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1
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Marciniak M, Stachowicz-Suhs M, Wagner M. The role of innate immune cells in modulating vascular dynamics in skin malignancies. Biochim Biophys Acta Rev Cancer 2025; 1880:189331. [PMID: 40280501 DOI: 10.1016/j.bbcan.2025.189331] [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: 01/28/2025] [Revised: 04/17/2025] [Accepted: 04/21/2025] [Indexed: 04/29/2025]
Abstract
A developing tumor relies heavily on blood vessels to supply oxygen and nutrients. As a result, angiogenesis, the formation of new blood vessels, supports tumor growth and progression. Similarly, lymphangiogenesis, the formation of new lymphatic vessels, plays a critical role in metastatic dissemination by providing pathways for malignant cells to spread. The tumor microenvironment is crucial for establishing and maintaining these vascular networks, with innate immune cells playing a key regulatory role. Notably, immune cells are specifically enriched in barrier tissues, such as the skin, emphasizing their importance in skin malignancies. Therefore, understanding their role in regulating angiogenesis and lymphangiogenesis is essential for developing novel therapeutic strategies. This review article explores how innate immune cells influence tumor vasculature and highlights the therapeutic potential that may arise from this knowledge.
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Affiliation(s)
- Mateusz Marciniak
- Innate Immunity Research Group, Life Sciences and Biotechnology Center, Łukasiewicz Research Network - PORT Polish Center for Technology Development, Wrocław, Poland; Department of Biochemistry and Immunochemistry, Wrocław Medical University, Wrocław, Poland
| | - Martyna Stachowicz-Suhs
- Innate Immunity Research Group, Life Sciences and Biotechnology Center, Łukasiewicz Research Network - PORT Polish Center for Technology Development, Wrocław, Poland
| | - Marek Wagner
- Innate Immunity Research Group, Life Sciences and Biotechnology Center, Łukasiewicz Research Network - PORT Polish Center for Technology Development, Wrocław, Poland.
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2
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Talukder A, Rahman MM, Rahi MS, Pountney DL, Wei MQ. Flagellins as Vaccine Adjuvants and Cancer Immunotherapy: Recent Advances and Future Prospects. Immunology 2025. [PMID: 40491306 DOI: 10.1111/imm.70001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 05/05/2025] [Accepted: 05/27/2025] [Indexed: 06/11/2025] Open
Abstract
Flagellin, an essential structural protein of bacterial flagella, has emerged as a potent modulator of both specific and nonspecific immunity, demonstrating significant potential as a vaccine adjuvant and carrier. By inducing the release of pro-inflammatory cytokines like IL-1β, TNF-α, IL-6, IL-8, and IL-12, flagellin activates the innate immune system, enhancing antigen-specific adaptive immune responses mediated by tumour-specific type 1 helper T cells and cytotoxic T cells, thus positioning it as a valuable adjuvant or complementary therapy for various cancers and infectious diseases. This review explores recent strategies, innovations, and clinical applications of flagellin-based immunotherapies, particularly in the context of infectious diseases and cancers. Flagellin from Salmonella typhimurium has been extensively studied as a vaccine adjuvant for diseases like HIV, influenza, dengue, West Nile virus, poultry cholera, and bursal diseases and shows promise in treating lung metastasis, melanoma, colon, and prostate cancers. It has also proven effective against multidrug-resistant bacteria, including Pseudomonas aeruginosa and S. typhimurium. Notably, S. typhimurium flagellin-based vaccines for influenza have progressed to clinical trials. Additionally, flagellins from S. typhi, S. enteritidis, P. aeruginosa, and Escherichia coli are being evaluated as vaccine candidates for plague, malaria, and infections caused by P. aeruginosa and E. coli. In cancer therapy, flagellin-based treatments, especially when combined with tumour antigens, have exhibited the ability to enhance anti-tumour immunity and improve patient outcomes. Other flagellin-based vaccines derived from S. Dublin, S. munchen, and Vibrio vulnificus have been employed in the treatment of prostate, lung, liver, breast, cervical, and colorectal cancers, as well as lymphoma, melanoma, and radiation-induced mucositis. Mobilan, a recombinant non-replicating adenovirus vector expressing Salmonella flagellin, is currently in a phase Ib clinical trial for prostate cancer. Overall, bacterial flagellin treatments are generally safe, well-tolerated, and associated with minimal side effects, making them a promising option for managing infectious diseases and cancers.
