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1
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Bousbaine D, Bauman KD, Chen YE, Lalgudi PV, Nguyen TTD, Swenson JM, Yu VK, Tsang E, Conlan S, Li DB, Jbara A, Zhao A, Naziripour A, Veinbachs A, Lee YE, Phung JL, Dimas A, Jain S, Meng X, Pham TPT, McLaughlin MI, Barkal LJ, Gribonika I, Van Rompay KKA, Kong HH, Segre JA, Belkaid Y, Barnes CO, Fischbach MA. Discovery and engineering of the antibody response to a prominent skin commensal. Nature 2025; 638:1054-1064. [PMID: 39662508 PMCID: PMC12045117 DOI: 10.1038/s41586-024-08489-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 12/04/2024] [Indexed: 12/13/2024]
Abstract
The ubiquitous skin colonist Staphylococcus epidermidis elicits a CD8+ T cell response pre-emptively, in the absence of an infection1. However, the scope and purpose of this anticommensal immune programme are not well defined, limiting our ability to harness it therapeutically. Here, we show that this colonist also induces a potent, durable and specific antibody response that is conserved in humans and non-human primates. A series of S. epidermidis cell-wall mutants revealed that the cell surface protein Aap is a predominant target. By colonizing mice with a strain of S. epidermidis in which the parallel β-helix domain of Aap is replaced by tetanus toxin fragment C, we elicit a potent neutralizing antibody response that protects mice against a lethal challenge. A similar strain of S. epidermidis expressing an Aap-SpyCatcher chimera can be conjugated with recombinant immunogens; the resulting labelled commensal elicits high antibody titres under conditions of physiologic colonization, including a robust IgA response in the nasal and pulmonary mucosa. Thus, immunity to a common skin colonist involves a coordinated T and B cell response, the latter of which can be redirected against pathogens as a new form of topical vaccination.
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Affiliation(s)
- Djenet Bousbaine
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- ChEM-H Institute, Stanford University, Stanford, CA, USA
| | - Katherine D Bauman
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- ChEM-H Institute, Stanford University, Stanford, CA, USA
| | - Y Erin Chen
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- ChEM-H Institute, Stanford University, Stanford, CA, USA
| | - Pranav V Lalgudi
- ChEM-H Institute, Stanford University, Stanford, CA, USA
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Tam T D Nguyen
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- ChEM-H Institute, Stanford University, Stanford, CA, USA
| | - Joyce M Swenson
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- ChEM-H Institute, Stanford University, Stanford, CA, USA
| | - Victor K Yu
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- ChEM-H Institute, Stanford University, Stanford, CA, USA
| | - Eunice Tsang
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- ChEM-H Institute, Stanford University, Stanford, CA, USA
| | - Sean Conlan
- Microbial Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - David B Li
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- ChEM-H Institute, Stanford University, Stanford, CA, USA
| | - Amina Jbara
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- ChEM-H Institute, Stanford University, Stanford, CA, USA
| | - Aishan Zhao
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- ChEM-H Institute, Stanford University, Stanford, CA, USA
| | - Arash Naziripour
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- ChEM-H Institute, Stanford University, Stanford, CA, USA
| | - Alessandra Veinbachs
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- ChEM-H Institute, Stanford University, Stanford, CA, USA
| | - Yu E Lee
- ChEM-H Institute, Stanford University, Stanford, CA, USA
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Jennie L Phung
- ChEM-H Institute, Stanford University, Stanford, CA, USA
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Alex Dimas
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- ChEM-H Institute, Stanford University, Stanford, CA, USA
| | - Sunit Jain
- Chan Zuckerberg Biohub, Stanford, CA, USA
| | - Xiandong Meng
- ChEM-H Institute, Stanford University, Stanford, CA, USA
| | - Thi Phuong Thao Pham
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- ChEM-H Institute, Stanford University, Stanford, CA, USA
| | - Martin I McLaughlin
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- ChEM-H Institute, Stanford University, Stanford, CA, USA
| | - Layla J Barkal
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- ChEM-H Institute, Stanford University, Stanford, CA, USA
- Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Inta Gribonika
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- NIAID Microbiome Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
| | - Koen K A Van Rompay
- California National Primate Research Center, University of California, Davis, CA, USA
- Department of Pathology, Microbiology, and Immunology, University of California, Davis, CA, USA
| | - Heidi H Kong
- Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Julia A Segre
- Microbial Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Yasmine Belkaid
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- NIAID Microbiome Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
| | - Christopher O Barnes
- ChEM-H Institute, Stanford University, Stanford, CA, USA
- Department of Biology, Stanford University, Stanford, CA, USA
- Chan Zuckerberg Biohub, Stanford, CA, USA
| | - Michael A Fischbach
- Department of Bioengineering, Stanford University, Stanford, CA, USA.
- ChEM-H Institute, Stanford University, Stanford, CA, USA.
- Chan Zuckerberg Biohub, Stanford, CA, USA.
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2
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Haghighi FH, Farsiani H. Is Lactococcus lactis a Suitable Candidate for Use as a Vaccine Delivery System Against Helicobacter pylori? Curr Microbiol 2024; 82:30. [PMID: 39643816 DOI: 10.1007/s00284-024-03994-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 11/15/2024] [Indexed: 12/09/2024]
Abstract
Helicobacter pylori was described in 1979. This bacterium, which thrives in the harsh conditions of the stomach, is typically acquired during childhood and can remain colonized for life. Approximately, 90% of the global population is affected, and H. pylori is linked to various conditions, including gastritis, peptic ulcers, lymphoproliferative gastric lymphoma, and even gastric cancer. Currently, antibiotics are the primary treatment method, but the associated challenges of antibiotic use have led to the consideration of oral vaccination as a viable preventive measure against this infection. However, the stomach's harsh environment characterized by its acidic conditions and numerous proteolytic enzymes poses significant obstacles to the development and effectiveness of oral vaccines. To address these challenges, researchers have proposed and evaluated several delivery systems. One of the most promising options is the use of probiotics. Among the various probiotics, Lactococcus lactis stands out as a suitable candidate for oral vaccine delivery against H. pylori due to the advancements in genetic engineering that have been applied to it. This review article discusses the limitations of current treatment strategies and rationalizes the shift toward vaccination, particularly oral vaccination for this infection. It also explores the advantages and challenges of using probiotic bacteria, with a focus on L. lactis as a delivery system. Ultimately, despite the existing challenges, L. lactis continues to be recognized as a promising delivery system. Nonetheless, further research is essential to fully assess its effectiveness and address the challenges associated with this approach.
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Affiliation(s)
- Faria Hasanzadeh Haghighi
- Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hadi Farsiani
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Azadi-Square, Medical Campus, Mashhad, 9177948564, Iran.
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3
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Bousbaine D, Bauman KD, Chen YE, Yu VK, Lalgudi PV, Naziripour A, Veinbachs A, Phung JL, Nguyen TTD, Swenson JM, Lee YE, Dimas A, Jain S, Meng X, Pham TPT, Zhao A, Barkal L, Gribonika I, Van Rompay KKA, Belkaid Y, Barnes CO, Fischbach MA. Discovery and engineering of the antibody response against a prominent skin commensal. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.23.576900. [PMID: 38328052 PMCID: PMC10849572 DOI: 10.1101/2024.01.23.576900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
The ubiquitous skin colonist Staphylococcus epidermidis elicits a CD8 + T cell response pre-emptively, in the absence of an infection 1 . However, the scope and purpose of this anti-commensal immune program are not well defined, limiting our ability to harness it therapeutically. Here, we show that this colonist also induces a potent, durable, and specific antibody response that is conserved in humans and non-human primates. A series of S. epidermidis cell-wall mutants revealed that the cell surface protein Aap is a predominant target. By colonizing mice with a strain of S. epidermidis in which the parallel β-helix domain of Aap is replaced by tetanus toxin fragment C, we elicit a potent neutralizing antibody response that protects mice against a lethal challenge. A similar strain of S. epidermidis expressing an Aap-SpyCatcher chimera can be conjugated with recombinant immunogens; the resulting labeled commensal elicits high titers of antibody under conditions of physiologic colonization, including a robust IgA response in the nasal mucosa. Thus, immunity to a common skin colonist involves a coordinated T and B cell response, the latter of which can be redirected against pathogens as a novel form of topical vaccination.
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Lin Z, Tang Y, Chen Z, Li S, Xu X, Hou X, Chen Z, Wen J, Zeng W, Meng X, Fan H. Soluble CD80 oral delivery by recombinant Lactococcus suppresses tumor growth by enhancing antitumor immunity. Bioeng Transl Med 2023; 8:e10533. [PMID: 37476068 PMCID: PMC10354755 DOI: 10.1002/btm2.10533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 04/04/2023] [Accepted: 04/12/2023] [Indexed: 07/22/2023] Open
Abstract
CD80 is an important co-stimulatory molecule that participates in the immune response. Soluble CD80 can induce T cell activation and overcome PDL1-mediated immune suppression. In this study, we aimed to construct recombinant Lactococcus lactis for oral delivery of the soluble CD80 (hsCD80) protein or the fusion protein containing the cholera toxin B subunit (CTB) and hsCD80 (CTB-hsCD80) under the control of the nisin-inducible expression system. The recombinant L. lactis expressed and secreted hsCD80 or CTB-hsCD80 fusion proteins after induction by nisin in vitro and in the enteric cavity. Additionally, the CTB-hsCD80 fusion protein showed uptake by intestinal epithelial cells, was cleaved by the furin protease, and was released as free hsCD80 protein into the blood circulation. Orally administered hsCD80 and CTB-hsCD80 containing L. lactis increased the proportion of activated T cells in the spleen and intestinal epithelium, inhibited tumor growth, and prolonged the survival of tumor-bearing mice. The hsCD80-containing L. lactis showed greater therapeutic effects on primary colonic adenoma in APCmin/- mice and completely suppressed tumor growth. Further, recombinant CTB-hsCD80 in L. lactis was more efficient than hsCD80-containing bacteria in inhibiting the growth of xenografted colon cancer and melanoma cells. hsCD80 engineered probiotics may serve as a promising new approach for antitumor immunotherapy, especially for colorectal cancer.
