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

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 β-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.

Th17 Cells Are the Dominant T Cell Subtype Primed by Shigella flexneri Mediating Protective Immunity

“…Regarding antimicrobial peptides, the ablation of Paneth cells, the main producers of a-defensins in the intestine, increases the susceptibility of new-born mice to intestinal infection with S. flexneri (56). In addition, it has been shown that S. flexneri represses, though type III secreted effectors, the production of b-defensin 3 and cathelicidin LL37 produced by intestinal epithelial cells (55).…”

“…Weight loss is expressed as mean 6 SEM and CFU counts are expressed as geometric means 6 SEM. both macrophages and antimicrobial peptides have been suggested to be critical in the pathogenesis of Shigella infection (30,31,55,56). Regarding antimicrobial peptides, the ablation of Paneth cells, the main producers of a-defensins in the intestine, increases the susceptibility of new-born mice to intestinal infection with S. flexneri (56).…”

Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

“…For example, human cathelicidin peptide LL-37 attracts neutrophils, monocytes, mast cells, and T lymphocytes (7,8), and also induces the production of neutrophil and monocyte chemoattractants by many cell types (22)(23)(24)(25). The reduced production of host defense peptides correlates with impaired influx of leukocytes into the gut in Shigella flexneri infections (26), and neutrophil-derived LL-37 is known to be essential for recruitment of inflammatory monocytes in several in vivo models (27). Similarly, IDR-1 also increases macrophage numbers at the site of infection in vivo (16).…”

Shigella

“…26 Although complex and logistically demanding, this model allows for the study of infection in a species-specific context, at least for the epithelial lining. It permits studies of the early phases of epithelial invasion, but does not allow for immunological studies, due to the immuno-deficient background of the transplanted mouse.…”