Limits...
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.

Show MeSH

Related in: MedlinePlus

Direction of the cross between A/J and C57BL/6 mice determines gender differences in the susceptibility to infection of the F1 offspring.Age-matched A/J, C57BL/6, F1(AXB) (offspring of A/J females and C57BL/6 males) and F1(BXA) (offspring of C57BL/6 females and A/J males) mice were infected i.p. with 1000 trypomastigotes of the Y strain of T. cruzi. Mortality of female (A) and male (B) mice was evaluated by daily inspection of the cages. Mouse numbers were as follows: A/J male (n = 10), A/J female (n = 10), C57BL/6 male (n = 11), C57BL/6 female (n = 08), F1(AXB) male (n = 08), F1(AXB) female (n = 11), F1(BXA) male (n = 7) and F1(BXA) female (n = 8). (C) Parasitemia of male mice was quantified by microscopically counting the parasites in 5 μl of citrated blood obtained from the tail lateral vein on days 7, 9, 11 and 13 post-infection. Data shown is one representative experiment of those found in three independent experiments. (*), (#), and (&) indicate P<0.05 in relation to C57BL/6, A/J and F1(BXA) respectively. (D) Parasitemia of F1(AXB) (open triangle) and F1 (BXA) (closed triangle) male mice on days 7, 9, 11, 13 post-infection. The data shown is a pool of 8 independent experiments; each plotted symbol represents the parasitemia of a single mouse. (*) indicates P<0.05.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3569416&req=5

pone-0056347-g005: Direction of the cross between A/J and C57BL/6 mice determines gender differences in the susceptibility to infection of the F1 offspring.Age-matched A/J, C57BL/6, F1(AXB) (offspring of A/J females and C57BL/6 males) and F1(BXA) (offspring of C57BL/6 females and A/J males) mice were infected i.p. with 1000 trypomastigotes of the Y strain of T. cruzi. Mortality of female (A) and male (B) mice was evaluated by daily inspection of the cages. Mouse numbers were as follows: A/J male (n = 10), A/J female (n = 10), C57BL/6 male (n = 11), C57BL/6 female (n = 08), F1(AXB) male (n = 08), F1(AXB) female (n = 11), F1(BXA) male (n = 7) and F1(BXA) female (n = 8). (C) Parasitemia of male mice was quantified by microscopically counting the parasites in 5 μl of citrated blood obtained from the tail lateral vein on days 7, 9, 11 and 13 post-infection. Data shown is one representative experiment of those found in three independent experiments. (*), (#), and (&) indicate P<0.05 in relation to C57BL/6, A/J and F1(BXA) respectively. (D) Parasitemia of F1(AXB) (open triangle) and F1 (BXA) (closed triangle) male mice on days 7, 9, 11, 13 post-infection. The data shown is a pool of 8 independent experiments; each plotted symbol represents the parasitemia of a single mouse. (*) indicates P<0.05.

Mentions: The data presented so far show that F1(AXB) males differ from F1(AXB) females in resistance to infection with T. cruzi, although the difference in resistance between the infected males and females within both parental strains was small and statistically insignificant (Fig. 4). These data suggest that sex-related physiological differences (such as hormonal influences) could not explain the difference in susceptibility of the sexes in the F1 generation. To further evaluate the sex-related differences in resistance seen in the F1(AXB) mice, we generated additional F1 progeny by breeding female C57BL/6 mice with male A/J mice (F1(BXA)). As show in Table 1, the direction of the cross between the parental A/J and C57BL/6 mice changed the composition of the sex chromosomes in the F1 generation only in the males (Table 1). This feature supports a role of the sex chromosomes in host resistance. We thus performed an experiment in which we simultaneously infected F1(AXB) and F1(BXA) females and males together with controls of the parental C57BL/6 and A/J strains and measured survival and parasite loads in the blood of the infected animals. We observed that F1 females from both types of cross (F1(AXB) and F1(BXA)) were as resistant to infection as the C57BL/6 parental females, supporting the conclusion that resistance to infection is a dominant trait (Fig. 5A). By contrast, the F1(BXA) males were as resistant as the C57BL/6 mice, whereas the F1(AXB) males showed a mortality rate intermediate between the two parental strains (Fig. 5B). The parasitemia of male siblings from both crossings was also compared 7, 9, 11 and 13 days after infection. Our results indicate that at days 7 and 11 after infection, the parasitemia of the F1(AXB) males was significantly higher as compared to parasitemia of F1(BXA) (Fig. 5C). To further evaluate the increased parasitemia in males of the F1(AXB) as compared to F1(BXA) we analyzed the parasitemia of infected F1 mice obtained in eight experiments performed independently. By pooling together data from different experiments, we found statistically significant differences in the parasitemia of F1(AXB) as compared to F1(BXA) only at day 11 post infection (Fig. 5D). Importantly, at day 11, we detected the higher differences in parasitemia of A/J as compared to C57BL/6 strain (Fig. 1B). Nonetheless, the results shown in Fig. 5D illustrate that parasite levels in the blood of mice infected with the Y strain of T. cruzi is highly variable, thus suggesting that parasitemia is not the best parameter to evaluate host resistance to Y strain of T. cruzi.