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Affiliation(s)
- Ziqing Lin
- Department of Cell Biology, School of Basic MedicineSouthern Medical UniversityGuangzhouChina
- Guangzhou Virotech Phamaceutical Co., LtdGuangzhouChina
| | - Yanqing Tang
- Department of Cell Biology, School of Basic MedicineSouthern Medical UniversityGuangzhouChina
| | - Zerong Chen
- Department of Cell Biology, School of Basic MedicineSouthern Medical UniversityGuangzhouChina
- Department of Urology, Nanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Simin Li
- Department of Cell Biology, School of Basic MedicineSouthern Medical UniversityGuangzhouChina
| | - Xueyan Xu
- Department of Cell Biology, School of Basic MedicineSouthern Medical UniversityGuangzhouChina
- Department of Dermatology, Dermatology Hospital of Southern Medical UniversitySouthern Medical UniversityGuangzhouChina
| | - Xufeng Hou
- Department of Cell Biology, School of Basic MedicineSouthern Medical UniversityGuangzhouChina
| | - Zhenhui Chen
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Junjie Wen
- Guangzhou Weisengene Biological Technology Co., Ltd.GuangzhouChina
| | - Weisen Zeng
- Department of Cell Biology, School of Basic MedicineSouthern Medical UniversityGuangzhouChina
| | - Xiaojing Meng
- Department of Occupational Health and Occupational Medicine, School of Public HealthSouthern Medical UniversityGuangzhouGuangdongChina
| | - Hongying Fan
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public HealthSouthern Medical UniversityGuangzhouChina
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Immunomodulatory action of Lactococcuslactis. J Biosci Bioeng 2023; 135:1-9. [PMID: 36428209 DOI: 10.1016/j.jbiosc.2022.10.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 09/07/2022] [Accepted: 10/24/2022] [Indexed: 11/24/2022]
Abstract
Fermented foods are gaining popularity due to health-promoting properties with high levels of nutrients, phytochemicals, bioactive compounds, and probiotic microorganisms. Due to its unique fermentation process, Lactococcus lactis plays a key role in the food business, notably in the manufacturing of dairy products. The superior biological activities of L. lactis in these functional foods include anti-inflammatory and immunomodulatory capabilities. L. lactis boosted growth performance, controlled amino acid profiles, intestinal immunology, and microbiota. Besides that, the administration of L. lactis increased the rate of infection clearance. Innate and acquired immune responses would be upregulated in both local and systemic compartments, resulting in these consequences. L. lactis is often employed in the food sector and is currently being exploited as a delivery vehicle for biological research. These bacteria are being eyed as potential candidates for biotechnological applications. With this in mind, we reviewed the immunomodulatory effects of different L. lactis strains.
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Tetanus Toxin Fragment C: Structure, Drug Discovery Research and Production. Pharmaceuticals (Basel) 2022; 15:ph15060756. [PMID: 35745675 PMCID: PMC9227095 DOI: 10.3390/ph15060756] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/09/2022] [Accepted: 06/13/2022] [Indexed: 12/05/2022] Open
Abstract
Tetanus toxoid (TTd) plays an important role in the pharmaceutical world, especially in vaccines. The toxoid is obtained after formaldehyde treatment of the tetanus toxin. In parallel, current emphasis in the drug discovery field is put on producing well-defined and safer drugs, explaining the interest in finding new alternative proteins. The tetanus toxin fragment C (TTFC) has been extensively studied both as a neuroprotective agent for central nervous system disorders owing to its neuronal properties and as a carrier protein in vaccines. Indeed, it is derived from a part of the tetanus toxin and, as such, retains its immunogenic properties without being toxic. Moreover, this fragment has been well characterized, and its entire structure is known. Here, we propose a systematic review of TTFC by providing information about its structural features, its properties and its methods of production. We also describe the large uses of TTFC in the field of drug discovery. TTFC can therefore be considered as an attractive alternative to TTd and remarkably offers a wide range of uses, including as a carrier, delivery vector, conjugate, booster, inducer, and neuroprotector.
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Gorain C, Khan A, Singh A, Mondal S, Mallick AI. Bioengineering of LAB vector expressing Haemolysin co-regulated protein (Hcp): a strategic approach to control gut colonization of Campylobacter jejuni in a murine model. Gut Pathog 2021; 13:48. [PMID: 34330327 PMCID: PMC8323230 DOI: 10.1186/s13099-021-00444-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 07/20/2021] [Indexed: 01/02/2023] Open
Abstract
Background Campylobacter jejuni (C. jejuni) is accountable for more than 400 million cases of gastroenteritis each year and is listed as a high-priority gut pathogen by the World Health Organization (WHO). Although the acute infection of C. jejuni (campylobacteriosis) is commonly treated with macrolides and fluoroquinolones, the emergence of antibiotic resistance among C. jejuni warrants the need for an alternative approach to control campylobacteriosis in humans. To this end, vaccines remain a safe, effective, and widely accepted strategy for controlling emerging and re-emerging infectious diseases. In search of a suitable vaccine against campylobacteriosis, recently, we demonstrated the potential of recombinant Haemolysin co-regulated protein (Hcp) of C. jejuni Type VI secretion system (T6SS) in imparting significant immune-protection against cecal colonization of C. jejuni; however, in the avian model. Since clinical features of human campylobacteriosis are more complicated than the avians, we explored the potential of Hcp as a T6SS targeted vaccine in a murine model as a more reliable and reproducible experimental host to study vaccine-induced immune-protection against C. jejuni. Because C. jejuni primarily utilizes the mucosal route for host pathogenesis, we analyzed the immunogenicity of a mucosally deliverable bioengineered Lactic acid bacteria (LAB), Lactococcus lactis (L. lactis), expressing Hcp. Considering the role of Hcp in both structural (membrane-bound) and functional (effector protein) exhibition of C. jejuni T6SS, a head-to-head comparison of two different forms of recombinant LAB vectors (cell wall anchored and secreted form of Hcp) were tested and assessed for the immune phenotypes of each modality in BALB/c mice. Results We show that regardless of the Hcp protein localization, mucosal delivery of bioengineered LAB vector expressing Hcp induced high-level production of antigen-specific neutralizing antibody (sIgA) in the gut with the potential to reduce the cecal load of C. jejuni in mice. Conclusion Together with the non-commensal nature of L. lactis, short gut transit time in humans, and the ability to express the heterologous protein in the gut, the present study highlights the benefits of bioengineered LAB vectors based mucosal vaccine modality against C. jejuni without the risk of immunotolerance. Supplementary Information The online version contains supplementary material available at 10.1186/s13099-021-00444-2.
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Affiliation(s)
- Chandan Gorain
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, Nadia, West Bengal, 741246, India
| | - Afruja Khan
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, Nadia, West Bengal, 741246, India
| | - Ankita Singh
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, Nadia, West Bengal, 741246, India
| | - Samiran Mondal
- Department of Veterinary Pathology, West Bengal University of Animal and Fishery Sciences, Belgachia, Kolkata, West Bengal, 700037, India
| | - Amirul Islam Mallick
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, Nadia, West Bengal, 741246, India.
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Mu Y, Xin Y, Guo T, Kong J. Identification and characterization of a moonlighting protein-enolase for surface display in Streptococcus thermophilus. Microb Cell Fact 2020; 19:132. [PMID: 32552809 PMCID: PMC7301973 DOI: 10.1186/s12934-020-01389-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 06/11/2020] [Indexed: 01/01/2023] Open
Abstract
Background Streptococcus thermophilus is an important food starter and receiving more attention to serve as cell factories for production of high-valued metabolites. However, the low yields of intracellular or extracellular expression of biotechnological and biomedical proteins limit its practical applications. Results Here, an enolase EnoM was identified from S. thermophilus CGMCC7.179 with about 94% identities to the surface-located enolases from other Streptococcus spp. strains. The EnoM was used as an anchor to achieve surface display in S. thermophilus using GFP as a reporter. After respectively mixing the GFP-EnoM fusion protein or GFP with S. thermophilus cells in vitro, the relative fluorescence units (RFU) of the S. thermophilus cells with GFP-EnoM was 80-folds higher than that with purified GFP. The sharp decrease in the RFU of sodium dodecyl sulfate (SDS) pretreated cells compared to those of non-pretreated cells demonstrated that the membrane proteins were the binding ligand of EnoM. Furthermore, an engineered β-galactosidase (β-Gal) was also successfully displayed on the cell surface of S. thermophilus CGMCC7.179 and the relative activity of the immobilized β-Gal remained up to 64% after reused 8 times. Finally, we also demonstrated that EnoM could be used as an anchor for surface display in L. casei, L. bulgaricus, L. lactis and Leuconostoc lactis. Conclusion To our knowledge, EnoM from S. thermophilus was firstly identified as an anchor and successfully achieved surface display in LAB. The EnoM-based surface display system provided a novel strategy for the enzyme immobilization.
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Affiliation(s)
- Yingli Mu
- State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Dadao, Qingdao, 266237, People's Republic of China
| | - Yongping Xin
- State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Dadao, Qingdao, 266237, People's Republic of China
| | - Tingting Guo
- State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Dadao, Qingdao, 266237, People's Republic of China
| | - Jian Kong
- State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Dadao, Qingdao, 266237, People's Republic of China.
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Liu C, Luo J, Xue RY, Guo L, Nie L, Li S, Ji L, Ma CJ, Chen DQ, Miao K, Zou QM, Li HB. The mucosal adjuvant effect of plant polysaccharides for induction of protective immunity against Helicobacter pylori infection. Vaccine 2019; 37:1053-1061. [DOI: 10.1016/j.vaccine.2018.12.066] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 12/22/2018] [Accepted: 12/31/2018] [Indexed: 12/26/2022]
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10
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Torkashvand A, Bahrami F, Adib M, Ajdary S. Mucosal and systemic immune responses elicited by recombinant Lactococcus lactis expressing a fusion protein composed of pertussis toxin and filamentous hemagglutinin from Bordetella pertussis. Microb Pathog 2018; 120:155-160. [PMID: 29738814 PMCID: PMC7125623 DOI: 10.1016/j.micpath.2018.05.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 05/03/2018] [Accepted: 05/04/2018] [Indexed: 01/30/2023]
Abstract
We constructed a food-grade expression system harboring a F1S1 fusion protein of Bordetella pertussis to be produced in Lactococcus lactis NZ3900 as a new oral vaccine model against whooping cough, caused by B. pertussis. F1S1 was composed of N-terminally truncated S1 subunit of pertussis toxin and type I immunodominant domain of filamentous hemagglutinin which are both known as protective immunogens against pertussis. The recombinant L. lactis was administered via oral or intranasal routes to BALB/c mice and the related specific systemic and mucosal immune responses were then evaluated. The results indicated significantly higher levels of specific IgA in the lung extracts and IgG in sera of mucosally-immunized mice, compared to their controls. It was revealed that higher levels of IgG2a, compared to IgG1, were produced in all mucosally-immunized mice. Moreover, immunized mice developed Th1 responses with high levels of IFN-γ production by the spleen cells. These findings provide evidence for L. lactis to be used as a suitable vehicle for expression and delivery of F1S1 fusion protein to mucosa and induction of appropriate systemic and mucosal immune responses against pertussis.
