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Zhang F, Chen J, Zhang Z, Wu J, Qu Y, Ni L, Zhang G, Liu K, Guo L. M cells targeted H. pylori antigen SAM-FAdE displayed on bacterium-like particles induce protective immunity. J Nanobiotechnology 2025; 23:23. [PMID: 39825347 PMCID: PMC11748607 DOI: 10.1186/s12951-025-03111-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 01/11/2025] [Indexed: 01/20/2025] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori), a specific bacterium capable of surviving in the acidic environment of the stomach, has been recognized as a group of causative agents of gastric cancer. Therefore, the development of mucosal vaccines against H. pylori is expected to provide an important direction for the treatment of chronic gastritis and the prevention of gastric cancer. METHODS AND RESULTS In this study, we used bacteria-like particles (BLPs) obtained by treating Lactic acid bacteria (L. lactis) with hot acid, and successfully displayed the M cell-targeted H. pylori multi-epitope purified antigen SAM-FAdE, with 90% display efficiency. In addition, BLPs-SAM-FAdE can effectively target M cell models and M cells of mouse Peyer's patches (PPs) through oral immunization, promote the transport of particulate vaccines to dendritic cells (BMDCs) and stimulate their maturation, significantly increased proportion of plasma cells and germinal centers B cells. This indicates that the vaccination can induce notable antigen-specific mucosal immune responses (production of sIgA), CD4+ T cell responses (Th1/Th2/Th17) and humoral immune responses (production of serum IgG). Furthermore, oral BLPs-SAM-FAdE dramatically reduced the H. pylori adhesion and specific 16S rRNA expression of H. pylori in gastric mucosal tissue, protecting gastric tissue from damage. CONCLUSION BLPs-SAM-FAdE can significantly reduce the adhesion of H. pylori in gastric mucosal tissue and inhibit gastritis and gastric damage caused by H. pylori infection.
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Affiliation(s)
- Furui Zhang
- School of First Clinical Medical, Ningxia Medical University, Yinchuan, 750004, China
- School of Laboratory, Ningxia Medical University, Yinchuan, 750004, China
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Jiale Chen
- School of First Clinical Medical, Ningxia Medical University, Yinchuan, 750004, China
| | - Zhen Zhang
- Department of Geriatrics and Special Needs Medicine, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Jing Wu
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Yuliang Qu
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Linhan Ni
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China
| | - Guolin Zhang
- Suzhou Institute for Drug Control, Suzhou, China
| | - Kunmei Liu
- Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China.
| | - Le Guo
- School of First Clinical Medical, Ningxia Medical University, Yinchuan, 750004, China.
- School of Laboratory, Ningxia Medical University, Yinchuan, 750004, China.
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China.
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2
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Khan FM, Rasheed F, Yang Y, Liu B, Zhang R. Endolysins: a new antimicrobial agent against antimicrobial resistance. Strategies and opportunities in overcoming the challenges of endolysins against Gram-negative bacteria. Front Pharmacol 2024; 15:1385261. [PMID: 38831886 PMCID: PMC11144922 DOI: 10.3389/fphar.2024.1385261] [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: 02/12/2024] [Accepted: 04/16/2024] [Indexed: 06/05/2024] Open
Abstract
Antibiotic-resistant bacteria are rapidly emerging, and the increasing prevalence of multidrug-resistant (MDR) Acinetobacter baumannii poses a severe threat to humans and healthcare organizations, due to the lack of innovative antibacterial drugs. Endolysins, which are peptidoglycan hydrolases encoded by a bacteriophage, are a promising new family of antimicrobials. Endolysins have been demonstrated as an effective therapeutic agent against bacterial infections of A. baumannii and many other Gram-positive and Gram-negative bacteria. Endolysin research has progressed from basic in vitro characterization to sophisticated protein engineering methodologies, including advanced preclinical and clinical testing. Endolysin are therapeutic agent that shows antimicrobial properties against bacterial infections caused by drug-resistant Gram-negative bacteria, there are still barriers to their implementation in clinical settings, such as safety concerns with outer membrane permeabilizers (OMP) use, low efficiency against stationary phase bacteria, and stability issues. The application of protein engineering and formulation techniques to improve enzyme stability, as well as combination therapy with other types of antibacterial drugs to optimize their medicinal value, have been reviewed as well. In this review, we summarize the clinical development of endolysin and its challenges and approaches for bringing endolysin therapies to the clinic. This review also discusses the different applications of endolysins.
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Affiliation(s)
- Fazal Mehmood Khan
- College of Civil and Transportation Engineering, Shenzhen University, Shenzhen, China
- Institute for Advanced Study, Shenzhen University, Shenzhen, China
| | - Fazal Rasheed
- Institute of Microscale Optoelectronics, Shenzhen University, Shenzhen, China
| | - Yunlan Yang
- Institute for Advanced Study, Shenzhen University, Shenzhen, China
| | - Bin Liu
- Institute for Advanced Study, Shenzhen University, Shenzhen, China
| | - Rui Zhang
- Institute for Advanced Study, Shenzhen University, Shenzhen, China
- Southern Marine Science and Engineering Guangdong Laboratory, Zhuhai, China
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3
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Guo Z, Ren H, Chang Q, Liu R, Zhou X, Xue K, Sun T, Luo J, Wang F, Ge J. Lactobacilli-derived adjuvants combined with immunoinformatics-driven multi-epitope antigens based approach protects against Clostridium perfringens in a mouse model. Int J Biol Macromol 2024; 267:131475. [PMID: 38608984 DOI: 10.1016/j.ijbiomac.2024.131475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 03/28/2024] [Accepted: 04/06/2024] [Indexed: 04/14/2024]
Abstract
Clostridium perfringens is ubiquitously distributed and capable of secreting toxins, posing a significant threat to animal health. Infections caused by Clostridium perfringens, such as Necrotic Enteritis (NE), result in substantial economic losses to the livestock industry annually. However, there is no effective commercial vaccine available. Hence, we set out to propose an effective approach for multi-epitope subunit vaccine construction utilizing biomolecules. We utilized immunoinformatics to design a novel multi-epitope antigen against C. perfringens (CPMEA). Furthermore, we innovated novel bacterium-like particles (BLPs) through thermal acid treatment of various Lactobacillus strains and selected BLP23017 among them. Then, we detailed the structure of CPMEA and BLPs and utilized them to prepare a multi-epitope vaccine. Here, we showed that our vaccine provided full protection against C. perfringens infection after a single dose in a mouse model. Additionally, BLP23017 notably augmented the secretion of secretory immunoglobulin A (sIgA) and enhanced antibody production. We conclude that our vaccine possess safety and high efficacy, making it an excellent candidate for preventing C. perfringens infection. Moreover, we demonstrate our approach to vaccine construction and the preparation of BLP23017 with distinct advantages may contribute to the prevention of a wider array of diseases and the novel vaccine development.
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Affiliation(s)
- Zhiyuan Guo
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Hongkun Ren
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Qingru Chang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Runhang Liu
- State Key Laboratory for Animal Disease control and prevention, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, China
| | - Xinyao Zhou
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Kun Xue
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Tong Sun
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Jilong Luo
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Fang Wang
- State Key Laboratory for Animal Disease control and prevention, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, China.
| | - Junwei Ge
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; Heilongjiang Provincial Key Laboratory of Zoonosis, Harbin 150030, China.
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4
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Das S, Konwar BK. Influence of connatural factors in shaping vaginal microflora and ensuring its health. Arch Gynecol Obstet 2024; 309:871-886. [PMID: 37676318 DOI: 10.1007/s00404-023-07200-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 08/21/2023] [Indexed: 09/08/2023]
Abstract
Vaginal canal (VC) is exposed to the external environment affected by habitual factors like hygiene and sexual behaviour as well as physiological factors like puberty, menstrual cycle, pregnancy, child birth and menopause. Healthy VC harbours beneficial microflora supported by vaginal epithelium and cervical fluid. Connatural antimicrobial peptide (AMPs) of female reproductive tract (FRT) conjunctly with these beneficial microbes provide protection from a large number of infectious diseases. Such infections may either be caused by native microbes of the VC or transitory microbes like bacteria or virus which are not a part of VC microflora. This review highlight's the role of hormones, enzymes, innate immunological factors, epithelial cells and vaginal mucus that support beneficial microbes over infectious ones thus, helping to maintain homeostasis in VC and further protect the FRT. We also discuss the prospective use of vaginal probiotics and AMPs against pathogens which can serve as a potential cure for vaginal infections.