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)

Direction of the cross between A/J and C57BL/6 mice determines gender differences in the susceptibility to infection of the F1 offspring.Age-matched A/J, C57BL/6, F1(AXB) (offspring of A/J females and C57BL/6 males) and F1(BXA) (offspring of C57BL/6 females and A/J males) mice were infected i.p. with 1000 trypomastigotes of the Y strain of T. cruzi. Mortality of female (A) and male (B) mice was evaluated by daily inspection of the cages. Mouse numbers were as follows: A/J male (n = 10), A/J female (n = 10), C57BL/6 male (n = 11), C57BL/6 female (n = 08), F1(AXB) male (n = 08), F1(AXB) female (n = 11), F1(BXA) male (n = 7) and F1(BXA) female (n = 8). (C) Parasitemia of male mice was quantified by microscopically counting the parasites in 5 μl of citrated blood obtained from the tail lateral vein on days 7, 9, 11 and 13 post-infection. Data shown is one representative experiment of those found in three independent experiments. (*), (#), and (&) indicate P<0.05 in relation to C57BL/6, A/J and F1(BXA) respectively. (D) Parasitemia of F1(AXB) (open triangle) and F1 (BXA) (closed triangle) male mice on days 7, 9, 11, 13 post-infection. The data shown is a pool of 8 independent experiments; each plotted symbol represents the parasitemia of a single mouse. (*) indicates P<0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3569416&req=5

pone-0056347-g005: Direction of the cross between A/J and C57BL/6 mice determines gender differences in the susceptibility to infection of the F1 offspring.Age-matched A/J, C57BL/6, F1(AXB) (offspring of A/J females and C57BL/6 males) and F1(BXA) (offspring of C57BL/6 females and A/J males) mice were infected i.p. with 1000 trypomastigotes of the Y strain of T. cruzi. Mortality of female (A) and male (B) mice was evaluated by daily inspection of the cages. Mouse numbers were as follows: A/J male (n = 10), A/J female (n = 10), C57BL/6 male (n = 11), C57BL/6 female (n = 08), F1(AXB) male (n = 08), F1(AXB) female (n = 11), F1(BXA) male (n = 7) and F1(BXA) female (n = 8). (C) Parasitemia of male mice was quantified by microscopically counting the parasites in 5 μl of citrated blood obtained from the tail lateral vein on days 7, 9, 11 and 13 post-infection. Data shown is one representative experiment of those found in three independent experiments. (*), (#), and (&) indicate P<0.05 in relation to C57BL/6, A/J and F1(BXA) respectively. (D) Parasitemia of F1(AXB) (open triangle) and F1 (BXA) (closed triangle) male mice on days 7, 9, 11, 13 post-infection. The data shown is a pool of 8 independent experiments; each plotted symbol represents the parasitemia of a single mouse. (*) indicates P<0.05.
Mentions: The data presented so far show that F1(AXB) males differ from F1(AXB) females in resistance to infection with T. cruzi, although the difference in resistance between the infected males and females within both parental strains was small and statistically insignificant (Fig. 4). These data suggest that sex-related physiological differences (such as hormonal influences) could not explain the difference in susceptibility of the sexes in the F1 generation. To further evaluate the sex-related differences in resistance seen in the F1(AXB) mice, we generated additional F1 progeny by breeding female C57BL/6 mice with male A/J mice (F1(BXA)). As show in Table 1, the direction of the cross between the parental A/J and C57BL/6 mice changed the composition of the sex chromosomes in the F1 generation only in the males (Table 1). This feature supports a role of the sex chromosomes in host resistance. We thus performed an experiment in which we simultaneously infected F1(AXB) and F1(BXA) females and males together with controls of the parental C57BL/6 and A/J strains and measured survival and parasite loads in the blood of the infected animals. We observed that F1 females from both types of cross (F1(AXB) and F1(BXA)) were as resistant to infection as the C57BL/6 parental females, supporting the conclusion that resistance to infection is a dominant trait (Fig. 5A). By contrast, the F1(BXA) males were as resistant as the C57BL/6 mice, whereas the F1(AXB) males showed a mortality rate intermediate between the two parental strains (Fig. 5B). The parasitemia of male siblings from both crossings was also compared 7, 9, 11 and 13 days after infection. Our results indicate that at days 7 and 11 after infection, the parasitemia of the F1(AXB) males was significantly higher as compared to parasitemia of F1(BXA) (Fig. 5C). To further evaluate the increased parasitemia in males of the F1(AXB) as compared to F1(BXA) we analyzed the parasitemia of infected F1 mice obtained in eight experiments performed independently. By pooling together data from different experiments, we found statistically significant differences in the parasitemia of F1(AXB) as compared to F1(BXA) only at day 11 post infection (Fig. 5D). Importantly, at day 11, we detected the higher differences in parasitemia of A/J as compared to C57BL/6 strain (Fig. 1B). Nonetheless, the results shown in Fig. 5D illustrate that parasite levels in the blood of mice infected with the Y strain of T. cruzi is highly variable, thus suggesting that parasitemia is not the best parameter to evaluate host resistance to Y strain of T. cruzi.

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