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Trypanosoma cruzi-Induced Host Immune System Dysfunction: A Rationale for Parasite Immunosuppressive Factor(s) Encoding Gene Targeting.

Ouaissi A, Da Silva AC, Guevara AG, Borges M, Guilvard E - J. Biomed. Biotechnol. (2001)

Bottom Line: In this paper, we review the data concerning the immunoregulatory effects of T. cruzi Tc24 (a B cell activator antigen) and Tc52 (an immunosuppressive protein) released molecules on the host immune system.Moreover, targeted Tc52 replacement allowed the obtention of parasite mutants exhibiting low virulence in vitro and in vivo.Thus, the generation of a complete deficiency state of virulence factors by gene targeting should provide a means to assess the importance of these factors in the pathophysiological processes and disease progression.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
An intense suppression of T cell proliferation to mitogens and to antigens is observed in a large number of parasitic infections. The impairment of T cell proliferation also occurred during the acute phase of Chagas' disease, caused by the intracellular protozoan parasite Trypanosoma cruzi. A wealth of evidence has accumulated that illustrates the ability of T. cruzi released molecules to influence directly a variety of diverse immunological functions. In this paper, we review the data concerning the immunoregulatory effects of T. cruzi Tc24 (a B cell activator antigen) and Tc52 (an immunosuppressive protein) released molecules on the host immune system. The gene targeting approach developed to further explore the biological function(s) of Tc52 molecule, revealed interesting unexpected functional properties. Indeed, in addition to its immunusuppressive activity a direct or indirect involvement of Tc52 gene product alone or in combination with other cellular components in T. cruzi differentiation control mechanisms have been evidenced. Moreover, targeted Tc52 replacement allowed the obtention of parasite mutants exhibiting low virulence in vitro and in vivo. Thus, the generation of a complete deficiency state of virulence factors by gene targeting should provide a means to assess the importance of these factors in the pathophysiological processes and disease progression. It is hoped that such approaches might allow rational design of tools to control T. cruzi infections.

No MeSH data available.


Related in: MedlinePlus

Panel (A)shows the fluorescence intensity vs. relative cellnumber, obtained using BALB/c mouse macrophages incubated at4°C with Tc52 and treated with rabbit anti-Tc52antibodies followed by fluoresceine-conjugated goat anti-rabbitIg (right peak, 78% fluorescent cells). The left peak representscells which were incubated in the absence of Tc52 and treatedwith the antibodies as above (12% fluorescent cells). Panel (B)shows that Tc52 “sticks” to macrophages upon its interactionwith these cells at 37°C. Panel (C) represents a highmagnification of the same cell preparation after incubation withTc52. The clumps of staining could be inside the cells or couldbe capped Tc52 that is on the upper surface of the cell.
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Figure 2: Panel (A)shows the fluorescence intensity vs. relative cellnumber, obtained using BALB/c mouse macrophages incubated at4°C with Tc52 and treated with rabbit anti-Tc52antibodies followed by fluoresceine-conjugated goat anti-rabbitIg (right peak, 78% fluorescent cells). The left peak representscells which were incubated in the absence of Tc52 and treatedwith the antibodies as above (12% fluorescent cells). Panel (B)shows that Tc52 “sticks” to macrophages upon its interactionwith these cells at 37°C. Panel (C) represents a highmagnification of the same cell preparation after incubation withTc52. The clumps of staining could be inside the cells or couldbe capped Tc52 that is on the upper surface of the cell.

Mentions: Our studies showed that Tc52 synergizes with IFN-γ tostimulate NO production by macrophages [14]. The inducibleiNOS mRNA levels were also increased upon stimulation ofmacrophages with Tc52 and IFN-γ, suggesting a possiblecontrol through transcriptional mechanisms. The mRNAs affected byTc52 included IL-1α, IL-12, and IL-10. However, thecombination of Tc52 and IFN-γ down-regulates IL-1αand IL-10 gene expression, but not IL-12. The Tc52 did not affectthe expression of constitutively expressed gene encoding GAPDH.Complementary experiments showed that Tc52 could be bound tomacrophage surface as evidenced by FACS analysis(Figure 2), and is expressed by intracellularamastigotes (Figure 3). The immunofluorescencemicrographs of macrophages incubated with Tc52 protein maysuggest a capping process. In fact the clumps of staining couldbe inside the cells or could be capped Tc52 that is on the uppersurface of the cell (Figure 2). Further electronmicroscopy studies are required to determine how the molecule istaken by the cells (cell surface receptors?) and how it interactsto modify the intracellular molecular events leading tomacrophage activation.