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Affiliation(s)
- Shreaya Das
- Department of MBBT, Tezpur University, Napaam, Assam, 784028, India.
| | - Bolin K Konwar
- Department of MBBT, Tezpur University, Napaam, Assam, 784028, India
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5
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Dotiwala F, Upadhyay AK. Next Generation Mucosal Vaccine Strategy for Respiratory Pathogens. Vaccines (Basel) 2023; 11:1585. [PMID: 37896988 PMCID: PMC10611113 DOI: 10.3390/vaccines11101585] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 10/06/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Inducing humoral and cytotoxic mucosal immunity at the sites of pathogen entry has the potential to prevent the infection from getting established. This is different from systemic vaccination, which protects against the development of systemic symptoms. The field of mucosal vaccination has seen fewer technological advances compared to nucleic acid and subunit vaccine advances for injectable vaccine platforms. The advent of the next-generation adenoviral vectors has given a boost to mucosal vaccine research. Basic research into the mechanisms regulating innate and adaptive mucosal immunity and the discovery of effective and safe mucosal vaccine adjuvants will continue to improve mucosal vaccine design. The results from clinical trials of inhaled COVID-19 vaccines demonstrate their ability to induce the proliferation of cytotoxic T cells and the production of secreted IgA and IgG antibodies locally, unlike intramuscular vaccinations. However, these mucosal vaccines induce systemic immune responses at par with systemic vaccinations. This review summarizes the function of the respiratory mucosa-associated lymphoid tissue and the advantages that the adenoviral vectors provide as inhaled vaccine platforms.
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Affiliation(s)
- Farokh Dotiwala
- Ocugen Inc., 11 Great Valley Parkway, Malvern, PA 19355, USA
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6
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Che Y, Fu S, Wang H, Suo J, Chen C, Pu D, Li C, Yang Y. Correlation of the Gut Microbiota and Antitumor Immune Responses Induced by a Human Papillomavirus Therapeutic Vaccine. ACS Infect Dis 2022; 8:2494-2504. [PMID: 36342280 DOI: 10.1021/acsinfecdis.2c00305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Human papillomavirus (HPV) is the most common sexually transmitted pathogen worldwide and the major risk factor for cervical cancer. According to our previous study, antitumor immune responses induced by a therapeutic vaccine based on HPV E7 peptide are highly variable among individuals. Many studies have demonstrated that the discrepancy in the gut microbiota is an important factor in the development and regulation of the immune system. Therefore, we performed a systematic comparative analysis of gut microbiota in two groups of mice with significant differences in antitumor effects induced by the vaccine, as well as the correlation between immune cells and gut microbiota. We divided the mice into group A, in which the tumor continued growing, and group B, in which the tumor volume was significantly reduced. In group B mice, the vaccination induced a stronger antitumor activity with significantly enhanced IFN-γ-producing CD4+ and CD8+ T lymphocytes, as well as decreased immunosuppressive cells. A detailed gut microbiota analysis revealed a positive Spearman correlation between the percentage of CD8+ T cells and the relative abundance of Corynebacteriales, Parabacteroides, and Bacteroides_sp. Furthermore, the percentage of CD4+ and CD8+ T cells negatively correlated with the abundance of Proteobacteria and Bilophila. By contrast, the abundance of Proteobacteria, Desulfovibrio, and Bilophila positively correlated with the percentage of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and type 2-polarized tumor-associated macrophages (M2-TAMs). Overall, the composition of gut microbiota is related to vaccine-induced antitumor effects, and there is a correlation between some gut bacteria and vaccine-induced immune responses.
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Affiliation(s)
- Yuxin Che
- Department of Microbiology and Parasitology, College of Basic Medical Science, China Medical University, Shenyang 110122, China.,Department of Biochemistry & Molecular Biology, Shanxi Medical University, Taiyuan 030001, China
| | - Shihan Fu
- International School, Beijing University of Posts and Telecommunications, Beijing 100876, China
| | - Huan Wang
- Nursing College, Jinzhou Medical University, Jinzhou 121001, China
| | - Jinguo Suo
- Department of Microbiology and Parasitology, College of Basic Medical Science, China Medical University, Shenyang 110122, China
| | - Chunyan Chen
- Department of Microbiology and Parasitology, College of Basic Medical Science, China Medical University, Shenyang 110122, China
| | - Dan Pu
- Department of Microbiology and Parasitology, College of Basic Medical Science, China Medical University, Shenyang 110122, China
| | - Can Li
- Department of Microbiology and Parasitology, College of Basic Medical Science, China Medical University, Shenyang 110122, China
| | - Yang Yang
- Department of Microbiology and Parasitology, College of Basic Medical Science, China Medical University, Shenyang 110122, China
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7
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Dai W, Gui L, Du H, Li S, Wu R. The association of cervicovaginal Langerhans cells with clearance of human papillomavirus. Front Immunol 2022; 13:918190. [PMID: 36311788 PMCID: PMC9596771 DOI: 10.3389/fimmu.2022.918190] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 09/27/2022] [Indexed: 12/03/2022] Open
Abstract
Human papillomavirus (HPV) clearance is important in eliminating cervical cancer which contributes to high morbidity and mortality in women. Nevertheless, it remains largely unknown about key players in clearing pre-existing HPV infections. HPV antigens can be detected by the most important cervical antigen-presenting cells (Langerhans cells, LCs), of which the activities can be affected by cervicovaginal microbiota. In this review, we first introduce persistent HPV infections and then describe HPV-suppressed LCs activities, including but not limited to antigen uptake and presentation. Given specific transcriptional profiling of LCs in cervical epithelium, we also discuss the impact of cervicovaginal microbiota on LCs activation as well as the promise of exploring key microbial players in activating LCs and HPV-specific cellular immunity.
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Affiliation(s)
- Wenkui Dai
- Department of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen, China
- Institute of Obstetrics and Gynecology, Shenzhen Peking University-Hong Kong University of Science and Technology Medical Center (PKU-HKUST) Medical Center, Shenzhen, China
- Shenzhen Key Laboratory on Technology for Early Diagnosis of Major Gynecologic Diseases, Shenzhen, China
| | - Liming Gui
- Department of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Hui Du
- Department of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen, China
- Institute of Obstetrics and Gynecology, Shenzhen Peking University-Hong Kong University of Science and Technology Medical Center (PKU-HKUST) Medical Center, Shenzhen, China
- Shenzhen Key Laboratory on Technology for Early Diagnosis of Major Gynecologic Diseases, Shenzhen, China
| | - Shuaicheng Li
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Ruifang Wu
- Department of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen, China
- Institute of Obstetrics and Gynecology, Shenzhen Peking University-Hong Kong University of Science and Technology Medical Center (PKU-HKUST) Medical Center, Shenzhen, China
- Shenzhen Key Laboratory on Technology for Early Diagnosis of Major Gynecologic Diseases, Shenzhen, China
- *Correspondence: Ruifang Wu,
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8
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Zhang S, Yan F, Liu D, Li E, Feng N, Xu S, Wang H, Gao Y, Yang S, Zhao Y, Xia X. Bacterium-Like Particles Displaying the Rift Valley Fever Virus Gn Head Protein Induces Efficacious Immune Responses in Immunized Mice. Front Microbiol 2022; 13:799942. [PMID: 35369468 PMCID: PMC8969503 DOI: 10.3389/fmicb.2022.799942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 02/03/2022] [Indexed: 11/13/2022] Open
Abstract
Rift Valley fever virus (RVFV), a mosquito-borne zoonotic phlebovirus, causes serious disease in humans and ruminants. According to the World Health Organization, Rift Valley fever is classified as a priority disease, and as such, vaccine development is of high priority due to the lack of licensed vaccines. In this study, a bacterium-like particle vaccine (BLP), RVFV-BLPs, is constructed. A novel display system is described, which is based on non-living and non-genetically modified Gram-positive bacterial cells, designated as Gram-positive enhancer matrix (GEM). The RVFV Gn head protein was displayed on the surface of GEM by co-expression with the peptidoglycan-binding domain (protein anchor) at the C-terminus. We determined that the RVFV Gn head-PA fusion protein was successfully displayed on the GEM. Mice immunized with RVFV-BLPs produced humoral and cellular immunity. Interestingly, comparing the production of RVFV Gn head-specific IgG and its subtype by vaccinating with different antigen doses of the RVFV-BLPs determined that the RVFV-BLPs (50 μg) group showed a greater effect than the other two groups. More importantly, antibodies produced by mice immunized with RVFV-BLPs (50 μg) exhibited potent neutralizing activity against RVFV pseudovirus. RVFV-BLPs (50 μg) also could induce IFN-γ and IL-4 in immunized mice; these mice generated memory cells among the proliferating T cell population after immunization with RVFV-BLPs with effector memory T cells as the major population, which means that RVFV-BLPs is an effective vaccine to establish a long-lived population of memory T cells. The findings suggest that the novel RVFV-BLPs subunit vaccine has the potential to be considered a safe and effective candidate vaccine against RVFV infection.