Lactococcus lactis was used for expression of fusion protein from Bordetella pertussis. BALB/c mice were immunized via oral or intranasal routes with recombinant L. lactis. Strong mucosal and Th1 systemic immune responses were developed. L. lactis is a suitable vehicle for expression and delivery of B. pertussis fusion protein.
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Affiliation(s)
- Ali Torkashvand
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Islamic Republic of Iran
| | - Fariborz Bahrami
- Department of Immunology, Pasteur Institute of Iran, 69 Pasteur Ave., Tehran, 13169-43551, Islamic Republic of Iran
| | - Minoo Adib
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Islamic Republic of Iran
| | - Soheila Ajdary
- Department of Immunology, Pasteur Institute of Iran, 69 Pasteur Ave., Tehran, 13169-43551, Islamic Republic of Iran.
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Liu M, Li S, Zhang Q, Xu Z, Wang J, Sun H. Oral engineered Bifidobacterium longum expressing rhMnSOD to suppress experimental colitis. Int Immunopharmacol 2018; 57:25-32. [PMID: 29455070 DOI: 10.1016/j.intimp.2018.02.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 01/22/2018] [Accepted: 02/09/2018] [Indexed: 12/13/2022]
Abstract
In recent years, using genetic engineering and bioengineering techniques, Bifidobacterium as a carrier to express specific functions of the protein or polypeptide, has become a new treatment for disease. Ulcerative colitis (UC) is a type of inflammatory bowel diseases (IBD). Although the cause of this inflammatory disorder is still unknown, a large amount of evidence suggests that ulcerative colitis is associated with increased activity of reactive oxygen species (ROS), manganese superoxide dismutase (MnSOD) is a kind of superoxide dismutase (SOD) has been demonstrated to play a key role in the pathophysiology of colitis. Here, we explored the Bifidobacterium as a drug delivery system to orally deliver a potent anti-inflammatory but poor penetration and stability antioxidant enzymes human MnSOD, transported into cells by a penetratin PEP-1. We constructed an expression vector expressing PEP-1-hMnSOD fusion protein, and successfully expressed hMnSOD fusion protein in engineered Bifidobacterium. Then we identified the bioactivity of engineered Bifidobacterium in LPS-induced inflammatory cell model. Finally, we used Bifidobacterium expressing PEP-1-hMnSOD fusion protein against DSS-induced ulcerative colitis mice. B. longum-PEP-1-rhMnSOD can successfully express rhMnSOD in the colon. We found that levels of inflammatory cytokines TNF-α, IL-1β, IL-6 and IL-8 as well as histological damage in colonic tissues showed that engineered Bifidobacterium effectively reduced dextran sulfate sodium(DSS)-induced ulcerative colitis, we also tested the MPO, verified the above conclusions. These results suggest that oral Bifidobacterium expressing PEP-1-hMnSOD fusion protein can be treated as a new method of UC treatment.
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Affiliation(s)
- Mengge Liu
- Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Shiyu Li
- Genetic Engineering Research Institute, Southern Medical University, Guangzhou 510515, China
| | - Qian Zhang
- Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Zhenrui Xu
- Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Jiajia Wang
- Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Hanxiao Sun
- Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou 510632, China.
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13
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Azizpour M, Hosseini SD, Jafari P, Akbary N. Lactococcus lactis : A New Strategy for Vaccination. Avicenna J Med Biotechnol 2017; 9:163-168. [PMID: 29090064 PMCID: PMC5650732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 12/05/2016] [Indexed: 11/16/2022] Open
Abstract
Needle free vaccines have a several advantages and very attractive way for vaccination. In a body, mucosal surfaces provide a universal entry portal for all the known and emerging infectious pathogenic microbes. Therefore, it seems, vaccination strategies need to be reorganized for vaccines that are hindering the entry capability of pathogenic microbes through mucosal surfaces. Lactic acid Bacteria (LAB) are widely used in the food industry and at the present, used as delivery vehicles for biological investigations. In this review, we summarized the Results of several studies which Lactococcus lactis (L. lactis) used as a live vector for vaccines. These bacteria are considered as promising candidates for heterologous expression of proteins and biotechnological usage. LAB are considered as promising candidates for heterologous expression of proteins and biotechnological usage. The results showed that these bacteria have an ability to deliver antigen to immune system. Therefore, developing mucosal live vaccines using lactic acid bacterium, L. lactis, as an antigen delivery vector, is an attractive alternative choice and a safer vaccination strategy against pathogens.
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Affiliation(s)
- Maryam Azizpour
- Department of Microbiology, Arak branch, Islamic Azad University, Arak, Iran
| | | | - Parvaneh Jafari
- Department of Microbiology, Islamic Azad University, Arak Branch, Arak, Iran
| | - Neda Akbary
- Department of Microbiology, Islamic Azad University, Arak Branch, Arak, Iran
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Low antigen dose formulated in CAF09 adjuvant Favours a cytotoxic T-cell response following intraperitoneal immunization in Göttingen minipigs. Vaccine 2017; 35:5629-5636. [DOI: 10.1016/j.vaccine.2017.08.057] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 08/14/2017] [Accepted: 08/19/2017] [Indexed: 12/18/2022]
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Michon C, Langella P, Eijsink VGH, Mathiesen G, Chatel JM. Display of recombinant proteins at the surface of lactic acid bacteria: strategies and applications. Microb Cell Fact 2016; 15:70. [PMID: 27142045 PMCID: PMC4855500 DOI: 10.1186/s12934-016-0468-9] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 04/21/2016] [Indexed: 01/07/2023] Open
Abstract
Lactic acid bacteria (LAB) are promising vectors of choice to deliver active molecules to mucosal tissues. They are recognized as safe by the World Health Organization and some strains have probiotic properties. The wide range of potential applications of LAB-driven mucosal delivery includes control of inflammatory bowel disease, vaccine delivery, and management of auto-immune diseases. Because of this potential, strategies for the display of proteins at the surface of LAB are gaining interest. To display a protein at the surface of LAB, a signal peptide and an anchor domain are necessary. The recombinant protein can be attached to the membrane layer, using a transmembrane anchor or a lipoprotein-anchor, or to the cell wall, by a covalent link using sortase mediated anchoring via the LPXTG motif, or by non-covalent liaisons employing binding domains such as LysM or WxL. Both the stability and functionality of the displayed proteins will be affected by the kind of anchor used. The most commonly surfaced exposed recombinant proteins produced in LAB are antigens and antibodies and the most commonly used LAB are lactococci and lactobacilli. Although it is not necessarily so that surface-display is the preferred localization in all cases, it has been shown that for certain applications, such as delivery of the human papillomavirus E7 antigen, surface-display elicits better biological responses, compared to cytosolic expression or secretion. Recent developments include the display of peptides and proteins targeting host cell receptors, for the purpose of enhancing the interactions between LAB and host. Surface-display technologies have other potential applications, such as degradation of biomass, which is of importance for some potential industrial applications of LAB.
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Affiliation(s)
- C. Michon
- />Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France
| | - P. Langella
- />Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France
| | - V. G. H. Eijsink
- />Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences (NMBU), Ås, Norway
| | - G. Mathiesen
- />Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences (NMBU), Ås, Norway
| | - J. M. Chatel
- />Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France
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Trombert A. Recombinant lactic acid bacteria as delivery vectors of heterologous antigens: the future of vaccination? Benef Microbes 2016; 6:313-24. [PMID: 25245573 DOI: 10.3920/bm2014.0068] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
UNLABELLED Lactic acid bacteria (LABs) are good candidates for the development of new oral vaccines and are attractive alternatives to attenuated pathogens. This review focuses on the use of wild-type and recombinant lactococci and lactobacilli with emphasis on their molecular design, immunomodulation and treatment of bacterial infections. The majority of studies related to recombinant LABs have focused on Lactococcus lactis, however, molecular tools have been successfully used for Lactobacillus spp. RESEARCH Recombinant lactobacilli and lactococci have several health benefits, such as immunomodulation, restoration of the microbiota, synthesis of antimicrobial substances and inhibition of virulence factors. In addition, protective immune responses that are well tolerated are induced by the expression of heterologous antigens from recombinant probiotics.
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Affiliation(s)
- A Trombert
- Center for Genomics and Bioinformatics, Faculty of Science, Universidad Mayor, Camino La Piramide 5750, Huechuraba, Santiago, Chile
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Implementation of the agmatine-controlled expression system for inducible gene expression in Lactococcus lactis. Microb Cell Fact 2015; 14:208. [PMID: 26715338 PMCID: PMC4696319 DOI: 10.1186/s12934-015-0399-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 12/16/2015] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Lactococcus lactis has been safely consumed in fermented foods for millennia. This Gram-positive bacterium has now become of industrial importance as an expression host for the overproduction of lipopolysaccharide-free recombinant proteins used as food ingredients, therapeutic proteins and biotechnological enzymes. RESULTS This paper reports an agmatine-controlled expression (ACE) system for L. lactis, comprising the lactococcal agmatine-sensor/transcriptional activator AguR and its target promoter P(aguB). The usefulness and efficiency of this system was checked via the reporter gene gfp and by producing PEP (Myxococcus xanthus prolyl-endopeptidase), an enzyme of biomedical interest able to degrade the immunotoxic peptides produced during the gastrointestinal breakdown of gluten. CONCLUSION The ACE system developed in this work was suitable for the efficient expression of the functional recombinant proteins GFP and PEP. The expression system was tightly regulated by the agmatine concentration and allowed high protein production without leakiness.
