A live vaccine rapidly protects against cholera in an infant rabbit model

Hubbard, Troy P.; Billings, Gabriel; Dörr, Tobias; Sit, Brandon; Warr, Alyson R.; Kuehl, Carole J.; Kim, Minsik; Delgado, Fernanda; Mekalanos, John J.; Lewnard, Joseph A; Waldor, Matthew K.

doi:10.1126/scitranslmed.aap8423

Cited by 59 publications

(66 citation statements)

References 42 publications

(57 reference statements)

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“…The use of microbiotamodulating interventions represents an emerging strategy that might confer rapid protection against fast-developing infections like cholera. Notably, Hubbard et al (27) created a live cholera vaccine candidate that provides colonization resistance in a probioticlike fashion, conferring cholera protection within 1 day in an infant rabbit model.…”

Section: Discussionmentioning

confidence: 99%

Probiotic strains detect and suppress cholera in mice

et al. 2018

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Microbiota-modulating interventions are an emerging strategy to promote gastrointestinal homeostasis. Yet, their use in the detection, prevention, and treatment of acute infections remains underexplored. We report the basis of a probiotic-based strategy to promote colonization resistance and point-of-need diagnosis of cholera, an acute diarrheal disease caused by the pathogen Vibrio cholerae. Oral administration of Lactococcus lactis, a common dietary fermentative bacterium, reduced intestinal V. cholerae burden and improved survival in infected infant mice through the production of lactic acid. Furthermore, we engineered an L. lactis strain that specifically detects quorum-sensing signals of V. cholerae in the gut and triggers expression of an enzymatic reporter that is readily detected in fecal samples. We postulate that preventive dietary interventions with fermented foods containing natural and engineered L. lactis strains may hinder cholera progression and improve disease surveillance in populations at risk of cholera outbreaks.

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Section: Discussionmentioning

confidence: 99%

Probiotic strains detect and suppress cholera in mice

et al. 2018

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“…We attempted to use transposon-insertion sequencing (TIS) to identify genetic loci contributing to S. flexneri colonization and pathogenesis, as we have done with V. cholerae (53, 54), V. parahaemolyticus (55), and EHEC (56). Initially, a high-density transposon mutant library in S. flexneri was created using a mariner -based transposon that inserts at TA dinucleotide sites in the genome.…”

Section: Resultsmentioning

confidence: 99%

“…At necropsy, the intestine from the duodenum to rectum was dissected, and divided into separate anatomical sections (small intestine, colon) as previously described (54, 78). 1-2 cm pieces of each anatomical section were used for measurements of tissue bacterial burden.…”

Section: Methodsmentioning

confidence: 99%

“…A transposon library was constructed in S. flexneri 2a 2457T Sm R (WT Sm R ) using pSC189 (79), using previously described protocols (54, 80) with additional modifications. Briefly, E. coli strain MFD pir (81) was transformed with pSC189.…”

Section: Methodsmentioning

confidence: 99%

“…Tn-seq library construction and data analysis was performed as previously described (54, 55, 82); briefly, genomic DNA was extracted, transposon junctions were amplified, sequencing was performed on an Illumina MiSeq, and data were analyzed using a modified ARTIST pipeline (54, 55). Sequence reads were mapped onto the S. flexneri 2a strain 2457T chromosome (Refseq NC_004741.1) and S. flexneri 2a strain 301 virulence plasmid (Refseq NC_004851.1).…”

Section: Methodsmentioning

confidence: 99%

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An oral inoculation infant rabbit model forShigellainfection

Kuehl

D’Gama

Warr

et al. 2019

Preprint

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250 words max) 18 Shigella species cause diarrheal disease globally. Shigellosis is typically characterized by 19 bloody stools and colitis with mucosal damage and is the leading bacterial cause of diarrheal 20 death worldwide. Following oral ingestion, the pathogen invades and replicates within the 21 colonic epithelium through mechanisms that rely on its type III secretion system (T3SS). 22 Currently, oral infection-based small animal models to study the pathogenesis of shigellosis are 23 lacking. Here, we found that oro-gastric inoculation of infant rabbits with S. flexneri resulted in 24 diarrhea and colonic pathology resembling that found in human shigellosis. Fasting animals 25 prior to S. flexneri inoculation increased the frequency of disease. The pathogen colonized the 26 colon, where both luminal and intraepithelial foci were observed. The intraepithelial foci likely 27 arise through S. flexneri spreading from cell-to-cell. Robust S. flexneri intestinal colonization, 28 invasion of the colonic epithelium, and epithelial sloughing all required the T3SS as well as IcsA, 29 a factor required for bacterial spreading and adhesion in vitro. Expression of the 30 proinflammatory chemokine IL-8, detected with in situ mRNA labeling, was higher in animals 31 infected with wild-type S. flexneri versus mutant strains deficient in icsA or T3SS, suggesting 32 that epithelial invasion promotes expression of this chemokine. Collectively, our findings 33 suggest that oral infection of infant rabbits offers a useful experimental model for studies of the 34 pathogenesis of shigellosis and for testing of new therapeutics. 35 42 dependent on the S. flexneri type III secretion system and IcsA, canonical Shigella virulence 43 factors. Thus, oral infection of infant rabbits offers a feasible model to study the pathogenesis 44 of shigellosis and to develop and test new therapeutics. 45 48 life-threatening (1). This enteric pathogen, which is spread by the fecal-oral route between 49 humans, does not have an animal reservoir or vector (1). Annually, Shigella infections cause 50 tens of millions of diarrhea cases and ~200,000 deaths (2, 3). It is likely the leading cause of 51 diarrheal mortality worldwide in individuals older than 5 years (2, 3). Most Shigella infections 52 are attributable to S. flexneri, one of the four Shigella species, although in developed nations 53the prevalence of S. sonnei is higher (4-7). 54 The pathogen primarily causes colonic pathology that usually includes mucosal 55 ulceration and erosion due to sloughing of epithelial cells, and is typically characterized by 56 acute inflammation, with recruitment of neutrophils and plasma cells, congestion of blood 57 vessels, distorted crypt architecture, and hemorrhage (8, 9). While inflammatory responses to 58 Shigella invasion of colonic epithelial cells were thought to be the underlying cause of epithelial 59 cell destruction and hemorrhage, recent evidence suggests that pathogen-mediated 60 destruction of epithelial cells also plays a role in...

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Oral Delivery of Biologics for Precision Medicine

2019

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Precision medicine has led to the identification of new biological drugs and targets for personalized treatments. A limitation of biological drugs relies on their difficulties for overcoming biological barriers. However, recent developments on drug delivery are opening new avenues that may soon make feasible the oral administration of biologics. In article number 1901935, María José Alonso and co‐workers provide an overview of the current situation, future prospects, barriers to clinical translation, and identified opportunities for advancement in this field.

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A live vaccine rapidly protects against cholera in an infant rabbit model

Cited by 59 publications

References 42 publications

Probiotic strains detect and suppress cholera in mice

Probiotic strains detect and suppress cholera in mice

An oral inoculation infant rabbit model forShigellainfection

Oral Delivery of Biologics for Precision Medicine

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