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Affiliation(s)
- Shengnan Zhang
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Feihu Yan
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Dongping Liu
- The Nanjing Unicorn Academy of Innovation, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Nanjing, China
| | - Entao Li
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Na Feng
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Shengnan Xu
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Hualei Wang
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Yuwei Gao
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Songtao Yang
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
- *Correspondence: Songtao Yang,
| | - Yongkun Zhao
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
- Yongkun Zhao,
| | - Xianzhu Xia
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
- Xianzhu Xia,
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9
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Dai W, Du H, Li S, Wu R. Cervicovaginal Microbiome Factors in Clearance of Human Papillomavirus Infection. Front Oncol 2021; 11:722639. [PMID: 34395294 PMCID: PMC8355615 DOI: 10.3389/fonc.2021.722639] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 07/13/2021] [Indexed: 01/13/2023] Open
Abstract
Persistent high-risk human papillomavirus (hrHPV) infection is the highest risk to cervical cancer which is the fourth most common cancer in women worldwide. A growing body of literatures demonstrate the role of cervicovaginal microbiome (CVM) in hrHPV susceptibility and clearance, suggesting the promise of CVM-targeted interventions in protecting against or eliminating HPV infection. Nevertheless, the CVM-HPV-host interactions are largely unknown. In this review, we summarize imbalanced CVM in HPV-positive women, with or without cervical diseases, and the progress of exploring CVM resources in HPV clearance. In addition, microbe- and host-microbe interactions in HPV infection and elimination are reviewed to understand the role of CVM in remission of HPV infection. Lastly, the feasibility of CVM-modulated and -derived products in promoting HPV clearance is discussed. Information in this article will provide valuable reference for researchers interested in cervical cancer prevention and therapy.
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Affiliation(s)
- Wenkui Dai
- Department of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen, China.,Institute of Obstetrics and Gynecology, Shenzhen Peking University-The Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, China.,Shenzhen Key Laboratory on Technology for Early Diagnosis of Major Gynecologic Diseases, Shenzhen, China
| | - Hui Du
- Department of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen, China.,Institute of Obstetrics and Gynecology, Shenzhen Peking University-The Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, China.,Shenzhen Key Laboratory on Technology for Early Diagnosis of Major Gynecologic Diseases, Shenzhen, China
| | - Shuaicheng Li
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China
| | - Ruifang Wu
- Department of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen, China.,Institute of Obstetrics and Gynecology, Shenzhen Peking University-The Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, China.,Shenzhen Key Laboratory on Technology for Early Diagnosis of Major Gynecologic Diseases, Shenzhen, China
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10
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Cid R, Bolívar J. Platforms for Production of Protein-Based Vaccines: From Classical to Next-Generation Strategies. Biomolecules 2021; 11:1072. [PMID: 34439738 PMCID: PMC8394948 DOI: 10.3390/biom11081072] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/16/2021] [Accepted: 07/17/2021] [Indexed: 12/12/2022] Open
Abstract
To date, vaccination has become one of the most effective strategies to control and reduce infectious diseases, preventing millions of deaths worldwide. The earliest vaccines were developed as live-attenuated or inactivated pathogens, and, although they still represent the most extended human vaccine types, they also face some issues, such as the potential to revert to a pathogenic form of live-attenuated formulations or the weaker immune response associated with inactivated vaccines. Advances in genetic engineering have enabled improvements in vaccine design and strategies, such as recombinant subunit vaccines, have emerged, expanding the number of diseases that can be prevented. Moreover, antigen display systems such as VLPs or those designed by nanotechnology have improved the efficacy of subunit vaccines. Platforms for the production of recombinant vaccines have also evolved from the first hosts, Escherichia coli and Saccharomyces cerevisiae, to insect or mammalian cells. Traditional bacterial and yeast systems have been improved by engineering and new systems based on plants or insect larvae have emerged as alternative, low-cost platforms. Vaccine development is still time-consuming and costly, and alternative systems that can offer cost-effective and faster processes are demanding to address infectious diseases that still do not have a treatment and to face possible future pandemics.
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Affiliation(s)
- Raquel Cid
- ADL Bionatur Solutions S.A., Av. del Desarrollo Tecnológico 11, 11591 Jerez de la Frontera, Spain
| | - Jorge Bolívar
- Department of Biomedicine, Biotechnology and Public Health-Biochemistry and Molecular Biology, Campus Universitario de Puerto Real, University of Cadiz, 11510 Puerto Real, Spain
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11
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Abdelrahman F, Easwaran M, Daramola OI, Ragab S, Lynch S, Oduselu TJ, Khan FM, Ayobami A, Adnan F, Torrents E, Sanmukh S, El-Shibiny A. Phage-Encoded Endolysins. Antibiotics (Basel) 2021; 10:124. [PMID: 33525684 PMCID: PMC7912344 DOI: 10.3390/antibiotics10020124] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 01/16/2021] [Accepted: 01/26/2021] [Indexed: 12/17/2022] Open
Abstract
Due to the global emergence of antibiotic resistance, there has been an increase in research surrounding endolysins as an alternative therapeutic. Endolysins are phage-encoded enzymes, utilized by mature phage virions to hydrolyze the cell wall from within. There is significant evidence that proves the ability of endolysins to degrade the peptidoglycan externally without the assistance of phage. Thus, their incorporation in therapeutic strategies has opened new options for therapeutic application against bacterial infections in the human and veterinary sectors, as well as within the agricultural and biotechnology sectors. While endolysins show promising results within the laboratory, it is important to document their resistance, safety, and immunogenicity for in-vivo application. This review aims to provide new insights into the synergy between endolysins and antibiotics, as well as the formulation of endolysins. Thus, it provides crucial information for clinical trials involving endolysins.
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Affiliation(s)
- Fatma Abdelrahman
- Center for Microbiology and Phage Therapy, Biomedical Sciences, Zewail City of Science and Technology, Giza 12578, Egypt
| | - Maheswaran Easwaran
- Department of Biomedical Engineering, Sethu Institute of Technology, Tamil Nadu 626115, India
| | - Oluwasegun I Daramola
- Department of Biomedical Laboratory Science, College of Medicine, University of Ibadan, Ibadan 200284, Nigeria
| | - Samar Ragab
- Center for Microbiology and Phage Therapy, Biomedical Sciences, Zewail City of Science and Technology, Giza 12578, Egypt
| | - Stephanie Lynch
- School of Life Sciences, La Trobe University, Melbourne, VIC 3086, Australia
| | - Tolulope J Oduselu
- Department of Biomedical Laboratory Science, College of Medicine, University of Ibadan, Ibadan 200284, Nigeria
| | - Fazal Mehmood Khan
- Center for Biosafety Mega-Science, Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China
- International College, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Akomolafe Ayobami
- Department of Biomedical Laboratory Science, College of Medicine, University of Ibadan, Ibadan 200284, Nigeria
| | - Fazal Adnan
- Atta ur Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad 24090, Pakistan
| | - Eduard Torrents
- Bacterial Infections: Antimicrobial Therapies Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
- Microbiology Section, Department of Genetics, Microbiology, and Statistics, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain
| | - Swapnil Sanmukh
- Bacterial Infections: Antimicrobial Therapies Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
| | - Ayman El-Shibiny
- Center for Microbiology and Phage Therapy, Biomedical Sciences, Zewail City of Science and Technology, Giza 12578, Egypt
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12
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Strategies to display heterologous proteins on the cell surface of lactic acid bacteria using as anchor the C-terminal domain of Lactobacillus acidophilus SlpA. World J Microbiol Biotechnol 2020; 36:169. [DOI: 10.1007/s11274-020-02945-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 09/30/2020] [Indexed: 01/19/2023]
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13
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Taghinezhad-S S, Keyvani H, Bermúdez-Humarán LG, Donders GGG, Fu X, Mohseni AH. Twenty years of research on HPV vaccines based on genetically modified lactic acid bacteria: an overview on the gut-vagina axis. Cell Mol Life Sci 2020; 78:1191-1206. [PMID: 32979054 PMCID: PMC7519697 DOI: 10.1007/s00018-020-03652-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 09/03/2020] [Accepted: 09/16/2020] [Indexed: 10/27/2022]
Abstract
Most cervical cancer (CxCa) are related to persistent infection with high-risk human papillomavirus (HR-HPV) in the cervical mucosa, suggesting that an induction of mucosal cell-mediated immunity against HR-HPV oncoproteins can be a promising strategy to fight HPV-associated CxCa. From this perspective, many pre-clinical and clinical trials have proved the potential of lactic acid bacteria (LAB) genetically modified to deliver recombinant antigens to induce mucosal, humoral and cellular immunity in the host. Altogether, the outcomes of these studies suggest that there are several key factors to consider that may offer guidance on improvement protein yield and improving immune response. Overall, these findings showed that oral LAB-based mucosal HPV vaccines expressing inducible surface-anchored antigens display a higher potential to induce particularly specific systemic and mucosal cytotoxic cellular immune responses. In this review, we describe all LAB-based HPV vaccine investigations by reviewing databases from international studies between 2000 and 2020. Our aim is to promote the therapeutic HPV vaccines knowledge and to complete the gaps in this field to empower scientists worldwide to make proper decisions regarding the best strategies for the development of therapeutic HPV vaccines.