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Mucosally administered Lactobacillus surface-displayed influenza antigens (sM2 and HA2) with cholera toxin subunit A1 (CTA1) Induce broadly protective immune responses against divergent influenza subtypes. Vet Microbiol 2015. [PMID: 26210951 DOI: 10.1016/j.vetmic.2015.07.020] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The development of a universal influenza vaccine that provides broad cross protection against existing and unforeseen influenza viruses is a critical challenge. In this study, we constructed and expressed conserved sM2 and HA2 influenza antigens with cholera toxin subunit A1 (CTA1) on the surface of Lactobacillus casei (pgsA-CTA1sM2HA2/L. casei). Oral and nasal administrations of recombinant L. casei into mice resulted in high levels of serum immunoglobulin G (IgG) and their isotypes (IgG1 & IgG2a) as well as mucosal IgA. The mucosal administration of pgsA-CTA1sM2HA2/L. casei may also significantly increase the levels of sM2- or HA2-specific cell-mediated immunity because increased release of both IFN-γ and IL-4 was observed. The recombinant pgsA-CTA1sM2HA2/L. casei provided better protection of BALB/c mice against 10 times the 50% mouse lethal doses (MLD50) of homologous A/EM/Korea/W149/06(H5N1) or A/Aquatic bird/Korea/W81/2005 (H5N2) and heterologous A/Puerto Rico/8/34(H1N1), or A/Chicken/Korea/116/2004(H9N2) or A/Philippines/2/08(H3N2) viruses, compared with L. casei harboring sM2HA2 and also the protection was maintained up to seven months after administration. These results indicate that recombinant L. casei expressing the highly conserved sM2, HA2 of influenza and CTA1 as a mucosal adjuvant could be a potential mucosal vaccine candidate or tool to protect against divergent influenza viruses for human and animal.
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Adler M, Murani E, Ponsuksili S, Wimmers K. PBMC transcriptomic responses to primary and secondary vaccination differ due to divergent lean growth and antibody titers in a pig model. Physiol Genomics 2015; 47:470-8. [PMID: 26175500 DOI: 10.1152/physiolgenomics.00015.2015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 07/09/2015] [Indexed: 11/22/2022] Open
Abstract
The genetic relationship between immune responsiveness and performance is not well understood, but a major topic of the evolution of resource allocation and of relevance in human medicine and livestock breeding, for instance. This study aims to show differences of transcript abundance changes during the time intervals before and after two tetanus toxoid (TT) vaccinations in domestic pigs differing in lean growth (LG) and anti-TT-antibody titers (AB) parameters of performance and immunocompetence. During response to the first vaccination all animals had a general decrease in transcript abundances related to various functional pathways as measured by comparative Affymetrix microarray hybridization and Ingenuity Pathway analyses. Low-AB phenotypes had predominantly decreased immune response transcripts. Combined phenotypes high-AB/high-LG had decreased transcripts related to growth factor signaling pathways. However, during the interval after the booster vaccination, high-LG and high-AB animals responded exclusively with increased immune transcripts, such as B-cell receptor signaling and cellular immune response pathways. In addition, high-LG and low-AB animals had predominantly increased transcripts of several cellular immune response pathways. Conversely, low-LG and high-AB animals had few elevated immune transcripts and decreased transcripts related to only two nonimmune-specific pathways. In response to booster vaccination high-LG phenotypes revealed enriched transcripts related to several different immune response pathways, regardless of AB phenotype. Different from the expected impact of AB titers, divergent AB phenotypes did not reflect considerable differences between immune transcripts. However, highly significant differences observed among divergent LG phenotypes suggest the compatibility of high performance and high vaccine responses.
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Affiliation(s)
- Marcel Adler
- Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Dummerstorf, Germany
| | - Eduard Murani
- Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Dummerstorf, Germany
| | - Siriluck Ponsuksili
- Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Dummerstorf, Germany
| | - Klaus Wimmers
- Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Dummerstorf, Germany
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20
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Mucosal immunization of BALB/c mice with DNA vaccines encoding the SEN1002 and SEN1395 open reading frames of Salmonella enterica serovar Enteritidis induces protective immunity. Epidemiol Infect 2015; 144:247-56. [PMID: 26113459 DOI: 10.1017/s095026881500120x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Salmonella Enteritidis is the main cause of foodborne salmonellosis worldwide. The limited effectiveness of current interventions against this pathogen has been the main incentive to develop new methods for the efficient control of this infection. To investigate the use of DNA vaccines against S. Enteritidis in humans, immune responses stimulated by two plasmids containing the genes designated SEN1002, located in the pathogenicity island SPI-19 and encoding a Hcp protein involved in transport mechanisms, and SEN1395, located in the genomic island ΦSE14 and encoding a protein of a new superfamily of lysozymes, were evaluated. Humoral and cellular responses following intranasal immunization of two groups of BALB/c mice with the plasmids pV1002 and pV1395 plus adjuvant were evaluated and it was observed that the IgG2a/IgG1 ratios were sixfold higher than control groups. Both plasmids stimulated specific secretory IgA production. Increased proliferation of lymphocytes and IFN-γ production were detected in both experimental groups. DNA-vaccinated mice developed protective immunity against a virulent strain of S. Enteritidis, with nearly 2 logs of protection level compared to the negative control values in the spleen. Therefore, DNA vaccines are efficient at stimulating cellular and humoral immune responses at systemic and mucosal levels.
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Yousefi M, Younesi V, Bayat AA, Jadidi-Niaragh F, Abbasi E, Razavi A, Khosravi-Eghbal R, Asgarian-Omran H, Shokri F. Comparative human and mouse antibody responses against tetanus toxin at clonal level. J Immunotoxicol 2015; 13:243-8. [DOI: 10.3109/1547691x.2015.1046572] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Mehdi Yousefi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran,
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran,
| | - Vahid Younesi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran,
| | - Ali Ahmad Bayat
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, and
| | - Farhad Jadidi-Niaragh
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran,
| | - Ebrahim Abbasi
- Department of Bacterial Vaccines, Razi Vaccine and Serum Research Institute, Karaj, Iran
| | - Alireza Razavi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran,
| | - Roya Khosravi-Eghbal
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran,
| | - Hossein Asgarian-Omran
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran,
| | - Fazel Shokri
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran,
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, and
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Mot D, Timbermont L, Haesebrouck F, Ducatelle R, Van Immerseel F. Progress and problems in vaccination against necrotic enteritis in broiler chickens. Avian Pathol 2015; 43:290-300. [PMID: 24980518 DOI: 10.1080/03079457.2014.939942] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Necrotic enteritis in broilers is caused by Clostridium perfringens type A strains that produce the NetB toxin. Necrotic enteritis is one of the gastrointestinal diseases in poultry that has gained worldwide importance during the last decade due to efforts to improve broiler performance. Prevention strategies include avoiding predisposing factors, such as coccidiosis, and in-feed supplementation with a variety of feed additives. However, vaccination with modified toxin or other secreted immunogenic proteins seems a logical preventive tool for protection against a toxin-producing bacterium. Formalin-inactivated crude supernatant has been used initially for vaccination. Several studies have been carried out recently to identify the most important immunogenic and protective proteins that can be used for vaccination. These include the NetB toxin, as well as a number of other proteins. There is evidence that immunization with single proteins is not protective against severe challenge and that combinations of different antigens are needed. Most published studies have used multiple dosage vaccination regimens that are not relevant for practical use in the broiler industry. Single vaccination regimens for 1-day-old chicks appear to be non-protective. This review describes the history of vaccination strategies against necrotic enteritis in broilers and gives an update on future vaccination strategies that are applicable in the field. These may include breeder hen vaccination, in ovo vaccination and live attenuated vectors to be used in feed or in drinking water.
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Affiliation(s)
- Dorien Mot
- a Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine , Ghent University , Merelbeke , Belgium
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Engineered Lactobacillus rhamnosus GG expressing IgG-binding domains of protein G: Capture of hyperimmune bovine colostrum antibodies and protection against diarrhea in a mouse pup rotavirus infection model. Vaccine 2013; 32:470-7. [PMID: 24291196 DOI: 10.1016/j.vaccine.2013.11.057] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Revised: 11/05/2013] [Accepted: 11/15/2013] [Indexed: 01/25/2023]
Abstract
Rotavirus-induced diarrhea causes more than 500,000 deaths annually in the world, and although vaccines are being made available, new effective treatment strategies should still be considered. Purified antibodies derived from hyperimmune bovine colostrum (HBC), from cows immunized with rotavirus, were previously used for treatment of rotavirus diarrhea in children. A combination of HBC antibodies and a probiotic strain of Lactobacillus (L. rhamnosus GG) was also found to be more effective than HBC alone in reducing diarrhea in a mouse model of rotavirus infection. In order to further improve this form of treatment, L. rhamnosus GG was engineered to display surface expressed IgG-binding domains of protein G (GB1, GB2, and GB3) which capture HBC-derived IgG antibodies (HBC-IgG) and thus target rotavirus. The expression of IgG-binding domains on the surface of the bacteria as well as their binding to HBC-IgG and to rotavirus (simian strain RRV) was demonstrated by Western blot, flow cytometry, and electron microscopy. The prophylactic effect of engineered L. rhamnosus GG and anti-rotaviral activity of HBC antibodies was evaluated in a mouse pup model of RRV infection. The combination therapy with engineered L. rhamnosus GG (PG3) and HBC was significantly more effective in reducing the prevalence, severity, and duration of diarrhea in comparison to HBC alone or a combination of wild-type L. rhamnosus GG and HBC. The new therapy reduces the effective dose of HBC between 10 to 100-fold and may thus decrease treatment costs. This antibody capturing platform, tested here for the first time in vivo, could potentially be used to target additional gastrointestinal pathogens.
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Oral immunization with recombinant Lactobacillus acidophilus expressing the adhesin Hp0410 of Helicobacter pylori induces mucosal and systemic immune responses. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2013; 21:126-32. [PMID: 24285819 DOI: 10.1128/cvi.00434-13] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Helicobacter pylori infection is relatively common worldwide and is closely related to gastric mucosa-associated lymphoid tissue (MALT) lymphoma, chronic gastritis, and stomach ulcers. Therefore, a safe and effective method for preventing H. pylori infection is urgently needed. Given that developing an effective vaccine against H. pylori is one of the best alternatives, H. pylori adhesin Hp0410 was expressed in the food-grade bacterium Lactobacillus acidophilus. The recombinant live bacterial vaccine was then used to orally vaccinate mice, and the immunoprotective effects of Hp0410-producing strains were investigated. H. pylori colonization in the stomach of mice immunized with the recombinant L. acidophilus was significantly reduced, in comparison with that in control groups. Furthermore, mucosal secretory IgA antibodies were elicited in the mucosal tissue of mice immunized with the recombinant bacteria, and specific anti-Hp0410 IgG responses were also detected in mouse serum. There was a significant increase in the level of protection against gastric Helicobacter infection following a challenge with H. pylori Sydney strain 1 (SS1). Our results collectively indicate that adhesin Hp0410 is a promising candidate vaccine antigen, and recombinant L. acidophilus expressing Hp0410 is likely to constitute an effective, low-cost, live bacterial vaccine against H. pylori.
