α-Defensins in Enteric Innate Immunity

Mastroianni, Jennifer R.; Ouellette, André J.

doi:10.1074/jbc.m109.050773

Cited by 96 publications

(48 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In vitro , Crps 2–4 kill 99.9% of most bacteria at ≤3 μM peptide levels when assayed under normoxia [13,19,24]. Here, we measured their relative activities in the presence or absence of air over 1 to 15 μM peptide levels.…”

Section: Resultsmentioning

confidence: 99%

Differential Susceptibility of Bacteria to Mouse Paneth Cell a-Defensins under Anaerobic Conditions

Mastroianni

Selsted

2014

Antibiotics

View full text Add to dashboard Cite

Small intestinal Paneth cells secrete α-defensin peptides, termed cryptdins (Crps) in mice, into the intestinal lumen, where they confer immunity to oral infections and define the composition of the ileal microbiota. In these studies, facultative bacteria maintained under aerobic or anaerobic conditions displayed differential sensitivities to mouse α-defensins under in vitro assay conditions. Regardless of oxygenation, Crps 2 and 3 had robust and similar bactericidal activities against S. typhimurium and S. flexneri, but Crp4 activity against S. flexneri was attenuated in the absence of oxygen. Anaerobic bacteria varied in their susceptibility to Crps 2-4, with Crp4 showing less activity than Crps 2 and 3 against Enterococcus faecalis, and Bacteroides fragilis in anaerobic assays, but Fusobacterium necrophorum was killed only by Crp4 and not by Crps 2 and 3. The influence of anaerobiosis in modulating Crp bactericidal activities in vitro suggests that α-defensin effects on the enteric microbiota may be subject to regulation by local oxygen tension.

show abstract

Section: Resultsmentioning

confidence: 99%

Differential Susceptibility of Bacteria to Mouse Paneth Cell a-Defensins under Anaerobic Conditions

Mastroianni

Selsted

2014

Antibiotics

View full text Add to dashboard Cite

show abstract

“…These results clearly suggest that ␣-defensins can circumvent the mechanisms of evasion adopted by C. difficile to resist cathelicidin LL-37 (33). A plausible explanation relies on cationic peptide structure: LL-37 is characterized by an extended ␣-helical structure and can be cleaved and inactivated by bacterial proteases (31), while mature HD5 and HNP1, due to their tightly folded structure, are inherently resistant to proteolysis (52,53).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, such a different range of activities is compatible with the different physiological roles of HD5 and HNP1. Indeed, HD5, which is secreted at high concentrations in the intestinal crypts, gets diluted in the mucous layer and still maintains its bactericidal activity (52,59). On the other hand, HNP1, whose role is to intervene once the inflammatory process is initiated and a massive bacterial invasion has to be tackled, is more active at the highest levels of the range (7 M).…”

Section: Discussionmentioning

confidence: 99%

New Role for Human α-Defensin 5 in the Fight against Hypervirulent Clostridium difficile Strains

et al. 2015

View full text Add to dashboard Cite

Clostridium difficile infection (CDI), one of the most common hospital-acquired infections, is increasing in incidence and severity with the emergence and diffusion of hypervirulent strains. CDI is precipitated by antibiotic treatment that destroys the equilibrium of the gut microbiota. Human ␣-defensin 5 (HD5), the most abundant enteric antimicrobial peptide, is a key regulator of gut microbiota homeostasis, yet it is still unknown if C. difficile, which successfully evades killing by other host microbicidal peptides, is susceptible to HD5. We evaluated, by means of viability assay, fluorescence-activated cell sorter (FACS) analysis, and electron microscopy, the antimicrobial activities of ␣-defensins 1 and 5 against a panel of C. difficile strains encompassing the most prevalent epidemic and hypervirulent PCR ribotypes in Europe (012, 014/020, 106, 018, 027, and 078). Here we show that (i) concentrations of HD5 within the intestinal physiological range produced massive C. difficile cell killing; (ii) HD5 bactericidal activity was mediated by membrane depolarization and bacterial fragmentation with a pattern of damage peculiar to C. difficile bacilli, compared to commensals like Escherichia coli and Enterococcus faecalis; and (iii) unexpectedly, hypervirulent ribotypes were among the most susceptible to both defensins. These results support the notion that HD5, naturally present at very high concentrations in the mucosa of the small intestine, could indeed control the very early steps of CDI by killing C. difficile bacilli at their germination site. As a consequence, HD5 can be regarded as a good candidate for the containment of hypervirulent C. difficile strains, and it could be exploited in the therapy of CDI and relapsing C. difficile-associated disease.

show abstract

“…In contrast to the numerous and diverse α-defensin genes expressed by mouse and macaque Paneth cells, humans make only two Paneth cell α-defensins, HD5 and HD6 (Figure 3) [103–107]. Paneth cell α-defensins also have been recovered from luminal rinses of human ileum [32], washings of mouse jejunum and ileum [96, 98], and from the distal colonic lumen [108]. …”

Section: α-Defensin Distribution and Gene Expressionmentioning

confidence: 99%

Paneth cell α-defensins in enteric innate immunity

Ouellette

2011

Cell. Mol. Life Sci.

135

138

View full text Add to dashboard Cite

Paneth cells at the base of small intestinal crypts of Lieberkühn secrete high levels of α-defensins in response to cholinergic and microbial stimuli. Paneth cell α-defensins are broad spectrum microbicides that function in the extracellular environment of the intestinal lumen, and they are responsible for the majority of secreted bactericidal peptide activity. Paneth cell α-defensins confer immunity to oral infection by Salmonella enterica serovar Typhimurium, and they are major determinants of the composition of the small intestinal microbiome. In addition to host defense molecules such as α-defensins, lysozyme, and Pla2g2a, Paneth cells also produce and release proinflammatory mediators as components of secretory granules. Disruption of Paneth cell homeostasis, with subsequent induction of endoplasmic reticulum (ER) stress, autophagy, or apoptosis, contributes to inflammation in diverse genetic and experimental mouse models.

show abstract

α-Defensins in Enteric Innate Immunity

Cited by 96 publications

References 68 publications

Differential Susceptibility of Bacteria to Mouse Paneth Cell a-Defensins under Anaerobic Conditions

Differential Susceptibility of Bacteria to Mouse Paneth Cell a-Defensins under Anaerobic Conditions

New Role for Human α-Defensin 5 in the Fight against Hypervirulent Clostridium difficile Strains

Paneth cell α-defensins in enteric innate immunity

Contact Info

Product

Resources

About