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Affiliation(s)
- Asma Talukder
- School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, Queensland, Australia
| | - Md Mijanur Rahman
- School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, Queensland, Australia
| | - Md Sifat Rahi
- School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, Queensland, Australia
| | - Dean L Pountney
- School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, Queensland, Australia
| | - Ming Q Wei
- School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, Queensland, Australia
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3
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Adeleke MA. Computational Development of Transmission-Blocking Vaccine Candidates Based on Fused Antigens of Pre- and Post-fertilization Gametocytes Against Plasmodium falciparum. Bioinform Biol Insights 2025; 19:11779322241306215. [PMID: 40034580 PMCID: PMC11873872 DOI: 10.1177/11779322241306215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 11/21/2024] [Indexed: 03/05/2025] Open
Abstract
Plasmodium falciparum is the most fatal species of malaria parasites in humans. Attempts at developing vaccines against the malaria parasites have not been very successful even after the approval of the RTS, S/AS01 vaccine. There is a continuous need for more effective vaccines including sexual-stage antigens that could block the transmission of malaria parasites between mosquitoes and humans. Low immunogenicity, expression, and stability are some of the challenges of transmission-blocking vaccine (TBV). This study was designed to computationally identify TBV candidates based on fused antigens by combining highly antigenic peptides from prefertilization (Pfs230, Pfs48/45) and postfertilization (Pfs25, Pfs28) gametocytes. The peptides were selected based on their antigenicity, nonallergenicity, and lack of similarity with the human proteome. Two fused antigens vaccine candidates (FAVCs) were constructed using Flagellin Salmonella enterica (FAVC-FSE) and Cholera toxin B (FAVC-CTB) as adjuvants. The constructs were evaluated for their physicochemical properties, structural stability, immunogenicity, and potential to elicit cross-protection across multiple Plasmodium species. The results yielded antigenic peptides, with antigenicity scores between 0.7589 and 1.1821. The structural analysis of FAVC-FSE and FAVC-CTB showed a Z-score of -6.70 and -4.79, a Ramachandran plot of 96.94% and 94.86% with overall quality of 94.20% and 89.85%, respectively. The FAVCs contained CD8+, CD4+, and linear B-cell epitopes with antigenicity scores between 1.2089 and 2.8623, 0.5663 and 2.4132, and 1.5196 and 2.2212, respectively. Each FAVC generated 6 conformational B-cells. High population coverage values were recorded for the FAVCs. The ability of the FAVCs to trigger immune response was evaluated through an in silico immune stimulation. The low-binding interaction energy that resulted from molecular docking and dynamics simulations showed a strong affinity of FAVCs to Toll-like receptor 5 (TLR5). The results indicate that the FAVC-FSE vaccine candidate is more promising to interrupt P falciparum transmission and provides a baseline for experimental validation.