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Adler M, Murani E, Ponsuksili S, Wimmers K. PBMC transcription profiles of pigs with divergent humoral immune responses and lean growth performance. Int J Biol Sci 2013; 9:907-16. [PMID: 24155665 PMCID: PMC3805897 DOI: 10.7150/ijbs.6769] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Accepted: 08/20/2013] [Indexed: 11/22/2022] Open
Abstract
Background: The identification of key genes and regulatory networks in the transcriptomic responses of blood cells to antigen stimulation could facilitate the understanding of host defence and disease resistance. Moreover, genetic relationships between immunocompetence and the expression of other phenotypes, such as those of metabolic interest, are debated but incompletely understood in farm animals. Both positive and negative associations between immune responsiveness and performance traits such as weight gain or lean growth have been reported. We designed an in vivo microarray study of transcriptional changes in porcine peripheral blood mononuclear cells (PBMCs) during the immune response to tetanus toxoid (TT) as a model antigen for combined cellular (Th1) and humoral (Th2) responses. The aim of the study was to investigate the responsiveness of PBMCs against the background of divergent lean growth (LG) performance and anti-TT antibody (AB) titers and to compare lean growth and humoral immune performance phenotypes. Results: In general, high LG phenotypes had increased cellular immune response transcripts, while low AB phenotypes had increased transcripts for canonical pathways that represented processes of intracellular and second messenger signaling and immune responses. Comparison of lean growth phenotypes in the context of high AB titers revealed higher cellular immune response transcripts in high LG phenotypes. Similar comparisons in the context of low AB titers failed to identify any corresponding pathways. When high and low AB titer phenotypes were differentially compared, low AB phenotypes had higher cellular immune response transcripts on a low LG background and higher cell signaling, growth, and proliferation transcripts on a high LG background. Conclusions: Divergent phenotypes of both lean growth performance and humoral immune response are affected by significant and functional transcript abundance changes throughout the immune response. The selected high-performance phenotypes demonstrated both high AB titers and increased transcript abundance of cellular immune response genes, which were possibly offset by lower expression of other cellular functions. Further, indications of compensatory effects were observed between cellular and humoral immune responses that became visible only in low-performance phenotypes.
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Affiliation(s)
- Marcel Adler
- 1. Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
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Esteban LE, Temprana CF, Argüelles MH, Glikmann G, Castello AA. Antigenicity and immunogenicity of rotavirus VP6 protein expressed on the surface of Lactococcus lactis. BIOMED RESEARCH INTERNATIONAL 2013; 2013:298598. [PMID: 23984337 PMCID: PMC3741945 DOI: 10.1155/2013/298598] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Revised: 06/25/2013] [Accepted: 07/09/2013] [Indexed: 12/19/2022]
Abstract
Group A rotaviruses are the major etiologic agents of acute gastroenteritis worldwide in children and young animals. Among its structural proteins, VP6 is the most immunogenic and is highly conserved within this group. Lactococcus lactis is a food-grade, Gram-positive, and nonpathogenic lactic acid bacteria that has already been explored as a mucosal delivery system of heterologous antigens. In this work, the nisin-controlled expression system was used to display the VP6 protein at the cell surface of L. lactis. Conditions for optimal gene expression were established by testing different nisin concentrations, cell density at induction, and incubation times after induction. Cytoplasmic and cell wall protein extracts were analyzed by Western blot and surface expression was confirmed by flow cytometry. Both analysis provided evidence that VP6 was efficiently expressed and displayed on the cell surface of L. lactis. Furthermore, the humoral response of mice immunized with recombinant L. lactis was evaluated and the displayed recombinant VP6 protein proved to be immunogenic. In conclusion, this is the first report of displaying VP6 protein on the surface of L. lactis to induce a specific immune response against rotavirus. These results provide the basis for further evaluation of this VP6-displaying L. lactis as a mucosal delivery vector in a mouse model of rotavirus infection.
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Affiliation(s)
- L. E. Esteban
- Laboratorio de Inmunología y Virología (LIV), Universidad Nacional de Quilmes, Bernal, B1876BXD Buenos Aires, Argentina
| | - C. F. Temprana
- Laboratorio de Inmunología y Virología (LIV), Universidad Nacional de Quilmes, Bernal, B1876BXD Buenos Aires, Argentina
| | - M. H. Argüelles
- Laboratorio de Inmunología y Virología (LIV), Universidad Nacional de Quilmes, Bernal, B1876BXD Buenos Aires, Argentina
| | - G. Glikmann
- Laboratorio de Inmunología y Virología (LIV), Universidad Nacional de Quilmes, Bernal, B1876BXD Buenos Aires, Argentina
| | - A. A. Castello
- Laboratorio de Inmunología y Virología (LIV), Universidad Nacional de Quilmes, Bernal, B1876BXD Buenos Aires, Argentina
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Adler M, Murani E, Brunner R, Ponsuksili S, Wimmers K. Transcriptomic response of porcine PBMCs to vaccination with tetanus toxoid as a model antigen. PLoS One 2013; 8:e58306. [PMID: 23536793 PMCID: PMC3607572 DOI: 10.1371/journal.pone.0058306] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Accepted: 02/01/2013] [Indexed: 11/18/2022] Open
Abstract
The aim of the present study was to characterize in vivo genome-wide transcriptional responses to immune stimulation in order to get insight into the resulting changes of allocation of resources. Vaccination with tetanus toxoid was used as a model for a mixed Th1 and Th2 immune response in pig. Expression profiles of PBMCs (peripheral blood mononuclear cells) before and at 12 time points over a period of four weeks after initial and booster vaccination at day 14 were studied by use of Affymetrix GeneChip microarrays and Ingenuity Pathway Analysis (IPA). The transcriptome data in total comprised more than 5000 genes with different transcript abundances (DE-genes). Within the single time stages the numbers of DE-genes were between several hundred and more than 1000. Ingenuity Pathway Analysis mainly revealed canonical pathways of cellular immune response and cytokine signaling as well as a broad range of processes in cellular and organismal growth, proliferation and development, cell signaling, biosynthesis and metabolism. Significant changes in the expression profiles of PBMCs already occurred very early after immune stimulation. At two hours after the first vaccination 679 DE-genes corresponding to 110 canonical pathways of cytokine signaling, cellular immune response and other multiple cellular functions were found. Immune competence and global disease resistance are heritable but difficult to measure and to address by breeding. Besides QTL mapping of immune traits gene expression profiling facilitates the detection of functional gene networks and thus functional candidate genes.
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Affiliation(s)
- Marcel Adler
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Dummerstorf, Germany
| | - Eduard Murani
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Dummerstorf, Germany
| | - Ronald Brunner
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Dummerstorf, Germany
| | - Siriluck Ponsuksili
- Leibniz Institute for Farm Animal Biology (FBN), Research Group Functional Genome Analysis, Dummerstorf, Germany
| | - Klaus Wimmers
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Dummerstorf, Germany
- * E-mail:
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Liu S, Li Y, Xu Z, Wang Y. Subcutaneous or oral immunization of mice with Lactococcus lactis expressing F4 fimbrial adhesin FaeG. J Vet Med Sci 2013; 75:779-84. [PMID: 23386358 DOI: 10.1292/jvms.12-0267] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Enterotoxigenic Escherichia coli (ETEC) is one of the most common causes of diarrhea in neonatal and postweaning piglets. Fimbrial adhesion of ETEC has been considered an important colonization factor with antigenicity. To safely and effectively deliver the F4 (K88) fimbrial adhesin FaeG to the immune system, we have previously constructed the secretory expression vector pNZ8112-faeG, and FaeG was produced in cytoplasmic form in Lactococcus lactis. In this work, BALB/c mice were immunized with recombinant L. lactis to further determine the immunogenicity of recombinant FaeG (rFaeG) via the subcutaneous or oral route. Subcutaneous immunization in mice with recombinant L. lactis induced a significant increase in the F4-specific serum IgG titer and the number of antibody-secreting cells (ASCs) in the spleen. Oral immunization of mice with recombinant L. lactis induced mucosal and systemic F4-specific immune responses and increased the number of ASCs in the spleen, mesenteric lymph nodes and Peyer's patches. High-dose (2.8 × 10(11) CFU) recombinant strains and adjuvant cholera toxin B subunit enhanced specific mucosal immune responses. The results suggest the feasibility of delivering rFaeG expressed in L. lactis to the immune system in order to induce an F4-specific immune response.
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Affiliation(s)
- Shujie Liu
- Institute of Animal Husbandry and Veterinary Science, Zhejiang Academy of Agricultural Sciences, 145 Shiqiao Road, Hangzhou 310021, Zhejiang, China
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Liu X, Li H, Lu A, Zhong Y, Hou X, Wang N, Jia D, Zan J, Zhao H, Xu J, Liu F. Reduction of intestinal mucosal immune function in heat-stressed rats and bacterial translocation. Int J Hyperthermia 2012; 28:756-65. [PMID: 23094661 DOI: 10.3109/02656736.2012.729173] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
PURPOSE The aim of this study was to further understand the effects and mechanism of heat stress on the intestinal mucosal immune system of the rat, including changes in the intestinal mucosal barrier and immune function and their effects on bacterial translocation. MATERIALS AND METHODS Sprague Dawley (SD) rats were randomly divided into control and heat-stress groups. Both groups were housed in a 25°C environment of 60% relative humidity. The heat-stress group was subjected to 40°C for 2 h daily over 3 days. RESULTS Compared with the control group villi length in the small intestines of the heat-stress group was shortened. Jejunal mucosa were seriously damaged and the number of goblet cells in the epithelia of the duodenum and jejunum was significantly reduced. Electron microscopy revealed intestinal mucosal disorder, a large number of exudates of inflammatory fibrous material, fuzzy tight junction structure between epithelial cells, and cell gap increases in the heat-stress group. Transcription of IFN-γ, IL-2, IL-4, and IL-10, was significantly reduced, as was that of the intestinal mucosal immune-related proteins TLR2, TLR4, and IgA. The number of CD3(+) T cells and CD3(+)CD4(+)CD8(-) T cells in the mesenteric lymph nodes (MLNs) was significantly lower, while the number of CD3(+)CD4(-)CD8(+) T cells was significantly increased. The bacteria isolated from the MLNs were Escherichia coli. CONCLUSIONS Heat stress damages rat intestinal mechanical and mucosal immune barriers, and reduces immune function of the intestinal mucosa and mesenteric lymphoid tissues, leading to bacterial translocation.
