, JG strongly reduced the expression of genes for ribosomal proteins and mitochondrial 23 proteins related to the electron transport chain. Interestingly, evaluation of gene expression in mice 24 inoculated with the mixture of parasites showed expression profiles for both up-and down-25 regulated genes, indicating the coexistence of both parasite strains in the heart during the acute 26 phase. This study suggests that different strains of T. cruzi may be distinguished by their efficiency 27 in activating the immune system, modulating host energy and reactive oxygen species production 28 and decreasing protein synthesis during early infection, which may be crucial in defining parasite 29 persistence in specific organs. 31 Author Summary 32The causative agent of Chagas disease, Trypanosoma cruzi, retains high genetic diversity, and its 33 populations vary greatly across geographic locations. The T. cruzi mammalian hosts, including 34 humans, also have high genetic variation, making it difficult to predict the disease outcome. 35Accordingly, this variability must be taken into account in several studies aiming to interrogate 36 the effect of polyparasitism in drug trials, vaccines, diagnosis or basic research. Therefore, there 37 is a growing need to consider the interaction between the pathogen and the host immune system 38 in mixed infections. In the present work, we present an in-depth analysis of the gene expression of 39 hearts from BALB/c mice infected with Col1.7G2 and JG alone or a mixture of both strains. 40Col1.7G2 induced a higher Th1 inflammatory response, while JG exhibited a weaker activation of 41 immune response genes. Furthermore, JG-infected mice showed a notable reduction in the 42 expression of genes responsible for mitochondrial oxidative phosphorylation and protein 43 synthesis. Interestingly, the mixture...

Differential Modulation of Mouse Heart Gene Expression by Infection With Two Trypanosoma cruzi Strains: A Transcriptome Analysis

“…We would like to acknowledge the valuable contributions of Neuza Antunes Rodrigues and Afonso da Costa Viana, who assisted us with the mouse procedures and parasite handling, and Fabricio Rodrigues dos Santos for providing access to the 7900HT Fast Real-Time PCR System for the qPCR analyses. This manuscript has been released as a pre-print at biorxiv ( Castro et al, 2019 ).…”

Cardiomyocyte transcriptomic signatures in response toTrypanosoma cruziinfection underpin Chagas cardiomyopathy progression

“…Thus, the host response against specific T. cruzi genotypes shall provide yet-tobe-clarified clues to the molecular pathophysiology of CCM progression. (25)(26)(27) The objective of the current study was to elucidate the differential transcriptomic signatures of the cardiomyocyte response against infection with variable T. cruzi strains, the CCMprone TcI/II, or the less typical TcVI and explore the biological processes underpinning CCM progression.…”