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Affiliation(s)
- Sedigheh Taghinezhad-S
- Department of Microbiology, Faculty of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran, 1477893855, Iran
| | - Hossein Keyvani
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, 1449614535, Iran
| | | | - Gilbert G G Donders
- Department of Obstetrics and Gynaecology, Antwerp University Hospital, Antwerp, Belgium.,Femicare Clinical Research for Women, Tienen, Belgium
| | - Xiangsheng Fu
- Department of Gastroenterology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, Sichuan, China
| | - Amir Hossein Mohseni
- Department of Microbiology, Faculty of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran, 1477893855, Iran.
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14
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Anchoring of heterologous proteins in multiple Lactobacillus species using anchors derived from Lactobacillus plantarum. Sci Rep 2020; 10:9640. [PMID: 32541679 PMCID: PMC7295990 DOI: 10.1038/s41598-020-66531-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 05/22/2020] [Indexed: 12/12/2022] Open
Abstract
Members of the genus Lactobacillus have a long history in food applications and are considered as promising and safe hosts for delivery of medically interesting proteins. We have assessed multiple surface anchors derived from Lactobacillus plantarum for protein surface display in multiple Lactobacillus species, using a Mycobacterium tuberculosis hybrid antigen as test protein. The anchors tested were a lipoprotein anchor and two cell wall anchors, one non-covalent (LysM domain) and one covalent (sortase-based anchoring using the LPXTG motif). Thus, three different expression vectors for surface-anchoring were tested in eight Lactobacillus species. When using the LPXTG and LysM cell wall anchors, surface display, as assessed by flow cytometry and fluorescence microscopy, was observed in all species except Lactobacillus acidophilus. Use of the cell membrane anchor revealed more variation in the apparent degree of surface-exposure among the various lactobacilli. Overproduction of the secreted and anchored antigen impaired bacterial growth rate to extents that varied among the lactobacilli and were dependent on the type of anchor. Overall, these results show that surface anchors derived from L. plantarum are promising candidates for efficient anchoring of medically interesting proteins in other food grade Lactobacillus species.
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15
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Smalley Rumfield C, Roller N, Pellom ST, Schlom J, Jochems C. Therapeutic Vaccines for HPV-Associated Malignancies. Immunotargets Ther 2020; 9:167-200. [PMID: 33117742 PMCID: PMC7549137 DOI: 10.2147/itt.s273327] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 09/03/2020] [Indexed: 12/13/2022] Open
Abstract
Human papillomavirus (HPV)-related malignancies are responsible for almost all cases of cervical cancer in women, and over 50% of all cases of head and neck carcinoma. Worldwide, HPV-positive malignancies account for 4.5% of the global cancer burden, or over 600,000 cases per year. HPV infection is a pressing public health issue, as more than 80% of all individuals have been exposed to HPV by age 50, representing an important target for vaccine development to reduce the incidence of cancer and the economic cost of HPV-related health issues. The approval of Gardasil® as a prophylactic vaccine for high-risk HPV 16 and 18 and low-risk HPV6 and 11 for people aged 11-26 in 2006, and of Cervarix® in 2009, revolutionized the field and has since reduced HPV infection in young populations. Unfortunately, prophylactic vaccination does not induce immunity in those with established HPV infections or HPV-induced neoplasms, and there are currently no therapeutic HPV vaccines approved by the US Food and Drug Administration. This comprehensive review will detail the progress made in the development of therapeutic vaccines against high-risk HPV types, and potential combinations with other immunotherapeutic agents for more efficient and rational designs of combination treatments for HPV-associated malignancies.
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Affiliation(s)
- Claire Smalley Rumfield
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Nicholas Roller
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Samuel Troy Pellom
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jeffrey Schlom
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Correspondence: Jeffrey Schlom Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, 10 Center Drive, Room 8B09, Bethesda, MD20892, USATel +1 240-858-3463Fax +1 240-541-4558 Email
| | - Caroline Jochems
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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16
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Kuczkowska K, Øverland L, Rocha SDC, Eijsink VGH, Mathiesen G. Comparison of eight Lactobacillus species for delivery of surface-displayed mycobacterial antigen. Vaccine 2019; 37:6371-6379. [PMID: 31526620 DOI: 10.1016/j.vaccine.2019.09.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 09/04/2019] [Indexed: 12/26/2022]
Abstract
Lactobacillus spp. comprise a large group of Gram-positive lactic acid bacteria with varying physiological, ecological and immunomodulatory properties that are widely exploited by mankind, primarily in food production and as health-promoting probiotics. Recent years have shown increased interest in using lactobacilli for delivery of vaccines, mainly due to their ability to skew the immune system towards pro-inflammatory responses. We have compared the potential of eight Lactobacillus species, L. plantarum, L. brevis, L. curvatus, L. rhamnosus, L. sakei, L. gasseri, L. acidophilus and L. reuteri, as immunogenic carriers of the Ag85B-ESAT-6 antigen from Mycobacterium tuberculosis. Surface-display of the antigen was achieved in L. plantarum, L. brevis, L. gasseri and L. reuteri and these strains were further analyzed in terms of their in vitro and in vivo immunogenicity. All strains activated human dendritic cells in vitro. Immunization of mice using a homologous prime-boost regimen comprising a primary subcutaneous immunization followed by three intranasal boosters, led to slightly elevated IgG levels in serum in most strains, and, importantly, to significantly increased levels of antigen-specific mucosal IgA. Cellular immunity was assessed by studying antigen-specific T cell responses in splenocytes, which did not reveal proliferation as assessed by the expression of Ki67, but which showed clear antigen-specific IFN-γ and IL-17 responses for some of the groups. Taken together, the present results indicate that L. plantarum and L. brevis are the most promising carriers of TB vaccines.
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Affiliation(s)
- Katarzyna Kuczkowska
- Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences (NMBU), P.O. Box 5003, 1432 Aas, Norway.
| | - Lise Øverland
- Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences (NMBU), P.O. Box 5003, 1432 Aas, Norway
| | - Sergio D C Rocha
- Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences (NMBU), P.O. Box 5003, 1432 Aas, Norway
| | - Vincent G H Eijsink
- Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences (NMBU), P.O. Box 5003, 1432 Aas, Norway
| | - Geir Mathiesen
- Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences (NMBU), P.O. Box 5003, 1432 Aas, Norway
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17
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Alexander LM, Oh JH, Stapleton DS, Schueler KL, Keller MP, Attie AD, van Pijkeren JP. Exploiting Prophage-Mediated Lysis for Biotherapeutic Release by Lactobacillus reuteri. Appl Environ Microbiol 2019; 85:e02335-18. [PMID: 30683744 PMCID: PMC6498169 DOI: 10.1128/aem.02335-18] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 01/18/2019] [Indexed: 12/13/2022] Open
Abstract
Lactobacillus reuteri has the potential to be developed as a microbial therapeutic delivery platform because of an established safety profile, health-promoting properties, and available genome editing tools. Here, we show that L. reuteri VPL1014 exhibits a low mutation rate compared to other Gram-positive bacteria, which we expect will contribute to the stability of genetically modified strains. VPL1014 encodes two biologically active prophages, which are induced during gastrointestinal transit. We hypothesized that intracellularly accumulated recombinant protein can be released following bacteriophage-mediated lysis. To test this, we engineered VPL1014 to accumulate leptin, our model protein, inside the cell. In vitro prophage induction of recombinant VPL1014 released leptin into the extracellular milieu, which corresponded to bacteriophage production. We also employed a plasmid system that does not require antibiotic in the growth medium for plasmid maintenance. Collectively, these data provide new avenues to exploit native prophages to deliver therapeutic molecules.IMPORTANCE Lactic acid bacteria (LAB) have been explored as potential biotherapeutic vehicles for the past 20 years. To secrete a therapeutic in the extracellular milieu, one typically relies on the bacterial secretion pathway, i.e., the Sec pathway. Overexpression of a secreted protein can overload the secretory pathway and impact the organism's fitness, and optimization of the signal peptide is also required to maximize the efficiency of the release of mature protein. Here, we describe a previously unexplored approach to release therapeutics from the probiotic Lactobacillus reuteri We demonstrate that an intracellularly accumulated recombinant protein is released following prophage activation. Since we recently demonstrated that prophages are activated during gastrointestinal transit, we propose that this method will provide a straightforward and efficient approach to deliver therapeutics in vivo.
