An engineered Lactococcus lactis strain exerts significant immune responses through efficient expression and delivery of Helicobacter pylori Lpp20 antigen

Zhang, Rongguang; Peng, Xiaoyan; Shi, Qingfeng; Chen, Shuaiyin; Wang, Chen; Fan, Qi-Wen; Xi, Yang

doi:10.1007/s10529-016-2209-x

Cited by 14 publications

(5 citation statements)

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“…The expression products were identified by electrophoresis and western blotting assays using mouse anti- H. pylori antisera as the detector antibody as reported previously 35 .…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, L. lactis dose not colonize the digestive tract, and thus less probably leads to tolerance towards the delivered immunogens, compared with human commensal bacteria 32 . To date, studies have used L. lactis to produce H. pylori antigens like UreB, Cag7 and NapA, resulting in immune efficacy from no protection to reduced bacterial colonization in mice 33 – 35 . Besides, certain L. lactis strains isolated from the environment were proved capable of promoting Th1 bias immune response, and show allergy-protective in mice 36 , 37 .…”

Section: Introductionmentioning

confidence: 99%

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Production and delivery of Helicobacter pylori NapA in Lactococcus lactis and its protective efficacy and immune modulatory activity

Peng

Zhang

Wang

et al. 2018

Sci Rep

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Helicobacter pylori neutrophil-activating protein A subunit (NapA) has been identified as a virulence factor, a protective antigen and a potent immunomodulator. NapA shows unique application potentials for anti-H. pylori vaccines and treatment strategies of certain allergic diseases and carcinomas. However, appropriate production and utilization modes of NapA still remain uncertain to date. This work has established a novel efficient production and utilization mode of NapA by using L. lactis as an expression host and delivery vector, and demonstrated immune protective efficacy and immune modulatory activity of the engineered L. lactis by oral vaccination of mice. It was observed for the first time that H. pylori NapA promotes both polarized Th17 and Th1 responses, which may greatly affect the clinical application of NapA. This report offers a promising anti-H. pylori oral vaccine candidate and a potent mucosal immune modulatory agent. Meanwhile, it uncovers a way to produce and deliver the oral vaccine and immunomodulator by fermentation of food like milk, which might have striking effects on control of H. pylori infection, gastrointestinal cancers, and Th2 bias allergic diseases, including many food allergies.

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“…The expression products were identified by electrophoresis and western blotting assays using mouse anti- H. pylori antisera as the detector antibody as reported previously 35 .…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Production and delivery of Helicobacter pylori NapA in Lactococcus lactis and its protective efficacy and immune modulatory activity

Peng

Zhang

Wang

et al. 2018

Sci Rep

Self Cite

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“…Similar to our own study, L. lactis expressing an unguided AMP has been used to treat H. pylori infection in mice ( 43 , 54 ). In contrast to our study, repeated probiotic administrations (10 10 CFU per dose) were used over a period of a month, and this resulted in only a reduction ( 55 ) rather than the elimination of H. pylori seen in our study, which needed only a single dose of engineered probiotic comprising only 10 7 CFU. Perhaps the increased control seen in our study was due to our use of the acid-inducible P1 promoter rather than the nisin-inducible system utilized ( 43 , 54 ).…”

Section: Discussionmentioning

confidence: 62%

Control of Helicobacter pylori with engineered probiotics secreting selective guided antimicrobial peptides

Choudhury,

Ortiz,

Young

et al. 2023

Microbiol Spectr

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Helicobacter pylori is the primary cause of 78% of gastric cancer cases, providing an opportunity to prevent cancer by controlling a single bacterial pathogen within the complex gastric microbiota. We developed highly selective antimicrobial agents against H. pylori by fusing an H. pylori -binding guide peptide (MM1) to broad-spectrum antimicrobial peptides. The common dairy probiotic Lactococcus lactis was then engineered to secrete these guided antimicrobial peptides (gAMPs). When co-cultured in vitro with H. pylori , the gAMP probiotics lost no toxicity compared to unguided AMP probiotics against the target, H. pylori , while losing >90% of their toxicity against two tested off-target bacteria. To test binding to H. pylori , the MM1 guide was fused to green fluorescent protein (GFP), resulting in enhanced binding compared to unguided GFP as measured by flow cytometry. In contrast, MM1-GFP showed no increased binding over GFP against five different off-target bacteria. These highly selective gAMP probiotics were then tested by oral gavage in mice infected with H. pylori . As a therapy, the probiotics outperformed antibiotic treatment, effectively eliminating H. pylori in just 5 days, and also protected mice from challenge infection as a prophylactic. As expected, the gAMP probiotics were as toxic against H. pylori as the unguided AMP probiotics. However, a strong rebound in gastric species diversity was found with both the selective gAMP probiotics and the non-selective AMP probiotics. Eliminating the extreme microbial dysbiosis caused by H. pylori appeared to be the major factor in diversity recovery. IMPORTANCE Alternatives to antibiotics in the control of Helicobacter pylori and the prevention of gastric cancer are needed. The high prevalence of H. pylori in the human population, the induction of microbial dysbiosis by antibiotics, and increasing antibiotic resistance call for a more sustainable approach. By selectively eliminating the pathogen and retaining the commensal community, H. pylori control may be achieved without adverse health outcomes. Antibiotics are typically used as a therapeutic post-infection, but a more targeted, less disruptive approach could be used as a long-term prophylactic against H. pylori or, by extension, against other gastrointestinal pathogens. Furthermore, the modular nature of the guided antimicrobial peptide (gAMP) technology allows for the substitution of different guides for different pathogens and the use of a cocktail of gAMPs to avoid the development of pathogen resistance.

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“…49,50 Several different adjuvants were used in the published studies, but as in previous years, the most common was cholera toxin B subunit. 44,45,49,51 Bacteria expressing H. pylori antigens, including Lactococcus lactis, 48,51,52 Vibrio cholerae, 46 and Bacillus subtilis, 44 were tested as recombinant vaccine vehicles. Oral administration of the vaccine was most common, but one study showed a stronger cellular immune response to H. pylori vaccine administered via the sublingual route.…”

Section: Immunization and Vaccinesmentioning

confidence: 99%

Helicobacter: Inflammation, immunology and vaccines

2017

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Helicobacter pylori is usually acquired in early childhood and the infection persists lifelong without causing symptoms. In a small of cases, the infection leads to gastric or duodenal ulcer disease, or gastric cancer. Why disease occurs in these individuals remains unclear, however the host response is known to play a very important part. Understanding the mechanisms involved in maintaining control over the immune and inflammatory response is therefore extremely important. Vaccines against H. pylori have remained elusive but are desperately needed for the prevention of gastric carcinogenesis. This review focuses on research findings which may prove useful in the development of prognostic tests for gastric cancer development, therapeutic agents to control immunopathology, and effective vaccines.

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An engineered Lactococcus lactis strain exerts significant immune responses through efficient expression and delivery of Helicobacter pylori Lpp20 antigen

Abstract: This report presents the first efficient expression and delivery of whole Lpp20 protein to the immunization sites by using L. lactis, demonstrating an efficient utilization mode of Lpp20 in anti-H. pylori vaccination.

Cited by 14 publications

References 14 publications

Production and delivery of Helicobacter pylori NapA in Lactococcus lactis and its protective efficacy and immune modulatory activity

Production and delivery of Helicobacter pylori NapA in Lactococcus lactis and its protective efficacy and immune modulatory activity

Control of Helicobacter pylori with engineered probiotics secreting selective guided antimicrobial peptides

Helicobacter: Inflammation, immunology and vaccines

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