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Affiliation(s)
- Xiaoxi Liu
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing, P.R. China
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Hugentobler F, Di Roberto RB, Gillard J, Cousineau B. Oral immunization using live Lactococcus lactis co-expressing LACK and IL-12 protects BALB/c mice against Leishmania major infection. Vaccine 2012; 30:5726-32. [PMID: 22814408 DOI: 10.1016/j.vaccine.2012.07.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Revised: 07/01/2012] [Accepted: 07/05/2012] [Indexed: 11/19/2022]
Abstract
Leishmaniasis is a parasitic disease affecting over 12 million individuals worldwide. Current treatments are laborious, expensive, cause severe side effects, and emerging drug resistance has been reported. While vaccination is the most cost-effective means to control infectious diseases there is no human vaccine currently available against Leishmania infections. Lactococcus lactis is a non-pathogenic, non-colonizing Gram-positive lactic acid bacterium commonly used in the dairy industry. Recently, L. lactis was used for the expression and delivery of biologically active molecules, such as antigens and cytokines, in mice and humans. In this study, we report the generation of L. lactis(alr-) strains solely expressing the protective Leishmania antigen, LACK, in the cytoplasm, secreted or anchored to the bacterial cell wall or co-expressing mouse IL-12. We show that oral immunization using live L. lactis, secreting both LACK and IL-12 was the only regimen that partially protected BALB/c mice against subsequent Leishmania major challenge. This highlights the importance of temporal and physical proximity of the delivered antigen and adjuvant for optimal immune priming by oral immunization since co-administration of L. lactis strains independently expressing secLACK and secIL-12 did not induce protective immunity. Protected animals displayed a delay in footpad swelling, which correlated with a significant reduction of parasite burden. Immunization with the L. lactis strain secreting both LACK and IL-12 induced an antigen-specific mucosal immune response and a LACK-specific T(H)1 immune response in splenocytes and mesenteric lymph node cells. Further, protection in immunized animals correlated with a strong Leishmania-specific T(H)1 immune response post-challenge, detectable in splenocytes and lymph node cells draining the site of infection. This report demonstrates the use of L. lactis as an oral live vaccine against L. major infection in susceptible BALB/c mice. The vaccine strains generated in this study provide the basis for the development of an inexpensive and safe oral live vaccine against the human parasite Leishmania.
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Affiliation(s)
- Felix Hugentobler
- Department of Microbiology & Immunology, McGill University, 3775 University Street, Montréal, Québec, H3A 2B4, Canada
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Oral vaccination with Lactococcus lactis expressing the Vibrio cholerae Wzm protein to enhance mucosal and systemic immunity. Vaccine 2012; 30:3231-8. [PMID: 22426330 DOI: 10.1016/j.vaccine.2012.02.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2011] [Revised: 02/02/2012] [Accepted: 02/05/2012] [Indexed: 11/22/2022]
Abstract
A gene associated with lipopolysaccharide (LPS) transport was cloned from a local clinical Vibrio cholerae O1 strain of the Ogawa serotype by using the Lactococcus lactis nisin-controlled expression (NICE) system. The V. cholerae wzm gene, which codes for an integral membrane transporter protein, was expressed and targeted to the cytoplasmic membrane, and was crudely isolated through simple centrifugation and SDS solubilization. To examine seroreactivity of this construct, rabbits were orally fed with 10(9) cfu/ml of live, recombinant L. lactis carrying the wzm gene, induced with nisin prior to administration. Recombinant plasmids were retrieved from L. lactis cultured directly from stool samples of inoculated rabbits. Reverse-transcriptase PCR of wzm using the retrieved plasmids confirmed transcription of this gene, indicating viability and stability of the recombinants in vivo. The L. lactis-Wzm construct elicited substantial levels of IgG and sIgA, and challenge with virulent V. cholerae O1 evoked severe diarrhoea in the naive, non-immunised control group, but not in those fed with either recombinant or non-recombinant L. lactis. Oral administration with recombinant L. lactis expressing the V. cholerae wzm gene increases both systemic and mucosal immunity, whereas L. lactis itself appears capable of protecting against the diarrhoeal symptoms caused by V. cholerae. Wzm is a conserved membrane protein associated with the LPS endotoxin, and together with the food-grade L. lactis, represent an attractive target for the development of a safer, live anti-infective therapy against V. cholerae.
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Hugentobler F, Yam KK, Gillard J, Mahbuba R, Olivier M, Cousineau B. Immunization against Leishmania major infection using LACK- and IL-12-expressing Lactococcus lactis induces delay in footpad swelling. PLoS One 2012; 7:e30945. [PMID: 22348031 PMCID: PMC3277590 DOI: 10.1371/journal.pone.0030945] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2011] [Accepted: 12/27/2011] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Leishmania is a mammalian parasite affecting over 12 million individuals worldwide. Current treatments are expensive, cause severe side effects, and emerging drug resistance has been reported. Vaccination is the most cost-effective means to control infectious disease but currently there is no vaccine available against Leishmaniasis. Lactococcus lactis is a non-pathogenic, non-colonizing Gram-positive lactic acid bacterium commonly used in the dairy industry. Recently, L. lactis was used to express biologically active molecules including vaccine antigens and cytokines. METHODOLOGY/PRINCIPAL FINDINGS We report the generation of L. lactis strains expressing the protective Leishmania antigen, LACK, in the cytoplasm, secreted or anchored to the bacterial cell wall. L. lactis was also engineered to secrete biologically active single chain mouse IL-12. Subcutaneous immunization with live L. lactis expressing LACK anchored to the cell wall and L. lactis secreting IL-12 significantly delayed footpad swelling in Leishmania major infected BALB/c mice. The delay in footpad swelling correlated with a significant reduction of parasite burden in immunized animals compared to control groups. Immunization with these two L. lactis strains induced antigen-specific multifunctional T(H)1 CD4(+) and CD8(+) T cells and a systemic LACK-specific T(H)1 immune response. Further, protection in immunized animals correlated with a Leishmania-specific T(H)1 immune response post-challenge. L. lactis secreting mouse IL-12 was essential for directing immune responses to LACK towards a protective T(H)1 response. CONCLUSIONS/SIGNIFICANCE This report demonstrates the use of L. lactis as a live vaccine against L. major infection in BALB/c mice. The strains generated in this study provide the basis for the development of an inexpensive and safe vaccine against the human parasite Leishmania.
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Affiliation(s)
- Felix Hugentobler
- Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada
| | - Karen K. Yam
- Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada
| | - Joshua Gillard
- Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada
| | - Raya Mahbuba
- Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada
| | - Martin Olivier
- Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada
- Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada
- Member of the Centre for Host-Parasite Interaction (CHPI), Ste. Anne de Bellevue, Québec, Canada
| | - Benoit Cousineau
- Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada
- Member of the Centre for Host-Parasite Interaction (CHPI), Ste. Anne de Bellevue, Québec, Canada
- * E-mail:
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Wells J. Mucosal vaccination and therapy with genetically modified lactic acid bacteria. Annu Rev Food Sci Technol 2012; 2:423-45. [PMID: 22129390 DOI: 10.1146/annurev-food-022510-133640] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Lactic acid bacteria (LAB) have proved to be effective mucosal delivery vehicles that overcome the problem of delivering functional proteins to the mucosal tissues. By the intranasal route, both live and killed LAB vaccine strains have been shown to elicit mucosal and systemic immune responses that afford protection against infectious challenges. To be effective via oral administration, frequent dosing over several weeks is required but new targeting and adjuvant strategies have clearly demonstrated the potential to increase the immunogenicity and protective immunity of LAB vaccines. Oral administration of Lactococcus lactis has been shown to induce antigen-specific oral tolerance (OT) to secreted recombinant antigens. LAB delivery is more efficient at inducing OT than the purified antigen, thus avoiding the need for purification of large quantities of antigen. This approach holds promise for new therapeutic interventions in allergies and antigen-induced autoimmune diseases. Several clinical and research reports demonstrate considerable progress in the application of genetically modified L. lactis for the treatment of inflammatory bowel disease (IBD). New medical targets are on the horizon, and the approval by several health authorities and biosafety committees of a containment system for a genetically modified L. lactis that secretes Il-10 should pave the way for new LAB delivery applications in the future.
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Affiliation(s)
- Jerry Wells
- Host-Microbe-Interactomics, University of Wageningen, Animal Sciences Department, 6700 AH, Wageningen, The Netherlands.
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Amalaradjou MAR, Bhunia AK. Modern approaches in probiotics research to control foodborne pathogens. ADVANCES IN FOOD AND NUTRITION RESEARCH 2012; 67:185-239. [PMID: 23034117 PMCID: PMC7150249 DOI: 10.1016/b978-0-12-394598-3.00005-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Foodborne illness is a serious public health concern. There are over 200 known microbial, chemical, and physical agents that are known to cause foodborne illness. Efforts are made for improved detection, control and prevention of foodborne pathogen in food, and pathogen associated diseases in the host. Several commonly used approaches to control foodborne pathogens include antibiotics, natural antimicrobials, bacteriophages, bacteriocins, ionizing radiations, and heat. In addition, probiotics offer a potential intervention strategy for the prevention and control of foodborne infections. This review focuses on the use of probiotics and bioengineered probiotics to control foodborne pathogens, their antimicrobial actions, and their delivery strategies. Although probiotics have been demonstrated to be effective in antagonizing foodborne pathogens, challenges exist in the characterization and elucidation of underlying molecular mechanisms of action and in the development of potential delivery strategies that could maintain the viability and functionality of the probiotic in the target organ.