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Affiliation(s)
- Laura M Alexander
- Department of Food Science, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Jee-Hwan Oh
- Department of Food Science, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Donald S Stapleton
- Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Kathryn L Schueler
- Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Mark P Keller
- Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Alan D Attie
- Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA
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Jacouton E, Michel ML, Torres-Maravilla E, Chain F, Langella P, Bermúdez-Humarán LG. Elucidating the Immune-Related Mechanisms by Which Probiotic Strain Lactobacillus casei BL23 Displays Anti-tumoral Properties. Front Microbiol 2019; 9:3281. [PMID: 30687269 PMCID: PMC6336716 DOI: 10.3389/fmicb.2018.03281] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Accepted: 12/17/2018] [Indexed: 12/13/2022] Open
Abstract
We have recently described antitumor properties of Lactobacillus casei BL23 strain in both a mouse allograft model of human papilloma virus (HPV)-induced cancer and dimethylhydrazine-associated colorectal cancer. However, the mechanisms underlying these beneficial effects are still unknown. Interestingly, in vitro cellular models show that this bacterium is able to stimulate the production of high levels of IL-2. Because this cytokine has well-known antitumor properties, we decided to explore its role in the anti-cancer effects of BL23 using the HPV-induced cancer model. We found a negative correlation between IL-2 and tumor size confirming the necessity of IL-2 to protect from tumor development. Then, we blocked IL-2 synthesis using neutralizing monoclonal antibodies in mice that were challenged with lethal levels of tumor cells; this led to a significant reduction in the protective abilities of BL23. Next, we used a genetically modified strain of Lactococcus lactis to deliver exogenous IL-2 to the system, and in doing so, we were able to partially mimic the antitumor properties of BL23. Additionally, we showed the systemic role of T-cells in tumor protection through a negative correlation between tumor size and T-cells subpopulations and an increasement of BL23-specific local Foxp3 levels in tumor-bearing mice. Finally, we observed a negative correlation between tumor size and NK+ cells, but local recruitment of NK cells and cytotoxic activity appeared specific to BL23 treatment. Taken together, our data suggest that IL-2 signaling pathway plays an important role in the anti-tumoral effects of probiotic strain L. casei BL23. These results encourage further investigation in the use of probiotic strains for potential therapeutic applications to clinical practice, in particular for the treatment of colorectal cancer. Furthermore, our approach could be extended and applied to other potential beneficial microorganisms, such as gut microbiota, in order to better understand the crosstalk between microbes and the host.
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Affiliation(s)
- Elsa Jacouton
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Marie-Laure Michel
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | | | - Florian Chain
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Philippe Langella
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
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19
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Abstract
Cervical cancer is a common malignant cancer among women worldwide. Changes in the vaginal microecological environment lead to multiple gynecological diseases, including cervical cancer. Recent research has shown that Lactobacillus may play an important role in the occurrence and development of cervical cancer. This review explores the role of Lactobacillus in cervical cancer. A total of 29 articles were included after identification and screening. The pertinent literature on Lactobacillus in cervical cancer from two perspectives, including clinical studies and experimental studies, was analyzed. An association network for the mechanism by which Lactobacillus induces cervical cancer was constructed. In addition, we provide direction and insight for further research on the role of Lactobacillus in cervical cancer.
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Affiliation(s)
- Xi Yang
- Department of Intervention and Radiotherapy, Huzhou Central Hospital
| | - Miao Da
- Medical College of Nursing, Huzhou University
| | | | - Quan Qi
- Department of Medical Oncology
| | - Chun Zhang
- Department of Infectious Diseases, Huzhou Central Hospital, Huzhou, Zhejiang Province, People's Republic of China
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20
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LeCureux JS, Dean GA. Lactobacillus Mucosal Vaccine Vectors: Immune Responses against Bacterial and Viral Antigens. mSphere 2018; 3:e00061-18. [PMID: 29769376 PMCID: PMC5956152 DOI: 10.1128/msphere.00061-18] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Lactic acid bacteria (LAB) have been utilized since the 1990s for therapeutic heterologous gene expression. The ability of LAB to elicit an immune response against expressed foreign antigens has led to their exploration as potential mucosal vaccine candidates. LAB vaccine vectors offer many attractive advantages: simple, noninvasive administration (usually oral or intranasal), the acceptance and stability of genetic modifications, relatively low cost, and the highest level of safety possible. Experimentation using LAB of the genus Lactobacillus has become popular in recent years due to their ability to elicit strong systemic and mucosal immune responses. This article reviews Lactobacillus vaccine constructs, including Lactobacillus species, antigen expression, model organisms, and in vivo immune responses, with a primary focus on viral and bacterial antigens.
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Affiliation(s)
- Jonathan S LeCureux
- Department of Natural and Applied Sciences, Evangel University, Springfield, Missouri, USA
| | - Gregg A Dean
- Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA
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21
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RETRACTED CHAPTER: Changing Paradigm of Probiotics from Functional Foods to Biotherapeutic Agents. Microb Biotechnol 2018. [DOI: 10.1007/978-981-10-7140-9_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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Antibodies Targeting Hsa and PadA Prevent Platelet Aggregation and Protect Rats against Experimental Endocarditis Induced by Streptococcus gordonii. Infect Immun 2016; 84:3557-3563. [PMID: 27736784 DOI: 10.1128/iai.00810-16] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 09/22/2016] [Indexed: 01/24/2023] Open
Abstract
Streptococcus gordonii and related species of oral viridans group streptococci (VGS) are common etiological agents of infective endocarditis (IE). We explored vaccination as a strategy to prevent VGS-IE, using a novel antigen-presenting system based on non-genetically modified Lactococcus lactis displaying vaccinogens on its surface. Hsa and PadA are surface-located S. gordonii proteins implicated in platelet adhesion and aggregation, which are key steps in the pathogenesis of IE. This function makes them ideal targets for vaccination against VGS-IE. In the present study, we report the use of nonliving L. lactis displaying at its surface the N-terminal region of Hsa or PadA by means of the cell wall binding domain of Lactobacillus casei A2 phage lysine LysA2 (Hsa-LysA2 and PadA-LysA2, respectively) and investigation of their ability to elicit antibodies in rats and to protect them from S. gordonii experimental IE. Immunized and control animals with catheter-induced sterile aortic valve vegetations were inoculated with 106 CFU of S. gordonii The presence of IE was evaluated 24 h later. Immunization of rats with L. lactis Hsa-LysA2, L. lactis PadA-LysA2, or both protected 6/11 (55%), 6/11 (55%), and 11/12 (91%) animals, respectively, from S. gordonii IE (P < 0.05 versus controls). Protection correlated with the induction of high levels of functional antibodies against both Hsa and PadA that delayed or totally inhibited platelet aggregation by S. gordonii These results support the value of L. lactis as a system for antigen delivery and of Hsa and PadA as promising candidates for a vaccine against VGS-IE.
