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A parent-of-origin effect determines the susceptibility of a non-informative F1 population to Trypanosoma cruzi infection in vivo.

Silva GK, Cunha LD, Horta CV, Silva AL, Gutierrez FR, Silva JS, Zamboni DS - PLoS ONE (2013)

Bottom Line: 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 effect is unlikely to result from imprinted genes because the inheritance of this susceptibility was affected by the direction of the parental crossing.Future linkage studies may reveal the locus and genes participating on the host resistance process reported herein.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, University of São Paulo, Medical School Ribeirão Preto, FMRP/USP, Ribeirão Preto, São Paulo, Brazil.

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.

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Inbred mouse strains vary in their susceptibility to infection by the Y strain of T. cruzi.Male mice were infected i.p. with 1000 trypomastigotes when eight weeks old and included A/J (n = 8), BALB/c (n = 10), C3H/HePas (n = 8), C57BL/6 (n = 7) and DBA (n = 8) strains. (A) Mortality was evaluated by daily inspection of the cages and differed (P<0.05) between BALB/c and C57BL/6, BALB/c and DBA, BALB/c and A/J, BALB/c and C3H/HePas, C57BL/6 and A/J, C57BL/6 and C3H/HePas, DBA and A/J, and DBA and C3H/HePas. Data are representative of those found in three independent experiments. (B) Parasitemia was quantified microscopically by counting the parasites in 5 μl of citrated blood obtained from the tail lateral vein at days 7, 9, 11 and 13 days postinfection. At day 11, (*) indicates P<0.05 between A/J and all other groups. At day 13, (*) indicates P<0.05 between A/J and BALB/c, A/J and C57BL/6, and A/J and DBA; (#) indicates P<0.05 between C3H/HePas and BALB/c, C3H/HePas and C57BL/6, and C3H/HePas and DBA; and (&) indicates P<0.05 between DBA and C57BL/6. Data are representative of those found in three independent experiments.
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pone-0056347-g001: Inbred mouse strains vary in their susceptibility to infection by the Y strain of T. cruzi.Male mice were infected i.p. with 1000 trypomastigotes when eight weeks old and included A/J (n = 8), BALB/c (n = 10), C3H/HePas (n = 8), C57BL/6 (n = 7) and DBA (n = 8) strains. (A) Mortality was evaluated by daily inspection of the cages and differed (P<0.05) between BALB/c and C57BL/6, BALB/c and DBA, BALB/c and A/J, BALB/c and C3H/HePas, C57BL/6 and A/J, C57BL/6 and C3H/HePas, DBA and A/J, and DBA and C3H/HePas. Data are representative of those found in three independent experiments. (B) Parasitemia was quantified microscopically by counting the parasites in 5 μl of citrated blood obtained from the tail lateral vein at days 7, 9, 11 and 13 days postinfection. At day 11, (*) indicates P<0.05 between A/J and all other groups. At day 13, (*) indicates P<0.05 between A/J and BALB/c, A/J and C57BL/6, and A/J and DBA; (#) indicates P<0.05 between C3H/HePas and BALB/c, C3H/HePas and C57BL/6, and C3H/HePas and DBA; and (&) indicates P<0.05 between DBA and C57BL/6. Data are representative of those found in three independent experiments.

Mentions: Although inbred mouse strains that differ in their susceptibility to a specific pathogen are an extremely useful tool for the identification of the relevant genes, little has been learned regarding the resistance to Chagas disease using this approach. Therefore, we initially infected distinct inbred mouse strains with the Y strain of T. cruzi to detect any differences in their susceptibility to the pathogen, as measured by blood parasitemia and mouse mortality. The results, presented in Figure 1, highlight the considerable variation in the susceptibility to acute infection among the A/J, BALB/c, C3H/HePas, C57BL/6 and DBA strains of mice. The C57BL/6 and DBA mice presented the highest survival rates, whereas the A/J and C3H/HePas mice presented higher mortality (Fig. 1A). The analysis of parasitemia on days 7, 9, 11, and 13 postinfection revealed that the A/J animals had a high peak count of parasites in the blood and maintained a higher number of circulating parasites in the blood, as illustrated by the high parasitemia of A/J mice at day 11 postinfection (Fig. 1B). The blood of the C57BL/6 mice had a low peak count of parasites and, after 13 days of infection, very few circulating parasites remained. Altogether, our data indicate that the A/J and C57BL/6 strains were the most different regarding host resistance. These features have been previously described for T. cruzi strains and, together with our data, emphasize the relevance of studying these two mouse strains to assess the host genetic factors contributing to the control of infection [27], [28], [29], [30].