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Affiliation(s)
- Matthew A. Adeleke
- Discipline of Genetics, School of Life Sciences, College of Agriculture, Engineering and Sciences, University of KwaZulu-Natal, Durban, South Africa
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Afzal H, Murtaza A, Cheng LT. Structural engineering of flagellin as vaccine adjuvant: quest for the minimal domain of flagellin for TLR5 activation. Mol Biol Rep 2025; 52:104. [PMID: 39775323 PMCID: PMC11706886 DOI: 10.1007/s11033-024-10146-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 12/02/2024] [Indexed: 01/11/2025]
Abstract
Flagellin stimulates Toll-like receptor 5 (TLR5), triggering both innate and adaptive immune responses, making it a potential vaccine adjuvant. On mucosal surfaces, flagellin induces a strong release of cytokines, chemokines, and immunoglobulins. When used in its free monomeric form, flagellin has been shown to enhance immune responses when combined with vaccine antigens. Further research demonstrated that genetically linking flagellin to the antigen provides a more consistent immune boost. However, the bulky structure of flagellin presents challenges in designing the antigen-adjuvant construct, leading to ongoing research to determine the minimal flagellin domain necessary for its adjuvant effect. Early findings suggest that only the D0 and D1 domains are required for immune enhancement. Functional analysis revealed that the TLR5-binding region is located in the D1 domain, while TLR5 dimerization and signaling require the presence of D0. Further reductions in the size of the D0 and D1 domains may be possible as deeper studies aim to identify the key residues responsible for TLR5 activation and immune enhancement. Additionally, flagellin is being tested as a hapten carrier alongside its established adjuvant role. Recently, significant advancements in flagellin application have been observed as it progresses through clinical studies as an adjuvant, anti-radiation, and anti-cancer agent.
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Affiliation(s)
- Haroon Afzal
- International Degree Program of Animal Vaccine Technology, International College, National Pingtung University of Science and Technology, 1, Shuefu Road, Neipu, Pingtung, 91201, Taiwan
| | - Asad Murtaza
- International Degree Program of Animal Vaccine Technology, International College, National Pingtung University of Science and Technology, 1, Shuefu Road, Neipu, Pingtung, 91201, Taiwan.
- Norwegian College of Fishery Science, Faculty of Biosciences, Fisheries and Economics, UiT - The Arctic University of Norway, Tromsø, Norway.
| | - Li-Ting Cheng
- International Degree Program of Animal Vaccine Technology, International College, National Pingtung University of Science and Technology, 1, Shuefu Road, Neipu, Pingtung, 91201, Taiwan.
- Graduate Institute of Animal Vaccine Technology, College of Veterinary Medicine, National Pingtung University of Science and Technology, 1, Shuefu Road, Neipu, Pingtung, 91201, Taiwan.
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Jeon D, Hill E, McNeel DG. Toll-like receptor agonists as cancer vaccine adjuvants. Hum Vaccin Immunother 2024; 20:2297453. [PMID: 38155525 PMCID: PMC10760790 DOI: 10.1080/21645515.2023.2297453] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 12/16/2023] [Indexed: 12/30/2023] Open
Abstract
Cancer immunotherapy has emerged as a promising strategy to treat cancer patients. Among the wide range of immunological approaches, cancer vaccines have been investigated to activate and expand tumor-reactive T cells. However, most cancer vaccines have not shown significant clinical benefit as monotherapies. This is likely due to the antigen targets of vaccines, "self" proteins to which there is tolerance, as well as to the immunosuppressive tumor microenvironment. To help circumvent immune tolerance and generate effective immune responses, adjuvants for cancer vaccines are necessary. One representative adjuvant family is Toll-Like receptor (TLR) agonists, synthetic molecules that stimulate TLRs. TLRs are the largest family of pattern recognition receptors (PRRs) that serve as the sensors of pathogens or cellular damage. They recognize conserved foreign molecules from pathogens or internal molecules from cellular damage and propel innate immune responses. When used with vaccines, activation of TLRs signals an innate damage response that can facilitate the development of a strong adaptive immune response against the target antigen. The ability of TLR agonists to modulate innate immune responses has positioned them to serve as adjuvants for vaccines targeting infectious diseases and cancers. This review provides a summary of various TLRs, including their expression patterns, their functions in the immune system, as well as their ligands and synthetic molecules developed as TLR agonists. In addition, it presents a comprehensive overview of recent strategies employing different TLR agonists as adjuvants in cancer vaccine development, both in pre-clinical models and ongoing clinical trials.