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Bahey-El-Din M. Lactococcus lactis-based vaccines from laboratory bench to human use: an overview. Vaccine 2011; 30:685-90. [PMID: 22154771 DOI: 10.1016/j.vaccine.2011.11.098] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2011] [Revised: 11/19/2011] [Accepted: 11/25/2011] [Indexed: 02/07/2023]
Abstract
Developing effective vaccines is an important weapon in the battle against potential pathogens and their evolving antibiotic resistance trends. Several vaccine delivery vectors have been investigated among which the generally regarded as safe (GRAS) Lactococcus lactis has a distinguished position. In this review, different factors affecting the efficacy of L. lactis-based vaccines are discussed. In addition, the issues of biological containment and pharmaceutical quality assurance of L. lactis vaccines are highlighted. These issues are critical for the success of medical translation of L. lactis-based vaccines from research laboratories to clinical use by ensuring consistent manufacturing of safe and efficacious vaccines.
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Pontes DS, de Azevedo MSP, Chatel JM, Langella P, Azevedo V, Miyoshi A. Lactococcus lactis as a live vector: heterologous protein production and DNA delivery systems. Protein Expr Purif 2011; 79:165-75. [PMID: 21704169 DOI: 10.1016/j.pep.2011.06.005] [Citation(s) in RCA: 105] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2011] [Revised: 06/07/2011] [Accepted: 06/08/2011] [Indexed: 11/30/2022]
Abstract
Lactic acid bacteria (LAB), widely used in the food industry, are present in the intestine of most animals, including humans. The potential use of these bacteria as mucosal delivery vehicles for vaccinal, medical or technological use has been extensively investigated. Lactococcus lactis, a LAB species, is a potential candidate for the production of biologically useful proteins and for plasmid DNA delivery to eukaryotic cells. Several delivery systems have been developed to target heterologous proteins to a specific cell location (i.e., cytoplasm, cell wall or extracellular medium) and more recently to efficiently transfer DNA to eukaryotic cells. A promising application of L. lactis is its use for the development of live mucosal vaccines. Here, we have reviewed the expression of heterologous protein and the various delivery systems developed for L. lactis, as well as its use as an oral vaccine carrier.
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Affiliation(s)
- Daniela Santos Pontes
- Laboratório de Genética Celular e Molecular, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte-MG, Brazil
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Evaluation of oral immunization with recombinant avian influenza virus HA1 displayed on the Lactococcus lactis surface and combined with the mucosal adjuvant cholera toxin subunit B. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2011; 18:1046-51. [PMID: 21632890 DOI: 10.1128/cvi.00050-11] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The development of safe and efficient avian influenza vaccines for human and animal uses is essential for preventing virulent outbreaks and pandemics worldwide. In this study, we constructed a recombinant (pgsA-HA1 gene fusion) Lactococcus lactis strain that expresses and displays the avian influenza virus HA1 antigens on its surface. The vectors were administered by oral delivery with or without the addition of cholera toxin subunit B (CTB). The resulting immune responses were analyzed, and the mice were eventually challenged with lethal doses of H5N1 viruses. Significant titers of hemagglutinin (HA)-specific serum IgG and fecal IgA were detected in the group that also received CTB. Cellular immunities were also shown in both cell proliferation and gamma interferon (IFN-γ) enzyme-linked immunospot (ELISpot) assays. Most importantly, the mice that received the L. lactis pgsA-HA1 strain combined with CTB were completely protected from lethal challenge of the H5N1 virus. These findings support the further development of L. lactis-based avian influenza virus vaccines for human and animal uses.
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Yam KK, Hugentobler F, Pouliot P, Stern AM, Lalande JD, Matlashewski G, Olivier M, Cousineau B. Generation and evaluation of A2-expressing Lactococcus lactis live vaccines against Leishmania donovani in BALB/c mice. J Med Microbiol 2011; 60:1248-1260. [PMID: 21527547 DOI: 10.1099/jmm.0.029959-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Leishmaniasis is a parasitic disease affecting over 12 million individuals worldwide. As current treatments are insufficient, the development of an effective vaccine is a priority. This study generated and assessed the efficacy of Leishmania vaccines engineered from the non-colonizing, non-pathogenic Gram-positive bacterium Lactococcus lactis. A truncated, codon-optimized version of the A2 antigen from Leishmania donovani was engineered for expression in Lactococcus lactis in three different subcellular compartments: in the cytoplasm, secreted outside the cell or anchored to the cell wall. These three A2-expressing Lactococcus lactis strains were tested for their ability to generate A2-specific immune responses and as live vaccines against visceral Leishmania donovani infection in BALB/c mice. Subcutaneous immunization with live Lactococcus lactis expressing A2 anchored to the cell wall effectively induced high levels of antigen-specific serum antibodies. It was demonstrated that Lactococcus lactis-based vaccines are a feasible approach in the generation of live vaccines against leishmaniasis. The Lactococcus lactis strains generated in this study provide an excellent foundation for further studies on live bacterial vaccines against leishmaniasis and other pathogens.
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Affiliation(s)
- Karen K Yam
- Department of Microbiology and Immunology, McGill University, 3775 University Street, Montreal, QC H3A 2B4, Canada
| | - Felix Hugentobler
- Department of Microbiology and Immunology, McGill University, 3775 University Street, Montreal, QC H3A 2B4, Canada
| | - Philippe Pouliot
- Department of Microbiology and Immunology, McGill University, 3775 University Street, Montreal, QC H3A 2B4, Canada
| | - Andrew M Stern
- Department of Microbiology and Immunology, McGill University, 3775 University Street, Montreal, QC H3A 2B4, Canada
| | - Jean-Daniel Lalande
- Department of Microbiology and Immunology, McGill University, 3775 University Street, Montreal, QC H3A 2B4, Canada
| | - Greg Matlashewski
- Department of Microbiology and Immunology, McGill University, 3775 University Street, Montreal, QC H3A 2B4, Canada
| | - Martin Olivier
- Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.,Department of Microbiology and Immunology, McGill University, 3775 University Street, Montreal, QC H3A 2B4, Canada
| | - Benoit Cousineau
- Department of Microbiology and Immunology, McGill University, 3775 University Street, Montreal, QC H3A 2B4, Canada
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Soria-Guerra RE, Rosales-Mendoza S, Moreno-Fierros L, López-Revilla R, Alpuche-Solís AG. Oral immunogenicity of tomato-derived sDPT polypeptide containing Corynebacterium diphtheriae, Bordetella pertussis and Clostridium tetani exotoxin epitopes. PLANT CELL REPORTS 2011; 30:417-24. [PMID: 21188384 DOI: 10.1007/s00299-010-0973-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2010] [Revised: 11/21/2010] [Accepted: 12/05/2010] [Indexed: 05/30/2023]
Abstract
DPT vaccine, designed to immunize against diphtheria, pertussis, and tetanus, has been shown to be effective in humans. Nevertheless, dissatisfaction with the whole-cell preparations is due to the reactogenicity, which has to lead to the development of new safer formulations. Previously, we described the expression in tomato of a plant-optimized synthetic gene encoding the recombinant polypeptide sDPT, containing mainly immunoprotective epitopes of the diphtheria, pertussis and tetanus exotoxins and two adjuvants. In this study, we examined whether the ingestion of tomato-derived sDPT protein induces specific antibodies in mice after three weekly doses scheme. A positive group immunized with DPT toxoids was included. Specific antibody levels were assessed in serum, gut and lung. Sera tested for IgG antibody response to pertussis, tetanus and diphtheria toxin showed responses to the foreign antigens; interestingly, the response to diphtheria epitope was similar to those observed in the positive group. We found higher IgG1 than IgG2a responses in serum. A modest IgG response was observed in the tracheopulmonary fluid. High response of IgA against tetanus toxin was evident in gut, which was statistically comparable to that obtained in the positive group. The levels of response in these groups were higher than those in mice that received wild-type tomato. These findings support the concept of using transgenic tomatoes expressing sDPT polypeptide as model for edible vaccine against diphtheria, pertussis, and tetanus.
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Affiliation(s)
- Ruth E Soria-Guerra
- División de Biología Molecular, IPICYT, Camino a la Presa San José 2055, 78216 San Luis Potosí, Mexico
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Oral immunization of mice with Lactococcus lactis expressing the rotavirus VP8* protein. Biotechnol Lett 2011; 33:1169-75. [PMID: 21302132 DOI: 10.1007/s10529-011-0551-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2010] [Accepted: 01/25/2011] [Indexed: 10/18/2022]
Abstract
The efficacy of recombinant Lactococcus lactis as a delivery vehicle for a rotavirus antigen was evaluated in a mouse model. The rotavirus VP8* protein was expressed intracellularly and extracellularly in L. lactis wild type and in an alr mutant deficient in alanine racemase activity, necessary for the synthesis of the cell-wall component D: -alanine. When the mucosal immune response was evaluated by measuring VP8*-specific IgA antibody in faeces, wild-type L. lactis triggered a low IgA synthesis only when the secreting strain was used. In contrast, VP8*-specific IgA was detected in faeces of both groups of mice orally given the alr mutant expressing extracellular VP8* and intracellular VP8*, which reached levels similar to that obtained with the wild type secreting strain. However, oral administration of the recombinant strains did not induce serum IgG or IgA responses. L. lactis cell-wall mutants may therefore provide certain advantages when low-antigenic proteins are expressed intracellularly. However, the low immune response obtained by using this antigen-bacterial host combination prompts to the use of new strains and vaccination protocols in order to develop acceptable rotavirus immunization levels.
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Yamamoto S, Wada J, Katayama T, Jikimoto T, Nakamura M, Kinoshita S, Lee KM, Kawabata M, Shirakawa T. Genetically modified Bifidobacterium displaying Salmonella-antigen protects mice from lethal challenge of Salmonella Typhimurium in a murine typhoid fever model. Vaccine 2010; 28:6684-91. [PMID: 20709009 DOI: 10.1016/j.vaccine.2010.08.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2010] [Revised: 07/09/2010] [Accepted: 08/02/2010] [Indexed: 02/06/2023]
Abstract
We developed a novel vaccine platform utilizing Bifidobacterium as an antigen delivery vehicle for mucosal immunization. Genetically modified Bifidobacterium longum displaying Salmonella-flagellin on the cell surface was constructed for the oral typhoid vaccine. The efficiency of this vaccine was evaluated in a murine model of typhoid fever. We then orally administered 2.5 × 10(7) CFU of the recombinant Bifidobacterium longum (vaccine) or parental Bifidobacterium longum, or PBS to BALB/C mice every other day for 2 weeks. After the administration, a total of 42 mice (14 mice in each group) were challenged with Salmonella Typhimurium (1.0 × 10(7) CFU/mouse). While 12 mice in the PBS group, and 9 in the parental Bifidobacterium longum group died (median survival: 14 and 25 days), only two in the vaccine group died. These data support that our genetically modified Bifidobacterium antigen delivery system offers a promising vaccine platform for inducing efficient mucosal immunity.
