Cross-Protective Shigella Whole-Cell Vaccine With a Truncated O-Polysaccharide Chain

Kim, Min Jung; Moon, Yong; Kim, Hee Joo; Rho, Semi; Shin, Young Kee; Song, Manki; Walker, Richard I.; Czerkinsky, Cécil; Kim, Dong Wook; Kim, Jae-Ouk

doi:10.3389/fmicb.2018.02609

Cited by 25 publications

(16 citation statements)

References 47 publications

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“…With this study, using serum from an ETEC controlled human infection study, we have provided an important link between protein glycosylation and the immunogenicity on an established and well investigated non-canonical ETEC antigen. It is possible that YghJ could show the same level of cross-protection as demonstrated in Shigella using the conserved protein outer membrane protein PSSP-1 ( Kim et al, 2018 ). Future investigations will include specific epitope analyses of the glycosylated YghJ and the non-modified protein variant to further study the antigenic potential of O-linked glycosylation.…”

Section: Discussionmentioning

confidence: 97%

Linking inherent O-Linked Protein Glycosylation of YghJ to Increased Antigen Potential

Thorsing¹,

Krogh²,

Vitved

et al. 2021

Front. Cell. Infect. Microbiol.

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Enterotoxigenic Escherichia coli (ETEC) is a WHO priority pathogen and vaccine target which causes infections in low-income and middle-income countries, travelers visiting endemic regions. The global urgent demand for an effective preventive intervention has become more pressing as ETEC strains have become increasingly multiple antibiotic resistant. However, the vaccine development pipeline has been slow to address this urgent need. To date, vaccine development has focused mainly on canonical antigens such as colonization factors and expressed toxins but due to genomic plasticity of this enteric pathogen, it has proven difficult to develop effective vaccines. In this study, we investigated the highly conserved non-canonical vaccine candidate YghJ/SsLE. Using the mass spectrometry-based method BEMAP, we demonstrate that YghJ is hyperglycosylated in ETEC and identify 54 O-linked Set/Thr residues within the 1519 amino acid primary sequence. The glycosylation sites are evenly distributed throughout the sequence and do not appear to affect the folding of the overall protein structure. Although the glycosylation sites only constitute a minor subpopulation of the available epitopes, we observed a notable difference in the immunogenicity of the glycosylated YghJ and the non-glycosylated protein variant. We can demonstrate by ELISA that serum from patients enrolled in an ETEC H10407 controlled infection study are significantly more reactive with glycosylated YghJ compared to the non-glycosylated variant. This study provides an important link between O-linked glycosylation and the relative immunogenicity of bacterial proteins and further highlights the importance of this observation in considering ETEC proteins for inclusion in future broad coverage subunit vaccine candidates.

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Section: Discussionmentioning

confidence: 97%

Linking inherent O-Linked Protein Glycosylation of YghJ to Increased Antigen Potential

Thorsing¹,

Krogh²,

Vitved

et al. 2021

Front. Cell. Infect. Microbiol.

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“…Although previous studies showed that Akkermansia muciniphila modulates pathways involved in intestinal integrity, basal metabolism and intestinal immunity [ 50 ], our results indicated Akkermansia may reduce the gene expression of the tight junction protein and the level of immunoglobulin resulting in increased intestinal permeability and weakened immune system, which was consistent with the results of sequencing data. Escherichia-Shigella and Bacteroides aggravated the impairment of the gut barrier and bacterial translocation by producing LPS [ 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

Structural and quantitative alterations of gut microbiota in experimental small bowel obstruction

