Human Enteric α-Defensin 5 Promotes Shigella Infection by Enhancing Bacterial Adhesion and Invasion

Xu, Dan; Liao, Chongbing; Zhang, Bing; Tolbert, W.D.; He, Wangxiao; Dai, Zhijun; Zhang, Wei; Yuan, Weirong; Pazgier, M.; Liu, Jiankang; Yu, Jun; Sansonetti, Philippe J.; Bevins, Charles L.; Shao, Yongping; Lu, Wuyuan

doi:10.1016/j.immuni.2018.04.014

Cited by 52 publications

(58 citation statements)

References 72 publications

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“…For example, depletion of Paneth cells makes newborn mice susceptible to S. flexneri infection (66), and mucins produced by goblet cells are linked to TNF-␣ expression during S. flexneri infection (67,68). Additionally, defensins secreted by the colonic epithelium have been shown to contribute to Shigella pathogenesis (69). Differentiated HIEs, which contain both Paneth and goblet cells, offer a promising holistic system to examine the impact of these and other factors on Shigella invasion and intracellular proliferation and to determine which Shigella factors contribute to overcoming obstacles of pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Human Intestinal Enteroids as a Model System of Shigella Pathogenesis

et al. 2019

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The enteric bacterium and intracellular human pathogen Shigella causes hundreds of millions of cases of the diarrheal disease shigellosis per year worldwide. Shigella is acquired by ingestion of contaminated food or water; upon reaching the colon, the bacteria invade colonic epithelial cells, replicate intracellularly, spread to adjacent cells, and provoke an intense inflammatory response. There is no animal model that faithfully recapitulates human disease; thus, cultured cells have been used to model Shigella pathogenesis. However, the use of transformed cells in culture does not provide the same environment to the bacteria as the normal human intestinal epithelium. Recent advances in tissue culture now enable the cultivation of human intestinal enteroids (HIEs), which are derived from human intestinal stem cells, grown ex vivo, and then differentiated into "mini-intestines." Here, we demonstrate that HIEs can be used to model Shigella pathogenesis. We show that Shigella flexneri invades polarized HIE monolayers preferentially via the basolateral surface. After S. flexneri invades HIE monolayers, S. flexneri replicates within HIE cells and forms actin tails. S. flexneri also increases the expression of HIE proinflammatory signals and the amino acid transporter SLC7A5. Finally, we demonstrate that disruption of HIE tight junctions enables S. flexneri invasion via the apical surface.

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Section: Discussionmentioning

confidence: 99%

Human Intestinal Enteroids as a Model System of Shigella Pathogenesis

et al. 2019

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“…This may be caused by the fact that multiple dominant antigens from these microbes may be shared with tolerated commensals or by inability of these microbes to produce immunodominant virulence factors when cultivated in vitro in artificial growth media [49][50][51]. Moreover, microbes may respond to inflammatory conditions, such as in inflamed mucosa during RAS, by producing different surface antigens, thus differing even from isolates from healthy mucosa [52,53]. Nevertheless, by preparing these microbes in vitro under standardized conditions, we were able to compare all tested groups within a single assay.…”

Section: Discussionmentioning

confidence: 99%

Oral Microbiota Composition and Antimicrobial Antibody Response in Patients with Recurrent Aphthous Stomatitis

et al. 2019

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Recurrent aphthous stomatitis (RAS) is the most common disease of the oral mucosa, and it has been recently associated with bacterial and fungal dysbiosis. To study this link further, we investigated microbial shifts during RAS manifestation at an ulcer site, in its surroundings, and at an unaffected site, compared with healed mucosa in RAS patients and healthy controls. We sampled microbes from five distinct sites in the oral cavity. The one site with the most pronounced differences in microbial alpha and beta diversity between RAS patients and healthy controls was the lower labial mucosa. Detailed analysis of this particular oral site revealed strict association of the genus Selenomonas with healed mucosa of RAS patients, whereas the class Clostridia and genera Lachnoanaerobaculum, Cardiobacterium, Leptotrichia, and Fusobacterium were associated with the presence of an active ulcer. Furthermore, active ulcers were dominated by Malassezia, which were negatively correlated with Streptococcus and Haemophilus and positively correlated with Porphyromonas species. In addition, RAS patients showed increased serum levels of IgG against Mogibacterium timidum compared with healthy controls. Our study demonstrates that the composition of bacteria and fungi colonizing healthy oral mucosa is changed in active RAS ulcers, and that this alteration persists to some extent even after the ulcer is healed.

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“…We made a surprising recent discovery that HD5, at sublethal concentrations, greatly promotes Shigella infectivity in vitro, in vivo, and ex vivo by enhancing bacterial adhesion to and invasion of host cells. The lack of fimbriae in Shigella affords a unique bacterial surface, onto which HD5 forms multimeric structures to mediate Shigella interactions with host epithelium, thereby inducing productive activation of the T3SS critical for Shigella pathogenicity (Xu et al, ).…”

Section: Introductionmentioning

confidence: 99%

Critical determinants of human neutrophil peptide 1 for enhancing host epithelial adhesion ofShigella flexneri

Liao

Fang

Xiao

et al. 2019

Cellular Microbiology

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Human neutrophil peptides (HNPs), also known as human myeloid α-defensins degranulated by infiltrating neutrophils at bacterial infection loci, exhibit broad antomicrobial activities against bacteria, fungi, and viruses. We have made a surprising recent finding that Shigella, a highly contagious, yet poorly adhesive enteric pathogen, exploits human α-defensins including HNP1 to enhance its adhesion to and invasion of host epithelial cells. However, the critical molecular determinants responsible for HNP1-enhanced Shigella adhesion and invasion have yet to be investigated. Using cultured epithelial cells and polarised Caco2 cells as an in vitro infection model,we demonstrated that HNP1 promoted Shigella infection in a structure-and sequence-dependent manner, with two bulky hydrophobic residues, Trp26 and Phe28 important for HNP1 self-assembly, being most critical. The functional importance of hydrophobicity for HNP1-enhanced Shigella infection was further verified by substitutions for Trp26 of a series of unnatural amino acids with straight aliphatic side chains of different lengths. Dissection of the Shigella infection process revealed that bacteria-rather than host cells-bound HNP1 contributed most to the enhancement. Further, mutagenesis analysis of bacterial surface components, while precluding the involvement of lipopolysaccharides (LPS) in the interaction with HNP1, identified outer membrane proteins and the Type 3 secretion apparatus as putative binding targets of HNP1 involved in enhanced Shigella adhesion and invasion. Our findings provide molecular and mechanistic insights into the mode of action of HNP1 in promoting Shigella infection, thus showcasing another example of how innate immune factors may serve as a double-edged sword in health and disease.

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Human Enteric α-Defensin 5 Promotes Shigella Infection by Enhancing Bacterial Adhesion and Invasion

Cited by 52 publications

References 72 publications

Human Intestinal Enteroids as a Model System of Shigella Pathogenesis

Human Intestinal Enteroids as a Model System of Shigella Pathogenesis

Oral Microbiota Composition and Antimicrobial Antibody Response in Patients with Recurrent Aphthous Stomatitis

Critical determinants of human neutrophil peptide 1 for enhancing host epithelial adhesion ofShigella flexneri

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