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23
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Mao R, Wu D, Wang Y. Surface display on lactic acid bacteria without genetic modification: strategies and applications. Appl Microbiol Biotechnol 2016; 100:9407-9421. [PMID: 27649963 DOI: 10.1007/s00253-016-7842-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 08/31/2016] [Accepted: 09/03/2016] [Indexed: 12/21/2022]
Abstract
Microbial cell surface display has attracted greater attention than ever and has numerous potential applications in biotechnology. With the safety and probiotic properties, lactic acid bacteria (LAB) have been used widely in food and industrial applications. In order to circumvent using genetically modified microorganisms which face low public acceptance and severe regulatory scrutiny, surface-engineered LAB without genetical modification are more preferred. According to the way used to obtain the fusion protein containing the passenger molecule and anchoring domain, the genetic or chemical approaches can be used to construct these surface-engineered LAB. In addition to the viable wide-type LAB, non-living bacterial-like particles (BLP) can be attached by these fusion proteins added from outside. Compared to the living LAB, BLP have a higher binding capacity and less anticarrier response. Mucosal vaccines are the predominant application of these surface-engineered LAB with no genetical modification.
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Affiliation(s)
- Ruifeng Mao
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, People's Republic of China
| | - Dongli Wu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, People's Republic of China
| | - Yefu Wang
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, People's Republic of China.
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Lactobacillus casei BL23 regulates Treg and Th17 T-cell populations and reduces DMH-associated colorectal cancer. J Gastroenterol 2016; 51:862-73. [PMID: 26749362 DOI: 10.1007/s00535-015-1158-9] [Citation(s) in RCA: 107] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 12/19/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND Chronic intestinal inflammation alters host physiology and could lead to colorectal cancer (CRC). We have previously reported beneficial effects of the probiotic strain of Lactobacillus casei BL23 in different murine models of intestinal inflammation. In addition, there is an emerging interest on the potential beneficial effects of probiotics to treat CRC. We thus explored whether L. casei BL23 displays protective effects on CRC. METHODS Mice were subcutaneously injected with 1,2-dimethylhydrazine (DMH) weekly during 10 weeks and orally administered with L. casei BL23 in the drinking water until the 10th week. Multiple plaque lesions in the large intestine were observed macroscopically and counted and intestinal tissues were also histologically analyzed. Finally, T-cell populations and cytokine production were evaluated after co-incubation of L. casei BL23 with spleen cells from non-treated mice to determine the immuno-modulatory effects of this bacterium. RESULTS Our results show that oral treatment with this probiotic bacterium modulates host immune responses and significantly protect mice against DMH-induced CRC. This protection may be associated with the modulation of regulatory T-cells towards a Th17-biased immune response accompanied by the expression of regulatory cytokines (IL-6, IL-17, IL-10 and TGF-β), as demonstrated in L. casei BL23-treated splenocytes, but also with the colonic expression of IL-22 observed in vivo on L. casei BL23-treated mice; suggesting the induction of a fine-tune Th17-biased response. CONCLUSIONS Altogether our results reveal the high potential of L. casei BL23 to treat CRC and opens new frontiers for the study of immunomodulatory functions of probiotics.
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25
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Lactic acid bacteria as mucosal delivery vehicles: a realistic therapeutic option. Appl Microbiol Biotechnol 2016; 100:5691-701. [DOI: 10.1007/s00253-016-7557-x] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 04/12/2016] [Accepted: 04/14/2016] [Indexed: 12/11/2022]
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26
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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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27
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Almeida JF, Breyner NM, Mahi M, Ahmed B, Benbouziane B, Boas PCBV, Miyoshi A, Azevedo V, Langella P, Bermúdez-Humarán LG, Chatel JM. Expression of fibronectin binding protein A (FnBPA) from Staphylococcus aureus at the cell surface of Lactococcus lactis improves its immunomodulatory properties when used as protein delivery vector. Vaccine 2016; 34:1312-8. [PMID: 26854905 DOI: 10.1016/j.vaccine.2016.01.022] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Revised: 01/07/2016] [Accepted: 01/13/2016] [Indexed: 12/18/2022]
Abstract
A recombinant strain of Lactococcus lactis displaying a cell-surface anchored fibronectin binding protein A (FnBPA) from Staphylococcus aureus (LL-FnBPA) had been shown to be more efficient in delivering plasmid than its wild-type counterpart both in vitro and in vivo, and have the ability to orientate the immune response toward a Th2 profile in a context of a DNA vaccination. The aim of this work was to test whether this LL-FnBPA strain could shape the immune response after mucosal administration in mice. For this, we used a mouse model of human papilloma virus (HPV)-induced cancer and a L. lactis strain displaying at its cell surface both HPV-16-E7 antigen (LL-E7) and FnBPA (LL-E7+FnBPA). Our results revealed a more efficient systemic Th1 immune response with recombinant LL-E7+FnBPA. Furthermore, mice vaccinated with LL-E7+FnBPA were better protected when challenged with HPV-16-induced tumors. Altogether, the results suggest that FnBPA displays adjuvant properties when used in the context of mucosal delivery using L. lactis as a live vector.
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Affiliation(s)
- Juliana F Almeida
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France; UFMG, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Natalia M Breyner
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France; UFMG, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Miloud Mahi
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France; Laboratory of Food Microbiology, Biology Department, University of Nature, Life and Hearth Sciences, Theniat el Had Street, 44225 Khemis Miliana, Algeria
| | - Bensoltane Ahmed
- Laboratory of Food Microbiology, Biology Department, University of Nature, Life and Hearth Sciences, Theniat el Had Street, 44225 Khemis Miliana, Algeria
| | - Bouasria Benbouziane
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France; Laboratory of Beneficial Microorganisms, Functional Foods and Health, Department of Biology, University of Mostaganem, Lahcen Street, P.O. Box 300, Mostaganem 27000, Algeria
| | - Priscilla C B Vilas Boas
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France; UFMG, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Anderson Miyoshi
- UFMG, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Vasco Azevedo
- UFMG, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Philippe Langella
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France
| | - Luis G Bermúdez-Humarán
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France
| | - Jean-Marc Chatel
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France.
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Rosales-Mendoza S, Angulo C, Meza B. Food-Grade Organisms as Vaccine Biofactories and Oral Delivery Vehicles. Trends Biotechnol 2016; 34:124-136. [DOI: 10.1016/j.tibtech.2015.11.007] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 11/11/2015] [Accepted: 11/20/2015] [Indexed: 12/26/2022]
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Kalyanasundram J, Chia SL, Song AAL, Raha AR, Young HA, Yusoff K. Surface display of glycosylated Tyrosinase related protein-2 (TRP-2) tumour antigen on Lactococcus lactis. BMC Biotechnol 2015; 15:113. [PMID: 26715153 PMCID: PMC4696278 DOI: 10.1186/s12896-015-0231-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 12/22/2015] [Indexed: 01/27/2023] Open
Abstract
Background The exploitation of the surface display system of food and commensal lactic acid bacteria (LAB) for bacterial, viral, or protozoan antigen delivery has received strong interest recently. The Generally Regarded as Safe (GRAS) status of the Lactococcus lactis coupled with a non-recombinant strategy of in-trans surface display, provide a safe platform for therapeutic drug and vaccine development. However, production of therapeutic proteins fused with cell-wall anchoring motifs is predominantly limited to prokaryotic expression systems. This presents a major disadvantage in the surface display system particularly when glycosylation has been recently identified to significantly enhance epitope presentation. In this study, the glycosylated murine Tyrosinase related protein-2 (TRP-2) with the ability to anchor onto the L. lactis cell wall was produced in suspension adapted Chinese Hamster Ovary (CHO-S) cells by expressing TRP-2 fused with cell wall anchoring LysM motif (cA) at the C-terminus. Results A total amount of 33 μg of partially purified TRP-2-cA from ~6.0 g in wet weight of CHO-S cells was purified by His-tag affinity chromatography. The purified TRP-2-cA protein was shown to be N-glycosylated and successfully anchored to the L. lactis cell wall. Conclusions Thus cell surface presentation of glycosylated mammalian antigens may now permit development of novel and inexpensive vaccine platforms.
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Affiliation(s)
- Jeevanathan Kalyanasundram
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Selangor Darul Ehsan, Malaysia.
| | - Suet Lin Chia
- Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor Darul Ehsan, Malaysia.
| | - Adelene Ai-Lian Song
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Selangor Darul Ehsan, Malaysia.
| | - Abdul Rahim Raha
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Selangor Darul Ehsan, Malaysia. .,Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor Darul Ehsan, Malaysia.
| | - Howard A Young
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
| | - Khatijah Yusoff
- Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor Darul Ehsan, Malaysia. .,Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor Darul Ehsan, Malaysia.