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Affiliation(s)
- Sakura Yamamoto
- Division of Infectious Disease Control, Kobe University Graduate School of Medicine, Kobe, Japan
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Liu Z, Ma Y, Shen T, Chen H, Zhou Y, Zhang P, Zhang M, Chu Z, Qin H. Identification of DC-SIGN as the receptor during the interaction of Lactobacillus plantarum CGMCC 1258 and dendritic cells. World J Microbiol Biotechnol 2010. [DOI: 10.1007/s11274-010-0495-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Immune responses elicited in mice with recombinant Lactococcus lactis expressing F4 fimbrial adhesin FaeG by oral immunization. Vet Res Commun 2010; 34:491-502. [PMID: 20532816 DOI: 10.1007/s11259-010-9418-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/21/2010] [Indexed: 10/19/2022]
Abstract
Enterotoxigenic Escherichia coli (ETEC) is a major pathogenic agent causing piglet diarrhea. The major subunit and adhesin FaeG of F4(+) ETEC is an important virulence factor with strong immunogenicity. To determine whether Lactococcus lactis (L. lactis) could effectively deliver FaeG to the mucosal immune system, recombinant L. lactis expressing FaeG was constructed, and immune responses in mice following oral route delivery of recombinant L. lactis were explored. The production of FaeG expressed in L. lactis was up to approximately 10% of soluble whole-cell proteins, and recombinant FaeG (rFaeG) possessed good immunoreactivity by Western blot analysis. Oral immunization with recombinant L. lactis expressing FaeG induced F4-specific mucosal and systemic immune responses in the mice. In addition, high dose recombinant L. lactis or co-administration of high dose recombinant L. lactis with CTB enhanced the immune responses. These results suggested that L. lactis expressing FaeG was a promising candidate vaccine against ETEC.
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Bahey-El-Din M, Casey PG, Griffin BT, Gahan CGM. Expression of two Listeria monocytogenes antigens (P60 and LLO) in Lactococcus lactis and examination for use as live vaccine vectors. J Med Microbiol 2010; 59:904-912. [PMID: 20488938 DOI: 10.1099/jmm.0.018770-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Listeria monocytogenes is a food-borne intracellular pathogen that mainly infects pregnant and immunocompromised individuals. The pore-forming haemolysin listeriolysin O (LLO), the main virulence factor of Listeria monocytogenes, allows bacteria to escape from the harsh environment of the phagosome to the cytoplasm of the infected cell. This leads to processing of bacterial antigens predominantly through the cytosolic MHC class I presentation pathway. We previously engineered the food-grade bacterium Lactococcus lactis to express LLO and demonstrated an LLO-specific CD8(+) response upon immunization of mice with the engineered L. lactis vaccine strains. In the present work, we examined the immune response and protective efficacy of an L. lactis strain co-expressing LLO and a truncated form of the listerial P60 antigen (tP60). Oral immunization revealed no significant protection against listeriosis with L. lactis expressing LLO, tP60 or the combined LLO/tP60. In contrast, intraperitoneal vaccination induced an LLO-specific CD8(+) immune response with LLO-expressing L. lactis but no significant improvement in protection was observed following vaccination with the combined LLO/tP60 expressing L. lactis strain. This may be due to the low level of tP60 expression in the LLO/tP60 strain. These results demonstrate the necessity for improved oral vaccination strategies using LLO-expressing L. lactis vaccine vectors.
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Affiliation(s)
- Mohammed Bahey-El-Din
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Alexandria University, Egypt
- Department of Microbiology, University College Cork, Cork, Ireland
- School of Pharmacy, University College Cork, Cork, Ireland
| | - Pat G Casey
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Department of Microbiology, University College Cork, Cork, Ireland
| | | | - Cormac G M Gahan
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Department of Microbiology, University College Cork, Cork, Ireland
- School of Pharmacy, University College Cork, Cork, Ireland
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Li L, Hu X, Wu Z, Xiong S, Zhou Z, Wang X, Xu J, Lu F, Yu X. Immunogenicity of self-adjuvanticity oral vaccine candidate based on use of Bacillus subtilis spore displaying Schistosoma japonicum 26 KDa GST protein. Parasitol Res 2009; 105:1643-51. [PMID: 19756753 DOI: 10.1007/s00436-009-1606-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2009] [Accepted: 08/21/2009] [Indexed: 12/16/2022]
Abstract
One of the promising approaches in mucosal immunization relies on live recombinant vaccine carriers. In this study, we used a six-extracellular protease-deficient Bacillus subtilis strain WB600 to express Schistosoma japonicum 26 kDa glutathione S-transferase (GST). Western blot, immunofluorescence, and flow cytometry analyses were used to identify SjGST expression on spore surface. SjGST recombinant spores were used for oral vaccination in mice and were shown to generate mucosal and systemic response. Both SjGST-specific secretory IgA in feces and IgG in serum augmented significantly on day 33 after oral administration. It seemed that surface display of recombinant S. japonicum SjGST on B. subtilis WB600 spores showed good immunogenicity, and B. subtilis spores could be used as potential mucosal delivery vehicles to provide more effective vaccination strategies for parasite prevention and control in the future.
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Affiliation(s)
- Li Li
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
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Kim SJ, Lee JY, Jun DY, Song JY, Lee WK, Cho MJ, Kim YH. Oral administration of Lactococcus lactis expressing Helicobacter pylori Cag7-ct383 protein induces systemic anti-Cag7 immune response in mice. ACTA ACUST UNITED AC 2009; 57:257-68. [PMID: 19807786 PMCID: PMC7110310 DOI: 10.1111/j.1574-695x.2009.00605.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
To express the 3′‐region (1152 bp) of the cag7 gene of Helicobacter pylori 51 strain, encoding the C‐terminal 383 amino acid (ct383 aa) region of Cag7 protein that is known to cover the needle region of T4SS, in a live delivery vehicle Lactococcus lactis, the cag7‐ct383 gene was amplified by PCR. DNA sequence analysis revealed that the amino acid sequence of Cag7‐ct383 of H. pylori 51 shared 98.4% and 97.4% identity with H. pylori 26695 and J99, respectively. Intramuscular injection of the GST‐Cag7‐ct383 fusion protein into a rat could raise the anti‐Cag7 antibody, indicating the immunogenicity of the Cag7‐ct383 protein. When the cag7‐ct383 gene was cloned in Escherichia coli–L. lactis shuttle vector (pMG36e) and transformed into L. lactis, the transformant could produce the Cag7‐ct383 protein, as evidenced by Western blot analysis. The Cag7‐ct383 protein level in the L. lactis transformant reached a maximum at the early stationary phase without extracellular secretion. The oral administration of the L. lactis transformant into mice generated anti‐Cag7 antibody in serum in five of five mice. These results suggest that L. lactis transformant expressing Cag7‐ct383 protein may be applicable as an oral vaccine to induce mucosal and systemic immunity to H. pylori.
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Affiliation(s)
- Su-Jung Kim
- School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Korea
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Age-dependent systemic antibody responses and immunisation-associated changes in mice orally and nasally immunised with Lactococcus lactis expressing a malaria parasite protein. Vaccine 2009; 27:4947-52. [DOI: 10.1016/j.vaccine.2009.06.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2008] [Revised: 04/30/2009] [Accepted: 06/04/2009] [Indexed: 12/12/2022]
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Gu Q, Song D, Zhu M. Oral vaccination of mice against Helicobacter pylori with recombinant Lactococcus lactis expressing urease subunit B. FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY 2009. [PMID: 19453750 DOI: 10.111/j.1574-695x.2009.00566.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
To determine whether a protective immune response could be elicited by oral delivery of a recombinant live bacterial vaccine, Helicobacter pylori urease subunit B (UreB) was expressed for extracellular expression in food-grade bacterium Lactococcus lactis. The UreB-producing strains were then administered orally to mice, and the immune response to UreB was examined. Orally vaccinated mice produced a significant UreB-specific serum immunoglobulin G (IgG) response. Specific anti-UreB IgA responses could be detected in the feces of mice immunized with the secreting lactococcal strain. Mice vaccinated orally were significantly protected against gastric Helicobacter infection following a challenge with H. pylori strain SS1. In conclusion, mucosal vaccination with L. lactis expressing UreB produced serum IgG and UreB-specific fecal IgA, and prevented gastric infection with H. pylori.
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Affiliation(s)
- Qing Gu
- Department of Biotechnology, Zhejiang Gongshang University, Hangzhou 310035, China.
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Gu Q, Song D, Zhu M. Oral vaccination of mice against Helicobacter pylori with recombinant Lactococcus lactis expressing urease subunit B. ACTA ACUST UNITED AC 2009; 56:197-203. [PMID: 19453750 PMCID: PMC7110364 DOI: 10.1111/j.1574-695x.2009.00566.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
To determine whether a protective immune response could be elicited by oral delivery of a recombinant live bacterial vaccine, Helicobacter pylori urease subunit B (UreB) was expressed for extracellular expression in food-grade bacterium Lactococcus lactis. The UreB-producing strains were then administered orally to mice, and the immune response to UreB was examined. Orally vaccinated mice produced a significant UreB-specific serum immunoglobulin G (IgG) response. Specific anti-UreB IgA responses could be detected in the feces of mice immunized with the secreting lactococcal strain. Mice vaccinated orally were significantly protected against gastric Helicobacter infection following a challenge with H. pylori strain SS1. In conclusion, mucosal vaccination with L. lactis expressing UreB produced serum IgG and UreB-specific fecal IgA, and prevented gastric infection with H. pylori.
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Affiliation(s)
- Qing Gu
- Department of Biotechnology, Zhejiang Gongshang University, Hangzhou 310035, China.
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