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Affiliation(s)
- Donghwan Jeon
- Department of Oncology, University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | - Ethan Hill
- Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | - Douglas G. McNeel
- Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, WI, USA
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Adugna T, Niu Q, Guan G, Du J, Yang J, Tian Z, Yin H. Advancements in nanoparticle-based vaccine development against Japanese encephalitis virus: a systematic review. Front Immunol 2024; 15:1505612. [PMID: 39759527 PMCID: PMC11695416 DOI: 10.3389/fimmu.2024.1505612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 11/25/2024] [Indexed: 01/07/2025] Open
Abstract
Vaccination remains the sole effective strategy for combating Japanese encephalitis (JE). Both inactivated and live attenuated vaccines exhibit robust immunogenicity. However, the production of these conventional vaccine modalities necessitates extensive cultivation of the pathogen, incurring substantial costs and presenting significant biosafety risks. Moreover, the administration of live pathogens poses potential hazards for individuals or animals with compromised immune systems or other health vulnerabilities. Subsequently, ongoing research endeavors are focused on the development of next-generation JE vaccines utilizing nanoparticle (NP) platforms. This systematic review seeks to aggregate the research findings pertaining to NP-based vaccine development against JE. A thorough literature search was conducted across established English-language databases for research articles on JE NP vaccine development published between 2000 and 2023. A total of twenty-eight published studies were selected for detailed analysis in this review. Of these, 16 studies (57.14%) concentrated on virus-like particles (VLPs) employing various structural proteins. Other approaches, including sub-viral particles (SVPs), biopolymers, and both synthetic and inorganic NP platforms, were utilized to a lesser extent. The results of these investigations indicated that, despite variations in the usage of adjuvants, dosages, NP types, antigenic proteins, and animal models employed across different studies, the candidate NP vaccines developed were capable of eliciting enhanced humoral and cellular adaptive immune responses, providing effective protection (70-100%) for immunized mice against lethal challenges posed by virulent Japanese encephalitis virus (JEV). In conclusion, prospective next-generation JE vaccines for humans and animals may emerge from these candidate formulations following further evaluation in subsequent vaccine development phases.
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Affiliation(s)
- Takele Adugna
- State Key Laboratory for Animal Disease Control and Prevention, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, State Key Laboratory of Veterinary Etiological Biology Project, Yangzhou, China
- College of Veterinary Medicine and Animal Sciences, University of Gondar, Gondar, Ethiopia
| | - Qingli Niu
- State Key Laboratory for Animal Disease Control and Prevention, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, State Key Laboratory of Veterinary Etiological Biology Project, Yangzhou, China
| | - Guiquan Guan
- State Key Laboratory for Animal Disease Control and Prevention, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, State Key Laboratory of Veterinary Etiological Biology Project, Yangzhou, China
| | - Junzheng Du
- State Key Laboratory for Animal Disease Control and Prevention, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, State Key Laboratory of Veterinary Etiological Biology Project, Yangzhou, China
| | - Jifei Yang
- State Key Laboratory for Animal Disease Control and Prevention, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, State Key Laboratory of Veterinary Etiological Biology Project, Yangzhou, China
| | - Zhancheng Tian
- State Key Laboratory for Animal Disease Control and Prevention, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, State Key Laboratory of Veterinary Etiological Biology Project, Yangzhou, China
| | - Hong Yin
- State Key Laboratory for Animal Disease Control and Prevention, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, State Key Laboratory of Veterinary Etiological Biology Project, Yangzhou, China
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7
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Wu Y, Liu B, Yan Y, Gong C, Wang K, Liu N, Zhu Y, Li M, Wang C, Yang Y, Feng L, Liu Z. Thermal-responsive activation of engineered bacteria to trigger antitumor immunity post microwave ablation therapy. Nat Commun 2024; 15:10503. [PMID: 39627266 PMCID: PMC11614905 DOI: 10.1038/s41467-024-54883-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 11/25/2024] [Indexed: 12/06/2024] Open
Abstract
Incomplete tumor removal after microwave ablation (MWA), a widely used hyperthermia-based therapy, can result in tumor recurrence. Herein, attenuated Salmonella typhimurium VNP20009 is engineered to release interleukin-15&interleukin-15-receptor-alpha (IL-15&IL-15Rα) in response to mildly elevated temperature. Such 15&15R@VNP colonizes in tumors upon intravenous injection, and the expression of IL-15&IL-15Rα is triggered by MWA. Anti-tumor immune responses are elicited, efficiently suppressing tumor growth even after incomplete microwave ablation. We further design VNP20009 with thermal-responsive co-expression of both IL-15&IL-15Rα and soluble programmed cell death protein (sPD-1). Such sPD-1-15&15R@VNP can also reverse the functional suppression of immune cells driven by PD-1/PD-L1 axis, reinvigorating progenitor exhausted T cells, a critical subset of cytotoxic T lymphocytes responsive to immune checkpoint blockade. Such thermal-responsive engineered bacteria are thus a promising adjuvant therapy to potentiate tumor ablation therapies via effectively activating antitumor immunity.