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30
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Ai C, Zhang Q, Ding J, Wang G, Liu X, Tian F, Zhao J, Zhang H, Chen W. Mucosal delivery of allergen peptides expressed by Lactococcus lactis inhibit allergic responses in a BALB/c mouse model. Appl Microbiol Biotechnol 2015; 100:1915-1924. [PMID: 26621801 DOI: 10.1007/s00253-015-7187-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Revised: 11/12/2015] [Accepted: 11/17/2015] [Indexed: 02/07/2023]
Abstract
Allergen-specific immunotherapy (SIT) is considered to be the only curative treatment of allergy, but its safety is always affected by immunologic properties and quality of allergen. Recombinant allergen derivative could be a potential therapeutic strategy, but clinical studies showed that macromolecular derivatives could not avoid T cell-mediated side effects. In this study, five Der p2-derived peptides (DPs) containing major T cell epitopes of Der p2 were first artificially synthesized. Compared with Der p2 macromolecular derivative DM, these DPs not only fully eliminated IgE-binding capacity but also reduced T cells reactivity, suggesting these DPs could be better therapeutic molecules. For their application in vivo, Lactococcus lactis was engineered to express these DPs, and their protective effects were evaluated in BALB/c mice models. Western blot showed that all DPs could be produced in the recombinant strains. Mucosal delivery of these strains could inhibit Der p2-induced allergic responses in Der p2-sensitized mice, characterized by a reduction in specific IgE antibody and lung inflammatory responses. These protective effects were associated with an increase of specific IgG2a in serum and regulatory T cells in the mesenteric lymph nodes. On the whole, the suppressive effect induced by the DP mixture could be better than single DP, but a bit weaker than DM. These DPs could be promising candidate molecules for active vaccination and induction of tolerance, and thus promote the development of non-allergenic peptide in the treatment and prevention of allergy.
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Affiliation(s)
- Chunqing Ai
- National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, 116034, People's Republic of China.,State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, People's Republic of China
| | - Qiuxiang Zhang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, People's Republic of China.
| | - Junrong Ding
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, People's Republic of China
| | - Gang Wang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, People's Republic of China
| | - Xiaoming Liu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, People's Republic of China
| | - Fengwei Tian
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, People's Republic of China
| | - Jianxin Zhao
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, People's Republic of China
| | - Hao Zhang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, People's Republic of China
| | - Wei Chen
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, People's Republic of China. .,Synergistic Innovation Center for Food Safety and Nutrition, Wuxi, 214122, People's Republic of China.
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Cano-Garrido O, Seras-Franzoso J, Garcia-Fruitós E. Lactic acid bacteria: reviewing the potential of a promising delivery live vector for biomedical purposes. Microb Cell Fact 2015; 14:137. [PMID: 26377321 PMCID: PMC4573465 DOI: 10.1186/s12934-015-0313-6] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Accepted: 08/10/2015] [Indexed: 12/19/2022] Open
Abstract
Lactic acid bacteria (LAB) have a long history of safe exploitation by humans, being used for centuries in food production and preservation and as probiotic agents to promote human health. Interestingly, some species of these Gram-positive bacteria, which are generally recognized as safe organisms by the US Food and Drug Administration (FDA), are able to survive through the gastrointestinal tract (GIT), being capable to reach and colonize the intestine, where they play an important role. Besides, during the last decades, an important effort has been done for the development of tools to use LAB as microbial cell factories for the production of proteins of interest. Given the need to develop effective strategies for the delivery of prophylactic and therapeutic molecules, LAB have appeared as an appealing option for the oral, intranasal and vaginal delivery of such molecules. So far, these genetically modified organisms have been successfully used as vehicles for delivering functional proteins to mucosal tissues in the treatment of many different pathologies including GIT related pathologies, diabetes, cancer and viral infections, among others. Interestingly, the administration of such microorganisms would suppose a significant decrease in the production cost of the treatments agents since being live organisms, such vectors would be able to autonomously amplify and produce and deliver the protein of interest. In this context, this review aims to provide an overview of the use of LAB engineered as a promising alternative as well as a safety delivery platform of recombinant proteins for the treatment of a wide range of diseases.
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Affiliation(s)
- Olivia Cano-Garrido
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, 08193, Cerdanyola del Vallès, Spain. .,Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, 08193, Cerdanyola del Vallès, Spain. .,CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Bellaterra, 08193, Cerdanyola del Vallès, Spain.
| | - Joaquin Seras-Franzoso
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, 08193, Cerdanyola del Vallès, Spain. .,Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, 08193, Cerdanyola del Vallès, Spain. .,CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Bellaterra, 08193, Cerdanyola del Vallès, Spain.
| | - Elena Garcia-Fruitós
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, 08193, Cerdanyola del Vallès, Spain. .,Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, 08193, Cerdanyola del Vallès, Spain. .,CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Bellaterra, 08193, Cerdanyola del Vallès, Spain. .,Department of Ruminant Production, Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Torre Marimon, Caldes de Montbui, 08140, Barcelona, Spain.
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Nizard M, Diniz MO, Roussel H, Tran T, Ferreira LC, Badoual C, Tartour E. Mucosal vaccines: novel strategies and applications for the control of pathogens and tumors at mucosal sites. Hum Vaccin Immunother 2015; 10:2175-87. [PMID: 25424921 DOI: 10.4161/hv.29269] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The mucosal immune system displays several adaptations reflecting the exposure to the external environment. The efficient induction of mucosal immune responses also requires specific approaches, such as the use of appropriate administration routes and specific adjuvants and/or delivery systems. In contrast to vaccines delivered via parenteral routes, experimental, and clinical evidences demonstrated that mucosal vaccines can efficiently induce local immune responses to pathogens or tumors located at mucosal sites as well as systemic response. At least in part, such features can be explained by the compartmentalization of mucosal B and T cell populations that play important roles in the modulation of local immune responses. In the present review, we discuss molecular and cellular features of the mucosal immune system as well as novel immunization approaches that may lead to the development of innovative and efficient vaccines targeting pathogens and tumors at different mucosal sites.
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Affiliation(s)
- Mevyn Nizard
- a INSERM U970; Universite Paris Descartes; Sorbonne Paris-Cité; Paris, France
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33
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Mobergslien A, Vasovic V, Mathiesen G, Fredriksen L, Westby P, Eijsink VGH, Peng Q, Sioud M. Recombinant Lactobacillus plantarum induces immune responses to cancer testis antigen NY-ESO-1 and maturation of dendritic cells. Hum Vaccin Immunother 2015; 11:2664-73. [PMID: 26185907 DOI: 10.1080/21645515.2015.1056952] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Given their safe use in humans and inherent adjuvanticity, Lactic Acid Bacteria may offer several advantages over other mucosal delivery strategies for cancer vaccines. The objective of this study is to evaluate the immune responses in mice after oral immunization with Lactobacillus (L) plantarum WCFS1 expressing a cell-wall anchored tumor antigen NY-ESO-1. And to investigate the immunostimulatory potency of this new candidate vaccine on human dendritic cells (DCs). L. plantarum displaying NY-ESO-1 induced NY-ESO-1 specific antibodies and T-cell responses in mice. By contrast, L. plantarum displaying conserved proteins such as heat shock protein-27 and galectin-1, did not induce immunity, suggesting that immune tolerance to self-proteins cannot be broken by oral administration of L. plantarum. With respect to immunomodulation, immature DCs incubated with wild type or L. plantarum-NY-ESO-1 upregulated the expression of co-stimulatory molecules and secreted a large amount of interleukin (IL)-12, TNF-α, but not IL-4. Moreover, they upregulated the expression of immunosuppressive factors such as IL-10 and indoleamine 2,3-dioxygenase. Although L. plantarum-matured DCs expressed inhibitory molecules, they stimulated allogeneic T cells in-vitro. Collectively, the data indicate that L. plantarum-NY-ESO-1 can evoke antigen-specific immunity upon oral administration and induce DC maturation, raising the potential of its use in cancer immunotherapies.
