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Virulent Shigella flexneri subverts the host innate immune response through manipulation of antimicrobial peptide gene expression.

Sperandio B, Regnault B, Guo J, Zhang Z, Stanley SL, Sansonetti PJ, Pédron T - J. Exp. Med. (2008)

Bottom Line: We also identify the MxiE bacterial regulator, which controls a regulon encompassing a set of virulence plasmid-encoded effectors injected into host cells and regulating innate signaling, as being responsible for this dedicated regulatory process.We demonstrate that this system is also able to down-regulate additional innate immunity genes, such as the chemokine CCL20 gene, leading to compromised recruitment of dendritic cells to the lamina propria of infected tissues.Thus, S. flexneri has developed a dedicated strategy to weaken the innate immunity to manage its survival and colonization ability in the intestine.

View Article: PubMed Central - PubMed

Affiliation: Unité de Pathogénie Microbienne Moléculaire, Département de Biologie Cellulaire et Infection, Institut Pasteur, 75724 Paris Cedex 15, France.

ABSTRACT
Antimicrobial factors are efficient defense components of the innate immunity, playing a crucial role in the intestinal homeostasis and protection against pathogens. In this study, we report that upon infection of polarized human intestinal cells in vitro, virulent Shigella flexneri suppress transcription of several genes encoding antimicrobial cationic peptides, particularly the human beta-defensin hBD-3, which we show to be especially active against S. flexneri. This is an example of targeted survival strategy. We also identify the MxiE bacterial regulator, which controls a regulon encompassing a set of virulence plasmid-encoded effectors injected into host cells and regulating innate signaling, as being responsible for this dedicated regulatory process. In vivo, in a model of human intestinal xenotransplant, we confirm at the transcriptional and translational level, the presence of a dedicated MxiE-dependent system allowing S. flexneri to suppress expression of antimicrobial cationic peptides and promoting its deeper progression toward intestinal crypts. We demonstrate that this system is also able to down-regulate additional innate immunity genes, such as the chemokine CCL20 gene, leading to compromised recruitment of dendritic cells to the lamina propria of infected tissues. Thus, S. flexneri has developed a dedicated strategy to weaken the innate immunity to manage its survival and colonization ability in the intestine.

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S. flexneri compromises the DCs recruitment in human intestinal xenografts. Anti–mouse CD11c immunostainings of human intestinal xenograft sections after 2 h of infection with the wild-type S. flexneri strain M90T (A), the mxiE mutant (B), the mxiD mutant (D), or in noninfected tissues (C). Arrow indicates the poor DC recruitment in submucosal areas, as well as in the lamina propria, typically observed in tissues infected by wild-type bacteria (A). Arrowheads highlight the resident DC in noninfected tissues (C), or the massive recruitment of DCs into the lamina propria and their accumulation in submucosal regions, typically found in tissues infected by the mxiE (B) or mxiD (D) mutants. n = 4 independent biological replicates per condition. Bars, 10 μm.
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fig7: S. flexneri compromises the DCs recruitment in human intestinal xenografts. Anti–mouse CD11c immunostainings of human intestinal xenograft sections after 2 h of infection with the wild-type S. flexneri strain M90T (A), the mxiE mutant (B), the mxiD mutant (D), or in noninfected tissues (C). Arrow indicates the poor DC recruitment in submucosal areas, as well as in the lamina propria, typically observed in tissues infected by wild-type bacteria (A). Arrowheads highlight the resident DC in noninfected tissues (C), or the massive recruitment of DCs into the lamina propria and their accumulation in submucosal regions, typically found in tissues infected by the mxiE (B) or mxiD (D) mutants. n = 4 independent biological replicates per condition. Bars, 10 μm.

Mentions: The β-defensins hBD-1 and -3, and the chemokine CCL20, are immune effectors known to have both antimicrobial properties and chemotactic activities. Our study so far has shown that the blocking of their expression at the mucosal surface by S. flexneri was coupled to deeper progression of bacteria toward crypts. To correlate these findings to mouse immune cell trafficking, additional immunostaining experiments were performed using a monoclonal antibody to mouse CD11c, one of the main antigens present on the surface of DCs. CD11c staining of mxiE-infected tissues revealed massive recruitment of DCs into the lamina propria and submucosal regions; they are probably attracted by the gradient of chemotactic molecules, such as CCL20, emanating from epithelial cells (Fig. 7 B). Similar observations were obtained in mxiD-infected tissues (Fig. 7 D). In contrast, M90T-infected xenotransplants showed a very different pattern characterized by a restricted presence of DCs in submucosal areas, as well as a poor migration into the lamina propria with much less staining than observed in noninfected tissues for resident DCs (Fig. 7, A and C). Collectively, these experiments highlight the existence of a dedicated MxiE-dependent system allowing S. flexneri to suppress expression of immune effectors, leading to compromised recruitment of DCs to the lamina propria of infected tissues.


