A Parent-of-Origin Effect Determines the Susceptibility of a Non-Informative F1 Population to Trypanosoma cruzi Infection In Vivo

Abstract

The development of Chagas disease is determined by a complex interaction between the genetic traits of both the protozoan parasite, T. cruzi, and the infected host. This process is regulated by multiple genes that control different aspects of the host-parasite interaction. While determination of the relevant genes in humans is extremely difficult, it is feasible to use inbred mouse strains to determine the genes and loci responsible for host resistance to infection. In this study, we investigated the susceptibility of several inbred mouse strains to infection with the highly virulent Y strain of T. cruzi and found a considerable difference in susceptibility between A/J and C57BL/6 mice. We explored the differences between these two mouse strains and found that the A/J strain presented higher mortality, exacerbated and uncontrolled parasitemia and distinct histopathology in the target organs, which were associated with a higher parasite burden and more extensive tissue lesions. We then employed a genetic approach to assess the pattern of inheritance of the resistance phenotype in an F1 population and detected a strong parent-of-origin effect determining the susceptibility of the F1 male mice. This effect is unlikely to result from imprinted genes because the inheritance of this susceptibility was affected by the direction of the parental crossing. Collectively, our genetic approach of using the F1 population suggests that genes contained in the murine chromosome X contribute to the natural resistance against T. cruzi infection. Future linkage studies may reveal the locus and genes participating on the host resistance process reported herein.

The genetic basis for individual differences in mRNA splicing and APOBEC1 editing activity in murine macrophages

“…The widely used laboratory inbred A/J (AJ) and C57BL/6J (B6) mice display variable susceptibility to a variety of infectious agentssuch as Staphylococcus aureus, T. gondii, and Trypanosoma cruzi (McLeod et al 1989;Parekh et al 1998;Ahn et al 2010;Silva et al 2013)-and inflammatory pathologies such as atherosclerosis, obesity, and type 2 diabetes (Paigen et al 1985;Surwit et al 1988;Surwit et al 1995). These phenotypic differences often replicate in the AXB/BXA RI mice, derived from an initial reciprocal cross of AJ and B6 mice followed by multiple rounds ($20) of inbreeding (Nesbitt and Skamene 1984;Marshall et al 1992).…”

Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection

“…These mice also exhibit differences in the amount of IL-10 and tumor necrosis factor (TNF) produced in response to bacterial infection [ 43 , 44 ]. Furthermore, the parental AJ and C57BL/6J vary in susceptibility to a variety of pathogens, including Staphylococcus aureus , Toxoplasma gondii and Trypanosoma cruzi [ 38 , 44 – 47 ]. By linking QTL analyses of defined macrophage phenotypes and macrophage transcriptional profiles, captured by high-throughput RNA-sequencing, we have identified many loci that affect the macrophage response to inflammatory stimuli and infection.…”

Relevance of Trypanothione Reductase Inhibitors on Trypanosoma cruzi Infection: A Systematic Review, Meta‐Analysis, and In Silico Integrated Approach

“…Thus, highly pathogenic and virulent parasite strains are realistically applicable only in acute models as the animals often die before developing a chronic infection [ 60 ]. Conversely, as parasitological cure and Chagas cardiomyopathy attenuation or reversion are the primary focus of anti- T. cruzi chemotherapy, models using pathogenic strains with low virulence are a more rational strategy [ 60 , 61 ]. Based on these latter models, the chances of instilling morphological, electrical, and mechanical changes typical of Chagas' cardiomyopathy are enhanced [ 61 – 63 ].…”

“…Conversely, as parasitological cure and Chagas cardiomyopathy attenuation or reversion are the primary focus of anti- T. cruzi chemotherapy, models using pathogenic strains with low virulence are a more rational strategy [ 60 , 61 ]. Based on these latter models, the chances of instilling morphological, electrical, and mechanical changes typical of Chagas' cardiomyopathy are enhanced [ 61 – 63 ]. Because the parasite strains used were aligned with the phases of interest in Chagas disease, the analyzed studies exhibited an important element of methodological consistence, with a positive reflection on construct validity.…”