Gao

Zhang

et al. 2021

PLoS ONE

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Objective To investigate structural and quantitative alterations of gut microbiota in an experimental model of small bowel obstruction. Method A rat model of small bowel obstruction was established by using a polyvinyl chloride ring surgically placed surrounding the terminal ileum. The alterations of gut microbiota were studied after intestinal obstruction. Intraluminal fecal samples proximal to the obstruction were collected at different time points (24, 48 and 72 hours after obstruction) and analyzed by 16s rDNA high-throughput sequencing technology and quantitative PCR (qPCR) for target bacterial groups. Furthermore, intestinal claudin-1 mRNA expression was examined by real-time polymerase chain reaction analysis, and serum sIgA, IFABP and TFF3 levels were determined by enzyme-linked immunosorbent assay. Results Small bowel obstruction led to significant bacterial overgrowth and profound alterations in gut microbiota composition and diversity. At the phylum level, the 16S rDNA sequences showed a marked decrease in the relative abundance of Firmicutes and increased abundance of Proteobacteria, Verrucomicrobia and Bacteroidetes. The qPCR analysis showed the absolute quantity of total bacteria increased significantly within 24 hours but did not change distinctly from 24 to 72 hours. Further indicators of intestinal mucosa damage and were observed as claudin-1 gene expression, sIgA and TFF3 levels decreased and IFABP level increased with prolonged obstruction. Conclusion Small bowel obstruction can cause significant structural and quantitative alterations of gut microbiota and induce disruption of gut mucosa barrier.

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“…One builds on the PSSP1 antigen strategy in that it involves the unmasking of surface antigens such as PSSP1 on the whole cell by limiting the length of polysaccharide chains synthesized to a single repeating unit. This is the Shigella Truncated Mutant (STM), which utilizes genetically modified (Δwzy) inactivated bacteria retaining only one repeating unit of O antigen chain on the bacterial surface [ 48 ]. The other candidate, ShigETEC, is attenuated by the deletion of the T3SS and is engineered to not express any LPS-O antigens through a targeted deletion of the rfbF gene [ 49 , 50 , 51 ].…”

Section: Shigella Componentmentioning

confidence: 99%

“…A third platform at an earlier stage of development than the previous two is the Shigella truncated mutant (STM) comprised of inactivated Shigella mutants with O-polysaccharide chains truncated to one repeating unit in length [ 48 ]. This, like the ShigETEC, enhances the immunological accessibility of conserved and protective Shigella outer membrane proteins such as PSSP-1 [ 46 ], and may also be a benefit to vectored antigens.…”

Section: Multi-pathogen Strategiesmentioning

confidence: 99%

Vaccines for Protecting Infants from Bacterial Causes of Diarrheal Disease

et al. 2021

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The global diarrheal disease burden for Shigella, enterotoxigenic Escherichia coli (ETEC), and Campylobacter is estimated to be 88M, 75M, and 75M cases annually, respectively. A vaccine against this target trio of enteric pathogens could address about one-third of diarrhea cases in children. All three of these pathogens contribute to growth stunting and have demonstrated increasing resistance to antimicrobial agents. Several combinations of antigens are now recognized that could be effective for inducing protective immunity against each of the three target pathogens in a single vaccine for oral administration or parenteral injection. The vaccine combinations proposed here would result in a final product consistent with the World Health Organization’s (WHO) preferred product characteristics for ETEC and Shigella vaccines, and improve the vaccine prospects for support from Gavi, the Vaccine Alliance, and widespread uptake by low- and middle-income countries’ (LMIC) public health stakeholders. Broadly protective antigens will enable multi-pathogen vaccines to be efficiently developed and cost-effective. This review describes how emerging discoveries for each pathogen component of the target trio could be used to make vaccines, which could help reduce a major cause of poor health, reduced cognitive development, lost economic productivity, and poverty in many parts of the world.

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Cross-Protective Shigella Whole-Cell Vaccine With a Truncated O-Polysaccharide Chain

Cited by 25 publications

References 47 publications

Linking inherent O-Linked Protein Glycosylation of YghJ to Increased Antigen Potential

Linking inherent O-Linked Protein Glycosylation of YghJ to Increased Antigen Potential

Structural and quantitative alterations of gut microbiota in experimental small bowel obstruction

Vaccines for Protecting Infants from Bacterial Causes of Diarrheal Disease

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