Trypanosoma cruzi-Induced Host Immune System Dysfunction: A Rationale for Parasite Immunosuppressive Factor(s) Encoding Gene Targeting.

Ouaissi A, Da Silva AC, Guevara AG, Borges M, Guilvard E - J. Biomed. Biotechnol. (2001)

Panel (A)shows the fluorescence intensity vs. relative cellnumber, obtained using BALB/c mouse macrophages incubated at4°C with Tc52 and treated with rabbit anti-Tc52antibodies followed by fluoresceine-conjugated goat anti-rabbitIg (right peak, 78% fluorescent cells). The left peak representscells which were incubated in the absence of Tc52 and treatedwith the antibodies as above (12% fluorescent cells). Panel (B)shows that Tc52 “sticks” to macrophages upon its interactionwith these cells at 37°C. Panel (C) represents a highmagnification of the same cell preparation after incubation withTc52. The clumps of staining could be inside the cells or couldbe capped Tc52 that is on the upper surface of the cell.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC79673&req=5

Figure 2: Panel (A)shows the fluorescence intensity vs. relative cellnumber, obtained using BALB/c mouse macrophages incubated at4°C with Tc52 and treated with rabbit anti-Tc52antibodies followed by fluoresceine-conjugated goat anti-rabbitIg (right peak, 78% fluorescent cells). The left peak representscells which were incubated in the absence of Tc52 and treatedwith the antibodies as above (12% fluorescent cells). Panel (B)shows that Tc52 “sticks” to macrophages upon its interactionwith these cells at 37°C. Panel (C) represents a highmagnification of the same cell preparation after incubation withTc52. The clumps of staining could be inside the cells or couldbe capped Tc52 that is on the upper surface of the cell.
Mentions: Our studies showed that Tc52 synergizes with IFN-γ tostimulate NO production by macrophages [14]. The inducibleiNOS mRNA levels were also increased upon stimulation ofmacrophages with Tc52 and IFN-γ, suggesting a possiblecontrol through transcriptional mechanisms. The mRNAs affected byTc52 included IL-1α, IL-12, and IL-10. However, thecombination of Tc52 and IFN-γ down-regulates IL-1αand IL-10 gene expression, but not IL-12. The Tc52 did not affectthe expression of constitutively expressed gene encoding GAPDH.Complementary experiments showed that Tc52 could be bound tomacrophage surface as evidenced by FACS analysis(Figure 2), and is expressed by intracellularamastigotes (Figure 3). The immunofluorescencemicrographs of macrophages incubated with Tc52 protein maysuggest a capping process. In fact the clumps of staining couldbe inside the cells or could be capped Tc52 that is on the uppersurface of the cell (Figure 2). Further electronmicroscopy studies are required to determine how the molecule istaken by the cells (cell surface receptors?) and how it interactsto modify the intracellular molecular events leading tomacrophage activation.

Bottom Line: In this paper, we review the data concerning the immunoregulatory effects of T. cruzi Tc24 (a B cell activator antigen) and Tc52 (an immunosuppressive protein) released molecules on the host immune system.Moreover, targeted Tc52 replacement allowed the obtention of parasite mutants exhibiting low virulence in vitro and in vivo.Thus, the generation of a complete deficiency state of virulence factors by gene targeting should provide a means to assess the importance of these factors in the pathophysiological processes and disease progression.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
An intense suppression of T cell proliferation to mitogens and to antigens is observed in a large number of parasitic infections. The impairment of T cell proliferation also occurred during the acute phase of Chagas' disease, caused by the intracellular protozoan parasite Trypanosoma cruzi. A wealth of evidence has accumulated that illustrates the ability of T. cruzi released molecules to influence directly a variety of diverse immunological functions. In this paper, we review the data concerning the immunoregulatory effects of T. cruzi Tc24 (a B cell activator antigen) and Tc52 (an immunosuppressive protein) released molecules on the host immune system. The gene targeting approach developed to further explore the biological function(s) of Tc52 molecule, revealed interesting unexpected functional properties. Indeed, in addition to its immunusuppressive activity a direct or indirect involvement of Tc52 gene product alone or in combination with other cellular components in T. cruzi differentiation control mechanisms have been evidenced. Moreover, targeted Tc52 replacement allowed the obtention of parasite mutants exhibiting low virulence in vitro and in vivo. Thus, the generation of a complete deficiency state of virulence factors by gene targeting should provide a means to assess the importance of these factors in the pathophysiological processes and disease progression. It is hoped that such approaches might allow rational design of tools to control T. cruzi infections.

No MeSH data available.


Related in: MedlinePlus