Virulent Shigella flexneri subverts the host innate immune response through manipulation of antimicrobial peptide gene expression.

Sperandio B, Regnault B, Guo J, Zhang Z, Stanley SL, Sansonetti PJ, Pédron T - J. Exp. Med. (2008)

S. flexneri compromises the DCs recruitment in human intestinal xenografts. Anti–mouse CD11c immunostainings of human intestinal xenograft sections after 2 h of infection with the wild-type S. flexneri strain M90T (A), the mxiE mutant (B), the mxiD mutant (D), or in noninfected tissues (C). Arrow indicates the poor DC recruitment in submucosal areas, as well as in the lamina propria, typically observed in tissues infected by wild-type bacteria (A). Arrowheads highlight the resident DC in noninfected tissues (C), or the massive recruitment of DCs into the lamina propria and their accumulation in submucosal regions, typically found in tissues infected by the mxiE (B) or mxiD (D) mutants. n = 4 independent biological replicates per condition. Bars, 10 μm.
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getmorefigures.php?uid=PMC2373844&req=5

fig7: S. flexneri compromises the DCs recruitment in human intestinal xenografts. Anti–mouse CD11c immunostainings of human intestinal xenograft sections after 2 h of infection with the wild-type S. flexneri strain M90T (A), the mxiE mutant (B), the mxiD mutant (D), or in noninfected tissues (C). Arrow indicates the poor DC recruitment in submucosal areas, as well as in the lamina propria, typically observed in tissues infected by wild-type bacteria (A). Arrowheads highlight the resident DC in noninfected tissues (C), or the massive recruitment of DCs into the lamina propria and their accumulation in submucosal regions, typically found in tissues infected by the mxiE (B) or mxiD (D) mutants. n = 4 independent biological replicates per condition. Bars, 10 μm.
Mentions: The β-defensins hBD-1 and -3, and the chemokine CCL20, are immune effectors known to have both antimicrobial properties and chemotactic activities. Our study so far has shown that the blocking of their expression at the mucosal surface by S. flexneri was coupled to deeper progression of bacteria toward crypts. To correlate these findings to mouse immune cell trafficking, additional immunostaining experiments were performed using a monoclonal antibody to mouse CD11c, one of the main antigens present on the surface of DCs. CD11c staining of mxiE-infected tissues revealed massive recruitment of DCs into the lamina propria and submucosal regions; they are probably attracted by the gradient of chemotactic molecules, such as CCL20, emanating from epithelial cells (Fig. 7 B). Similar observations were obtained in mxiD-infected tissues (Fig. 7 D). In contrast, M90T-infected xenotransplants showed a very different pattern characterized by a restricted presence of DCs in submucosal areas, as well as a poor migration into the lamina propria with much less staining than observed in noninfected tissues for resident DCs (Fig. 7, A and C). Collectively, these experiments highlight the existence of a dedicated MxiE-dependent system allowing S. flexneri to suppress expression of immune effectors, leading to compromised recruitment of DCs to the lamina propria of infected tissues.

Bottom Line: We also identify the MxiE bacterial regulator, which controls a regulon encompassing a set of virulence plasmid-encoded effectors injected into host cells and regulating innate signaling, as being responsible for this dedicated regulatory process.We demonstrate that this system is also able to down-regulate additional innate immunity genes, such as the chemokine CCL20 gene, leading to compromised recruitment of dendritic cells to the lamina propria of infected tissues.Thus, S. flexneri has developed a dedicated strategy to weaken the innate immunity to manage its survival and colonization ability in the intestine.

View Article: PubMed Central - PubMed

Affiliation: Unité de Pathogénie Microbienne Moléculaire, Département de Biologie Cellulaire et Infection, Institut Pasteur, 75724 Paris Cedex 15, France.

ABSTRACT
Antimicrobial factors are efficient defense components of the innate immunity, playing a crucial role in the intestinal homeostasis and protection against pathogens. In this study, we report that upon infection of polarized human intestinal cells in vitro, virulent Shigella flexneri suppress transcription of several genes encoding antimicrobial cationic peptides, particularly the human beta-defensin hBD-3, which we show to be especially active against S. flexneri. This is an example of targeted survival strategy. We also identify the MxiE bacterial regulator, which controls a regulon encompassing a set of virulence plasmid-encoded effectors injected into host cells and regulating innate signaling, as being responsible for this dedicated regulatory process. In vivo, in a model of human intestinal xenotransplant, we confirm at the transcriptional and translational level, the presence of a dedicated MxiE-dependent system allowing S. flexneri to suppress expression of antimicrobial cationic peptides and promoting its deeper progression toward intestinal crypts. We demonstrate that this system is also able to down-regulate additional innate immunity genes, such as the chemokine CCL20 gene, leading to compromised recruitment of dendritic cells to the lamina propria of infected tissues. Thus, S. flexneri has developed a dedicated strategy to weaken the innate immunity to manage its survival and colonization ability in the intestine.

Show MeSH
Related in: MedlinePlus