Shigella Vaccine Development: Finding the Path of Least Resistance

Chen, Wilbur H.; Kotloff, Karen L.

doi:10.1128/cvi.00444-16

Cited by 16 publications

(16 citation statements)

References 49 publications

(43 reference statements)

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“…Shigellosis has been increasingly recognized worldwide and the need for better tools that improve testing of vaccines and other interventions is clearly evident. 14,16 This is the first study that describes a murine model of intestinal shigellosis mimicking the clinical outcomes that are commonly seen in children, including diarrhea and weight loss, with host zinc deficiency promoting more prolonged infection.…”

Section: Discussionmentioning

confidence: 99%

A murine model of diarrhea, growth impairment and metabolic disturbances withShigella flexneriinfection and the role of zinc deficiency

et al. 2019

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Shigella is one of the major enteric pathogens worldwide. We present a murine model of S. flexneri infection and investigate the role of zinc deficiency (ZD). C57BL/6 mice fed either standard chow (HC) or ZD diets were pretreated with an antibiotic cocktail and received S. flexneri strain 2457T orally. Antibiotic pre-treated ZD mice showed higher S. flexneri colonization than non-treated mice. ZD mice showed persistent colonization for at least 50 days post-infection (pi). S. flexneriinfected mice showed significant weight loss, diarrhea and increased levels of fecal MPO and LCN in both HC and ZD fed mice. S. flexneri preferentially colonized the colon, caused epithelial disruption and inflammatory cell infiltrate, and promoted cytokine production which correlated with weight loss and histopathological changes. Infection with S. flexneri ΔmxiG (critical for type 3 secretion system) did not cause weight loss or diarrhea, and had decreased stool shedding duration and tissue burden. Several biochemical changes related to energy, inflammation and gut-microbial metabolism were observed. Zinc supplementation increased weight gains and reduced intestinal inflammation and stool shedding in ZD infected mice. In conclusion, young antibiotic-treated mice provide a new model of oral S. flexneri infection, with ZD promoting prolonged infection outcomes.

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Section: Discussionmentioning

confidence: 99%

A murine model of diarrhea, growth impairment and metabolic disturbances withShigella flexneriinfection and the role of zinc deficiency

et al. 2019

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“…Preventing shigellosis remains more than ever a public health priority. [98][99][100] Indeed, as recently reviewed, 101 there is a growing appreciation for the role of vaccines in confronting the problem of antimicrobial resistance, which includes the alarming emergence of multi-drug resistant Shigella strains. 98…”

Section: Implications For Vaccine Developmentmentioning

confidence: 99%

Shigella-mediated immunosuppression in the human gut: subversion extends from innate to adaptive immune responses

Brunner

Samassa

Sansonetti

et al. 2019

Human Vaccines & Immunotherapeutics

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The enteropathogen, Shigella, is highly virulent and remarkably adjusted to the intestinal environment of its almost exclusive human host. Key for Shigella pathogenicity is the injection of virulence effectors into the host cell via its type three secretion system (T3SS), initiating disease onset and progression by the vast diversity of the secreted T3SS effectors and their respective cellular targets. The multifaceted modulation of host signaling pathways exerted by Shigella T3SS effectors, which include the subversion of host innate immune defenses and the promotion of intracellular bacterial survival and dissemination, have been extensively reviewed in the recent past. This review focuses on the human species specificity of Shigella by discussing some possible evasion mechanisms towards the human, but not non-human or rodent gut innate defense barrier, leading to the lack of a relevant animal infection model. In addition, subversion mechanisms of the adaptive immune response are highlighted summarizing research advances of the recent years. In particular, the new paradigm of Shigella pathogenicity constituted of invasion-independent T3SS effector-mediated targeting of activated, human lymphocytes is discussed. Along with consequences on vaccine development, these findings offer new directions for future research endeavors towards a better understanding of immunity to Shigella infection.

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“…Sf6TSP binds octasaccharide O‐antigen fragments with relatively low affinity due to a highly flexible reducing end pointing towards the enzyme's active site residues (Figure ). Sf6TSP therefore is a valuable target for generating mutants with increased O‐antigen affinity, as it can be used as a sensor for S. flexneri , an important diagnostic target pathogen that causes dysentery in infants . In solution, fluorescence amplitude changes upon glycan ligand binding were used to detect O‐polysaccharide binding via a cysteine coupled, environment‐sensitive fluorescent label in the Sf6TSP binding site .…”

Section: Introductionmentioning

confidence: 99%

Increasing the Affinity of an O‐Antigen Polysaccharide Binding Site in Shigella flexneri Bacteriophage Sf6 Tailspike Protein

Kunstmann

Engström

Wehle

et al. 2020

Chemistry A European J

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Broad and unspecific use of antibiotics accelerates spread of resistances. Sensitive and robust pathogen detection is thus important for a more targeted application. Bacteriophages contain a large repertoire of pathogen‐binding proteins. These tailspike proteins (TSP) often bind surface glycans and represent a promising design platform for specific pathogen sensors. We analysed bacteriophage Sf6 TSP that recognizes the O‐polysaccharide of dysentery‐causing Shigella flexneri to develop variants with increased sensitivity for sensor applications. Ligand polyrhamnose backbone conformations were obtained from 2D 1H,1H‐trNOESY NMR utilizing methine–methine and methine–methyl correlations. They agreed well with conformations obtained from molecular dynamics (MD), validating the method for further predictions. In a set of mutants, MD predicted ligand flexibilities that were in good correlation with binding strength as confirmed on immobilized S. flexneri O‐polysaccharide (PS) with surface plasmon resonance. In silico approaches combined with rapid screening on PS surfaces hence provide valuable strategies for TSP‐based pathogen sensor design.

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Shigella Vaccine Development: Finding the Path of Least Resistance

Cited by 16 publications

References 49 publications

A murine model of diarrhea, growth impairment and metabolic disturbances withShigella flexneriinfection and the role of zinc deficiency

A murine model of diarrhea, growth impairment and metabolic disturbances withShigella flexneriinfection and the role of zinc deficiency

Shigella-mediated immunosuppression in the human gut: subversion extends from innate to adaptive immune responses

Increasing the Affinity of an O‐Antigen Polysaccharide Binding Site in Shigella flexneri Bacteriophage Sf6 Tailspike Protein

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