A parent-of-origin effect determines the susceptibility of a non-informative F1 population to Trypanosoma cruzi infection in vivo.

Silva GK, Cunha LD, Horta CV, Silva AL, Gutierrez FR, Silva JS, Zamboni DS - PLoS ONE (2013)

Inbred mouse strains vary in their susceptibility to infection by the Y strain of T. cruzi.Male mice were infected i.p. with 1000 trypomastigotes when eight weeks old and included A/J (n = 8), BALB/c (n = 10), C3H/HePas (n = 8), C57BL/6 (n = 7) and DBA (n = 8) strains. (A) Mortality was evaluated by daily inspection of the cages and differed (P<0.05) between BALB/c and C57BL/6, BALB/c and DBA, BALB/c and A/J, BALB/c and C3H/HePas, C57BL/6 and A/J, C57BL/6 and C3H/HePas, DBA and A/J, and DBA and C3H/HePas. Data are representative of those found in three independent experiments. (B) Parasitemia was quantified microscopically by counting the parasites in 5 μl of citrated blood obtained from the tail lateral vein at days 7, 9, 11 and 13 days postinfection. At day 11, (*) indicates P<0.05 between A/J and all other groups. At day 13, (*) indicates P<0.05 between A/J and BALB/c, A/J and C57BL/6, and A/J and DBA; (#) indicates P<0.05 between C3H/HePas and BALB/c, C3H/HePas and C57BL/6, and C3H/HePas and DBA; and (&) indicates P<0.05 between DBA and C57BL/6. Data are representative of those found in three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3569416&req=5

pone-0056347-g001: Inbred mouse strains vary in their susceptibility to infection by the Y strain of T. cruzi.Male mice were infected i.p. with 1000 trypomastigotes when eight weeks old and included A/J (n = 8), BALB/c (n = 10), C3H/HePas (n = 8), C57BL/6 (n = 7) and DBA (n = 8) strains. (A) Mortality was evaluated by daily inspection of the cages and differed (P<0.05) between BALB/c and C57BL/6, BALB/c and DBA, BALB/c and A/J, BALB/c and C3H/HePas, C57BL/6 and A/J, C57BL/6 and C3H/HePas, DBA and A/J, and DBA and C3H/HePas. Data are representative of those found in three independent experiments. (B) Parasitemia was quantified microscopically by counting the parasites in 5 μl of citrated blood obtained from the tail lateral vein at days 7, 9, 11 and 13 days postinfection. At day 11, (*) indicates P<0.05 between A/J and all other groups. At day 13, (*) indicates P<0.05 between A/J and BALB/c, A/J and C57BL/6, and A/J and DBA; (#) indicates P<0.05 between C3H/HePas and BALB/c, C3H/HePas and C57BL/6, and C3H/HePas and DBA; and (&) indicates P<0.05 between DBA and C57BL/6. Data are representative of those found in three independent experiments.
Mentions: Although inbred mouse strains that differ in their susceptibility to a specific pathogen are an extremely useful tool for the identification of the relevant genes, little has been learned regarding the resistance to Chagas disease using this approach. Therefore, we initially infected distinct inbred mouse strains with the Y strain of T. cruzi to detect any differences in their susceptibility to the pathogen, as measured by blood parasitemia and mouse mortality. The results, presented in Figure 1, highlight the considerable variation in the susceptibility to acute infection among the A/J, BALB/c, C3H/HePas, C57BL/6 and DBA strains of mice. The C57BL/6 and DBA mice presented the highest survival rates, whereas the A/J and C3H/HePas mice presented higher mortality (Fig. 1A). The analysis of parasitemia on days 7, 9, 11, and 13 postinfection revealed that the A/J animals had a high peak count of parasites in the blood and maintained a higher number of circulating parasites in the blood, as illustrated by the high parasitemia of A/J mice at day 11 postinfection (Fig. 1B). The blood of the C57BL/6 mice had a low peak count of parasites and, after 13 days of infection, very few circulating parasites remained. Altogether, our data indicate that the A/J and C57BL/6 strains were the most different regarding host resistance. These features have been previously described for T. cruzi strains and, together with our data, emphasize the relevance of studying these two mouse strains to assess the host genetic factors contributing to the control of infection [27], [28], [29], [30].

Bottom Line: 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 effect is unlikely to result from imprinted genes because the inheritance of this susceptibility was affected by the direction of the parental crossing.Future linkage studies may reveal the locus and genes participating on the host resistance process reported herein.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, University of São Paulo, Medical School Ribeirão Preto, FMRP/USP, Ribeirão Preto, São Paulo, Brazil.

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.

Show MeSH
Related in: MedlinePlus