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Affiliation(s)
- Anne Mobergslien
- a Department of Cancer Immunology ; Institute for Cancer Research; Oslo University Hospital ; Oslo , Norway
| | - Vlada Vasovic
- b Department of Pathology ; Oslo University Hospital ; Oslo , Norway
| | - Geir Mathiesen
- c Department of Chemistry ; Biotechnology and Food Science; Norwegian University of Life Sciences (NMBU) ; Ås , Norway
| | - Lasse Fredriksen
- c Department of Chemistry ; Biotechnology and Food Science; Norwegian University of Life Sciences (NMBU) ; Ås , Norway
| | - Phuong Westby
- a Department of Cancer Immunology ; Institute for Cancer Research; Oslo University Hospital ; Oslo , Norway
| | - Vincent G H Eijsink
- c Department of Chemistry ; Biotechnology and Food Science; Norwegian University of Life Sciences (NMBU) ; Ås , Norway
| | - Qian Peng
- b Department of Pathology ; Oslo University Hospital ; Oslo , Norway
| | - Mouldy Sioud
- a Department of Cancer Immunology ; Institute for Cancer Research; Oslo University Hospital ; Oslo , Norway
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Rodríguez-Rubio L, Gutiérrez D, Donovan DM, Martínez B, Rodríguez A, García P. Phage lytic proteins: biotechnological applications beyond clinical antimicrobials. Crit Rev Biotechnol 2015; 36:542-52. [PMID: 25603721 DOI: 10.3109/07388551.2014.993587] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Most bacteriophages encode two types of cell wall lytic proteins: endolysins (lysins) and virion-associated peptidoglycan hydrolases. Both enzymes have the ability to degrade the peptidoglycan of Gram-positive bacteria resulting in cell lysis when they are applied externally. Bacteriophage lytic proteins have a demonstrated potential in treating animal models of infectious diseases. There has also been an increase in the study of these lytic proteins for their application in areas such as food safety, pathogen detection/diagnosis, surfaces disinfection, vaccine development and nanotechnology. This review summarizes the more recent developments, outlines the full potential of these proteins to develop new biotechnological tools and discusses the feasibility of these proposals.
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Affiliation(s)
- Lorena Rodríguez-Rubio
- a DairySafe Group, Department of Technology and Biotechnology of Dairy Products , Instituto de Productos Lácteos de Asturias (IPLA-CSIC) , Villaviciosa , Asturias , Spain and
| | - Diana Gutiérrez
- a DairySafe Group, Department of Technology and Biotechnology of Dairy Products , Instituto de Productos Lácteos de Asturias (IPLA-CSIC) , Villaviciosa , Asturias , Spain and
| | - David M Donovan
- b Animal Biosciences and Biotechnology Laboratory , BARC, ARS, USDA , Beltsville , MD , USA
| | - Beatriz Martínez
- a DairySafe Group, Department of Technology and Biotechnology of Dairy Products , Instituto de Productos Lácteos de Asturias (IPLA-CSIC) , Villaviciosa , Asturias , Spain and
| | - Ana Rodríguez
- a DairySafe Group, Department of Technology and Biotechnology of Dairy Products , Instituto de Productos Lácteos de Asturias (IPLA-CSIC) , Villaviciosa , Asturias , Spain and
| | - Pilar García
- a DairySafe Group, Department of Technology and Biotechnology of Dairy Products , Instituto de Productos Lácteos de Asturias (IPLA-CSIC) , Villaviciosa , Asturias , Spain and
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Panatto D, Amicizia D, Bragazzi NL, Rizzitelli E, Tramalloni D, Valle I, Gasparini R. Human Papillomavirus Vaccine. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2015:231-322. [DOI: 10.1016/bs.apcsb.2015.08.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Aragón F, Perdigón G, LeBlanc ADMD. Modification in the diet can induce beneficial effects against breast cancer. World J Clin Oncol 2014; 5:455-464. [PMID: 25114859 PMCID: PMC4127615 DOI: 10.5306/wjco.v5.i3.455] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 05/15/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
The population tends to consume foods that in addition to their nutritional values can offer some benefits to their health. There are many epidemiological evidences and research studies in animal models suggesting that diet plays an important role in breast cancer prevention or progression. This review summarized some of the relevant researches about nutrition and cancer during the last years, especially in breast cancer. The analysis of probiotics and fermented products containing lactic acid bacteria in cancer prevention and/or treatment was especially discussed. It was observed that a balance of fatty acids similar to those of traditional Mediterranean diet, the consumption of fruits and vegetables, dietary fiber intake, vitamin supplementation are, along with the intake of probiotic products, the most extensively studied by the negative association to breast cancer risk. The consumption of probiotics and fermented products containing lactic acid bacteria was associated to reduce breast cancer risk in some epidemiological studies. The use of animal models showed the modulation of the host’s immune response as one of the important effects associated to the benefices observed with most probiotics. However; future assays in human are very important before the medical community can accept the addition of probiotic or fermented milks containing lactic acid bacteria as supplements for cancer patients.
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Hanin A, Culligan EP, Casey PG, Bahey-El-Din M, Hill C, Gahan CGM. Two-tiered biological containment strategy for Lactococcus lactis-based vaccine or immunotherapy vectors. Hum Vaccin Immunother 2013; 10:333-7. [PMID: 24196273 DOI: 10.4161/hv.26954] [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: 11/19/2022] Open
Abstract
The concept of biological containment was developed as a strategy to prevent environmental dissemination of engineered live vaccine or drug delivery vehicles. A mutation in the gene encoding thymidylate synthase (thyA), a key enzyme in the pyrimidine biosynthetic pathway, has previously been shown to limit growth of L. lactis vectors under restrictive conditions. We hypothesized that further mutations in the pyrimidine biosynthetic pathway might enhance the stability and safety of live L. lactis vectors. We show that a double mutation in the genes encoding ThyA and CTP synthase (PyrG) in L. lactis confers double auxotrophy for both thymidine and cytidine. However, the combination of two mutations failed to enhance the biological containment phenotype of the engineered strain. In the absence of thymine/thymidine, the thyA mutant exhibited a strong bactericidal phenotype. However, creation of the double mutant caused the loss of this phenotype, though survival in the mouse GI tract was enhanced. The implications for biological containment of live L. lactis based delivery vectors are discussed.
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Affiliation(s)
- Aurelie Hanin
- Alimentary Pharmabiotic Centre; University College Cork; Cork, Ireland; Department of Microbiology; University College Cork; Cork, Ireland
| | - Eamonn P Culligan
- Alimentary Pharmabiotic Centre; University College Cork; Cork, Ireland; Department of Microbiology; University College Cork; Cork, Ireland
| | - Pat G Casey
- Alimentary Pharmabiotic Centre; University College Cork; Cork, Ireland; Department of Microbiology; University College Cork; Cork, Ireland
| | - Mohammed Bahey-El-Din
- Department of Pharmaceutical Microbiology; Faculty of Pharmacy; Alexandria University; Alexandria, Egypt
| | - Colin Hill
- 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
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Regulski K, Courtin P, Kulakauskas S, Chapot-Chartier MP. A novel type of peptidoglycan-binding domain highly specific for amidated D-Asp cross-bridge, identified in Lactobacillus casei bacteriophage endolysins. J Biol Chem 2013; 288:20416-26. [PMID: 23733182 DOI: 10.1074/jbc.m112.446344] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Peptidoglycan hydrolases (PGHs) are responsible for bacterial cell lysis. Most PGHs have a modular structure comprising a catalytic domain and a cell wall-binding domain (CWBD). PGHs of bacteriophage origin, called endolysins, are involved in bacterial lysis at the end of the infection cycle. We have characterized two endolysins, Lc-Lys and Lc-Lys-2, identified in prophages present in the genome of Lactobacillus casei BL23. These two enzymes have different catalytic domains but similar putative C-terminal CWBDs. By analyzing purified peptidoglycan (PG) degradation products, we showed that Lc-Lys is an N-acetylmuramoyl-L-alanine amidase, whereas Lc-Lys-2 is a γ-D-glutamyl-L-lysyl endopeptidase. Remarkably, both lysins were able to lyse only Gram-positive bacterial strains that possess PG with D-Ala(4)→D-Asx-L-Lys(3) in their cross-bridge, such as Lactococcus casei, Lactococcus lactis, and Enterococcus faecium. By testing a panel of L. lactis cell wall mutants, we observed that Lc-Lys and Lc-Lys-2 were not able to lyse mutants with a modified PG cross-bridge, constituting D-Ala(4)→L-Ala-(L-Ala/L-Ser)-L-Lys(3); moreover, they do not lyse the L. lactis mutant containing only the nonamidated D-Asp cross-bridge, i.e. D-Ala(4)→D-Asp-L-Lys(3). In contrast, Lc-Lys could lyse the ampicillin-resistant E. faecium mutant with 3→3 L-Lys(3)-D-Asn-L-Lys(3) bridges replacing the wild-type 4→3 D-Ala(4)-D-Asn-L-Lys(3) bridges. We showed that the C-terminal CWBD of Lc-Lys binds PG containing mainly D-Asn but not PG with only the nonamidated D-Asp-containing cross-bridge, indicating that the CWBD confers to Lc-Lys its narrow specificity. In conclusion, the CWBD characterized in this study is a novel type of PG-binding domain targeting specifically the D-Asn interpeptide bridge of PG.
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