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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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Gender influences susceptibility to infection in F1 offspring of A/J females crossed with C57BL/6 males.Age-matched males and females of parental A/J and C57BL/6 mouse strains together with heterozygous F1 offspring (F1(AXB)) of A/J females crossed with C57BL/6 males were infected i.p. with 1000 trypomastigotes of the Y strain of T. cruzi. Mouse numbers were as follows: A/J male (n = 11), A/J female (n = 8), C57BL/6 male (n = 11) C57BL/6 female (n = 8), F1(AXB) male (n = 9), F1(AXB) female (n = 11). Mortality was evaluated by daily inspection of the cages. Data are representative of those found in seven independent experiments. (*) indicates P<0.05 in comparisons between F1(AXB) males and the other experimental groups.
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pone-0056347-g004: Gender influences susceptibility to infection in F1 offspring of A/J females crossed with C57BL/6 males.Age-matched males and females of parental A/J and C57BL/6 mouse strains together with heterozygous F1 offspring (F1(AXB)) of A/J females crossed with C57BL/6 males were infected i.p. with 1000 trypomastigotes of the Y strain of T. cruzi. Mouse numbers were as follows: A/J male (n = 11), A/J female (n = 8), C57BL/6 male (n = 11) C57BL/6 female (n = 8), F1(AXB) male (n = 9), F1(AXB) female (n = 11). Mortality was evaluated by daily inspection of the cages. Data are representative of those found in seven independent experiments. (*) indicates P<0.05 in comparisons between F1(AXB) males and the other experimental groups.

Mentions: A genetic approach to the identification of traits that contribute to a specific resistant phenotype demands a thorough understanding of the pattern of inheritance for the phenotype. To investigate the genetic source of resistance variation to T. cruzi infection by the C57BL/6 and A/J mice, we established a heterozygous F1 population (F1(AXB)) by breeding A/J females with C57BL/6 males. Females and males of the F1(AXB) population were infected together with controls of the C57BL/6 and A/J parental strains. The mortality was evaluated over a period of 50 days. As expected, the A/J male and female mice were highly susceptible and succumbed at day 18–20 after infection, whereas both sexes of the parental C57BL/6 strain were resistant (Fig. 4). Males of the F1(AXB) generation showed mortality intermediate between the parental strains; however, F1(AXB) females were resistant, suggesting dominance of the C57BL/6 resistance trait.


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)

Gender influences susceptibility to infection in F1 offspring of A/J females crossed with C57BL/6 males.Age-matched males and females of parental A/J and C57BL/6 mouse strains together with heterozygous F1 offspring (F1(AXB)) of A/J females crossed with C57BL/6 males were infected i.p. with 1000 trypomastigotes of the Y strain of T. cruzi. Mouse numbers were as follows: A/J male (n = 11), A/J female (n = 8), C57BL/6 male (n = 11) C57BL/6 female (n = 8), F1(AXB) male (n = 9), F1(AXB) female (n = 11). Mortality was evaluated by daily inspection of the cages. Data are representative of those found in seven independent experiments. (*) indicates P<0.05 in comparisons between F1(AXB) males and the other experimental groups.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3569416&req=5

pone-0056347-g004: Gender influences susceptibility to infection in F1 offspring of A/J females crossed with C57BL/6 males.Age-matched males and females of parental A/J and C57BL/6 mouse strains together with heterozygous F1 offspring (F1(AXB)) of A/J females crossed with C57BL/6 males were infected i.p. with 1000 trypomastigotes of the Y strain of T. cruzi. Mouse numbers were as follows: A/J male (n = 11), A/J female (n = 8), C57BL/6 male (n = 11) C57BL/6 female (n = 8), F1(AXB) male (n = 9), F1(AXB) female (n = 11). Mortality was evaluated by daily inspection of the cages. Data are representative of those found in seven independent experiments. (*) indicates P<0.05 in comparisons between F1(AXB) males and the other experimental groups.
Mentions: A genetic approach to the identification of traits that contribute to a specific resistant phenotype demands a thorough understanding of the pattern of inheritance for the phenotype. To investigate the genetic source of resistance variation to T. cruzi infection by the C57BL/6 and A/J mice, we established a heterozygous F1 population (F1(AXB)) by breeding A/J females with C57BL/6 males. Females and males of the F1(AXB) population were infected together with controls of the C57BL/6 and A/J parental strains. The mortality was evaluated over a period of 50 days. As expected, the A/J male and female mice were highly susceptible and succumbed at day 18–20 after infection, whereas both sexes of the parental C57BL/6 strain were resistant (Fig. 4). Males of the F1(AXB) generation showed mortality intermediate between the parental strains; however, F1(AXB) females were resistant, suggesting dominance of the C57BL/6 resistance trait.

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