Virulent Shigella flexneri subverts the host innate immune response through manipulation of antimicrobial peptide gene expression.
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.
Sperandio
Brice
B
Unité de Pathogénie Microbienne Moléculaire, Département de Biologie Cellulaire et Infection, Institut Pasteur, 75724 Paris Cedex 15, France.
Regnault
Béatrice
B
Guo
Jianhua
J
Zhang
Zhi
Z
Stanley
Samuel L
SL
Sansonetti
Philippe J
PJ
Pédron
Thierry
T
D023181:Antimicrobial Cationic Peptides / Q000235:genetics*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D017931:DNA Primers; D004405:Dysentery, Bacillary / Q000235:genetics / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007113:Immunity, Innate; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000235:genetics; D012763:Shigella flexneri / Q000276:immunology* / Q000472:pathogenicity*; D014183:Transplantation, Heterologous; D014774:Virulence
D023181:Antimicrobial Cationic Peptides; D017931:DNA Primers; D012334:RNA, Neoplasm