Shigella-mediated oxygen depletion is essential for intestinal mucosa colonization

Tinévez, Jean-Yves; Arena, Ellen T.; Anderson, Mark; Nigro, Giulia; Injarabian, Louise; Andre, Antonin; Ferrari, Mariana L.; Campbell-Valois, François-Xavier; Devin, Anne; Shorte, Spencer; Sansonetti, Philippe J.; Marteyn, Benoît

doi:10.1038/s41564-019-0525-3

Cited by 30 publications

(44 citation statements)

References 27 publications

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“…In addition, it was shown that older animals (5-week and more) are no longer susceptible to Shigella infection (11). We confirmed these results in our laboratory and used this model in routine in various studies to characterize Shigella virulence mechanisms in vivo (18)(19)(20).…”

Section: Optimization Of the Guinea Pig Diet To Induce A Moderate Ascsupporting

confidence: 80%

“…4A-C). Until now, only transient infections were observed, associated with foci of infection formation within the upper part of the colonic submucosa (20,25), Shigella being further cleared during the immune response in this model. The ascorbate-deficient guinea pig model of shigellosis will be of a great help to investigate the role of the different immunoglubulins and immune cell populations to limit the dissemination of Shigella within the colonic mucosa, but also, conversely, to better understand the molecular bases of the subversion and their antimicrobial activity by Shigella to mediates its efficient dissemination within the infected tissues and to the bloodstream as reported here (Fig.…”

Section: Discussionmentioning

confidence: 75%

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The ascorbate-deficient guinea pig model of shigellosis allows the study of the entireShigellalife cycle

Andre

Mulet

Anderson

et al. 2020

Preprint

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Shigella spp. are the causative agents of bacillary dysentery or shigellosis, mainly in children living in developing countries. The study of Shigella entire life cycle in vivo and the evaluation of vaccine candidates’ protection efficacy have been hampered by the lack of a suitable animal model of infection (1). None of the ones evaluated so far (mouse, rabbit, guinea pig) allows to recapitulate shigellosis symptoms upon Shigella oral challenge. Historical reports suggest that dysentery and scurvy are both metabolic diseases associated with ascorbate-deficiency. Mammals which are susceptible to Shigella infection (humans, non-human primates and guinea pigs) are the lonely ones which are unable to synthesize ascorbate. We optimized a low-ascorbate diet to induce moderate ascorbate-deficiency but not scurvy in guinea pigs (Ascplasma conc.=1.6 μM vs 36 μM with optimal ascorbate supply). We demonstrated that moderate ascorbate-deficiency increases shigellosis severity during extended period of time (up to 48h) with all strains tested (Shigella flexneri 5a and 2a, Shigella sonnei). At late time-points, a massive influx of neutrophils was observed both within the disrupted colonic mucosa and in the luminal compartment, although Shigella remains able to disseminate deep into the organ to reach the sub-mucosal layer and the bloodstream. This new model of shigellosis opens new doors for the study both of Shigella infection strategy and innate and adaptive immune responses to Shigella infection. It may be also of a great interest to study the virulence of other pathogen for which no suitable animal model of infection is available (Vibrio cholerae, Yersinia pestis, Mycobacterium tuberculosis or Campylobacter jejuni, among others).SignificanceThe study of Shigella virulence cycle in vivo has been hampered by the lack of a suitable animal model, which would allow the colonic mucosa infection upon oral challenge. Based on historical reports and physiological aspects, it was suggested that ascorbate-deficiency may stand as a new dysentery risk-factor. To test this hypothesis, we set up a new ascorbate-deficient guinea pig model and demonstrated for the first time that the Shigella infectious process occurred for extended period of time (up to 48h) and demonstrated that shigellosis severity was higher in ascorbate-deficient animal. Ascorbate-deficient guinea pig model of infection may be used to assess the virulence of other pathogens for which no suitable animal model of infection is still lacking.

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Section: Optimization Of the Guinea Pig Diet To Induce A Moderate Ascsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 75%

The ascorbate-deficient guinea pig model of shigellosis allows the study of the entireShigellalife cycle

Andre

Mulet

Anderson

et al. 2020

Preprint

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“…Infection of the colon by Shigella is a multi-stage process involving competition with the microbiome, survival in anaerobic and hypoxic environments, invasion of epithelial cells, direct cell-to-cell spread, and invasion of immune cells [1,10]. Each stage is controlled by various transcription factors that turn on or off specific suites of genes.…”

Section: Introductionmentioning

confidence: 99%

IlvY is an important regulator ofShigellainfectionin vitroandin vivo

Holly

Anderson

Rabago

et al. 2020

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Shigellosis results from oral ingestion of the Gram-negative bacteria Shigella, and symptoms include severe diarrhea and dysentery. In the absence of vaccines, small molecule antibacterial drugs have provided treatment options for shigellosis. However, Shigella drug resistance is rapidly emerging, and Shigella strains with resistance to both third-generation cephalosporins and azithromycin have been identified in Asia. A re-conceptualization is needed regarding the development of therapeutics that target bacterial pathogens in order to reduce resistance development and alteration of gut microbiota, which is depleted upon treatment with wide spectrum antibiotics, thereby increasing susceptibility to subsequent enteric infections. A more organism-specific approach is to develop agents targeting virulence factors such as toxins, adhesins, invasins, quorum sensing, and protein secretion systems. For Shigella, there is interest in targeting transcription factors essential for Shigella infection in vivo rather than specific effectors. Here we describe the importance of the Shigella transcription factor IlvY in Shigella virulence in vitro and in vivo. This work included the development of a novel, oral mouse model of Shigella infection with wild-type adult mice. Unlike previous models, mice do not require antibiotic pretreatment or diet modifications. This mouse model was used to demonstrate the importance of IlvY for Shigella in vivo survival and that deletion of ilvY impacts host responses to infection. These results illustrate that IlvY is a potential therapeutic target for the treatment of shigellosis. In addition, the novel mouse model provides an exciting new opportunity to investigate therapeutic efficacy against Shigella infection and host responses to infection.

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“…However, this model bypasses the normal route of infection and challenges the small intestine, which is not the primary site of pathology in human infections. Intra-rectal guinea pig infection induces colonic pathology and bloody diarrhea (21), and has been used to dissect the contribution of Shigella and host factors in several aspects of pathogenesis (22–24). Adult mice, the most genetically tractable mammalian model organism, are recalcitrant to developing disease when inoculated orally (25).…”

Section: Introductionmentioning

confidence: 99%

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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Shigella-mediated oxygen depletion is essential for intestinal mucosa colonization

Cited by 30 publications

References 27 publications

The ascorbate-deficient guinea pig model of shigellosis allows the study of the entireShigellalife cycle

The ascorbate-deficient guinea pig model of shigellosis allows the study of the entireShigellalife cycle

IlvY is an important regulator ofShigellainfectionin vitroandin vivo

An oral inoculation infant rabbit model forShigellainfection

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