Botulinum toxin A complex exploits intestinal M cells to enter the host and exert neurotoxicity

Matsumura, Tomohiro; Sugawara, Yo; Yutani, Masahiro; Amatsu, Sho; Yagita, Hideo; Kohda, Tomoko; Fukuoka, Shin Ichi; Nakamura, Yutaka; Fukuda, Shinji; Hase, Koji; Ohno, Hiroshi; Fujinaga, Yukako

doi:10.1038/ncomms7255

Cited by 69 publications

(47 citation statements)

References 38 publications

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“…A variety of bacterial and viral pathogens including Brucella abortus [24], Salmonella Typhimurium [25], Yersinia enterocolitica [26], norovirus [27, 28] and reovirus [28] appear to exploit the transcytotic activity of M cells to cross the gut epithelium and infect the host. The food-borne botulinum neurotoxin [29] has also been suggested to exert its toxicity after transcytosis by M cells [29]. Independent studies suggest orally administered prions may similarly be transported by M cells into host tissues [9, 30–32] and that this transport may be important to establish host infection [9].…”

Section: Introductionmentioning

confidence: 99%

Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

et al. 2016

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Many natural prion diseases of humans and animals are considered to be acquired through oral consumption of contaminated food or pasture. Determining the route by which prions establish host infection will identify the important factors that influence oral prion disease susceptibility and to which intervention strategies can be developed. After exposure, the early accumulation and replication of prions within small intestinal Peyer’s patches is essential for the efficient spread of disease to the brain. To replicate within Peyer’s patches, the prions must first cross the gut epithelium. M cells are specialised epithelial cells within the epithelia covering Peyer’s patches that transcytose particulate antigens and microorganisms. M cell-development is dependent upon RANKL-RANK-signalling, and mice in which RANK is deleted only in the gut epithelium completely lack M cells. In the specific absence of M cells in these mice, the accumulation of prions within Peyer’s patches and the spread of disease to the brain was blocked, demonstrating a critical role for M cells in the initial transfer of prions across the gut epithelium in order to establish host infection. Since pathogens, inflammatory stimuli and aging can modify M cell-density in the gut, these factors may also influence oral prion disease susceptibility. Mice were therefore treated with RANKL to enhance M cell density in the gut. We show that prion uptake from the gut lumen was enhanced in RANKL-treated mice, resulting in shortened survival times and increased disease susceptibility, equivalent to a 10-fold higher infectious titre of prions. Together these data demonstrate that M cells are the critical gatekeepers of oral prion infection, whose density in the gut epithelium directly limits or enhances disease susceptibility. Our data suggest that factors which alter M cell-density in the gut epithelium may be important risk factors which influence host susceptibility to orally acquired prion diseases.

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Section: Introductionmentioning

confidence: 99%

Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

et al. 2016

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“…These proteins may serve a role in shielding the neurotoxin from the severe conditions of the gastrointestinal tract and may aid in moving the neurotoxin across the intestinal epithelium through interaction with E-cadherin [2,3,7]. Accurate identification of the proteins present during each stage of intoxication would help to understand this process more fully.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Hemagglutinin Negative Botulinum Progenitor Toxins

Kalb

Baudys

Smith

et al. 2017

Toxins

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Botulism is a disease involving intoxication with botulinum neurotoxins (BoNTs), toxic proteins produced by Clostridium botulinum and other clostridia. The 150 kDa neurotoxin is produced in conjunction with other proteins to form the botulinum progenitor toxin complex (PTC), alternating in size from 300 kDa to 500 kDa. These progenitor complexes can be classified into hemagglutinin positive or hemagglutinin negative, depending on the ability of some of the neurotoxin-associated proteins (NAPs) to cause hemagglutination. The hemagglutinin positive progenitor toxin complex consists of BoNT, nontoxic non-hemagglutinin (NTNH), and three hemagglutinin proteins; HA-70, HA-33, and HA-17. Hemagglutinin negative progenitor toxin complexes contain BoNT and NTNH as the minimally functional PTC (M-PTC), but not the three hemagglutinin proteins. Interestingly, the genome of hemagglutinin negative progenitor toxin complexes comprises open reading frames (orfs) which encode for three proteins, but the existence of these proteins has not yet been extensively demonstrated. In this work, we demonstrate that these three proteins exist and form part of the PTC for hemagglutinin negative complexes. Several hemagglutinin negative strains producing BoNT/A, /E, and /F were found to contain the three open reading frame proteins. Additionally, several BoNT/A-containing bivalent strains were examined, and NAPs from both genes, including the open reading frame proteins, were associated with BoNT/A. The open reading frame encoded proteins are more easily removed from the botulinum complex than the hemagglutinin proteins, but are present in several BoNT/A and /F toxin preparations. These are not easily removed from the BoNT/E complex, however, and are present even in commercially-available purified BoNT/E complex.

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“…One model for the transit of BoNTs suggests that the holotoxin itself can transcytose through the intestinal epithelium [33,34,35]. A second model for the BoNT absorption from the epithelium implicates the hemagglutin proteins (HA) in this process by binding cell surface receptors on the apical side, transcytosis, and potential disruption of the epithelial barrier at the basolateral side to allow for paracellular transport of the toxins in certain situations [33,36]. Our lab has shown in in vitro and in vivo intoxication models that neurotoxin-accessory proteins enhanced the rate of entry of BoNT/A in comparison to holotoxin alone, and entry was localized first to intestinal villi and subsequently to the intestinal crypts [18].…”

Section: Discussionmentioning

confidence: 99%

Probiotic Microorganisms Inhibit Epithelial Cell Internalization of Botulinum Neurotoxin Serotype A

Lam

Tam

Stanker

et al. 2016

Toxins

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Botulinum neurotoxins (BoNTs) are some of the most poisonous natural toxins known to man and are threats to public health and safety. Previous work from our laboratory showed that both BoNT serotype A complex and holotoxin can bind and transit through the intestinal epithelia to disseminate in the blood. The timing of BoNT/A toxin internalization was shown to be comparable in both the Caco-2 in vitro cell culture and in the oral mouse intoxication models. Probiotic microorganisms have been extensively studied for their beneficial effects in not only maintaining the normal gut mucosa but also protection from allergens, pathogens, and toxins. In this study, we evaluate whether probiotic microorganisms will block BoNT/A uptake in the in vitro cell culture system using Caco-2 cells. Several probiotics tested (Saccharomyces boulardii, Lactobacillus acidophilus, Lactobacillus rhamnosus LGG, and Lactobacillus reuteri) blocked BoNT/A uptake in a dose-dependent manner whereas a non-probiotic strain of Escherichia coli did not. We also showed that inhibition of BoNT/A uptake was not due to the degradation of BoNT/A nor by sequestration of toxin via binding to probiotics. These results show for the first time that probiotic treatment can inhibit BoNT/A binding and internalization in vitro and may lead to the development of new therapies.

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Botulinum toxin A complex exploits intestinal M cells to enter the host and exert neurotoxicity

Cited by 69 publications

References 38 publications

Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

Characterization of Hemagglutinin Negative Botulinum Progenitor Toxins

Probiotic Microorganisms Inhibit Epithelial Cell Internalization of Botulinum Neurotoxin Serotype A

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