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Affiliation(s)
- Yumin Wu
- Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, 215123, Jiangsu, China
| | - Bo Liu
- Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, 215123, Jiangsu, China
| | - Yifan Yan
- Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, 215123, Jiangsu, China
| | - Chuntao Gong
- InnoBM Pharmaceuticals, Suzhou, 215123, Jiangsu, China
| | - Kaiwei Wang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Nanhui Liu
- Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, 215123, Jiangsu, China
| | - Yujie Zhu
- Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, 215123, Jiangsu, China
| | - Maoyi Li
- Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, 215123, Jiangsu, China
| | - Chunjie Wang
- Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, 215123, Jiangsu, China
| | - Yizhe Yang
- Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, 215123, Jiangsu, China
| | - Liangzhu Feng
- Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, 215123, Jiangsu, China.
| | - Zhuang Liu
- Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, 215123, Jiangsu, China.
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8
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Xia W, Wu J. Flagellate bacteria-mediated tumour antigen delivery: A novel approach to enhance dendritic cell activation for in situ cancer vaccination. Microb Biotechnol 2024; 17:e70028. [PMID: 39422491 PMCID: PMC11487680 DOI: 10.1111/1751-7915.70028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 09/26/2024] [Indexed: 10/19/2024] Open
Abstract
In situ vaccination is a therapeutic approach aimed at exploiting tumour antigens available at a tumour site to induce tumour-specific adaptive immune responses. Antigens released from dying tumour cells are assumed to be taken up by activated dendritic cells and presented to T cells that seek out and destroy tumour cells. This process is significantly impeded in the immunosuppressive microenvironment of tumours. There is a growing trend in in situ vaccine strategies that utilize bacteria as natural adjuvants or as factories for cytokines, aiming to enhance the presentation of in situ antigens by antigen-presenting cells. Recently, a novel approach using flagellate bacteria-mediated antigen delivery to activate dendritic cells has been proposed. This method actively facilitates the delivery of intratumoral antigens, improving their presentation for in situ cancer vaccination. Here, we highlight how flagellate bacteria-mediated antigen delivery enhances the immune activation capabilities of in situ vaccines. Meanwhile, we provide perspectives and outlooks on these promising antigen delivery technologies.
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Affiliation(s)
- Wen Xia
- State Key Laboratory of Pharmaceutical BiotechnologyMedical School of Nanjing UniversityNanjingChina
- Chemistry and Biomedicine Innovation CentreNanjing UniversityNanjingChina
- Jiangsu Key Laboratory of Molecular MedicineNanjing UniversityNanjingChina
| | - Jinhui Wu
- State Key Laboratory of Pharmaceutical BiotechnologyMedical School of Nanjing UniversityNanjingChina
- Chemistry and Biomedicine Innovation CentreNanjing UniversityNanjingChina
- Jiangsu Key Laboratory of Molecular MedicineNanjing UniversityNanjingChina
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9
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Chung YC, Cheng LT, Chu CY, Afzal H, Doan TD. Flagellin Enhances the Immunogenicity of Pasteurella multocida Lipoprotein E Subunit Vaccine. Avian Dis 2024; 68:183-191. [PMID: 39400212 DOI: 10.1637/aviandiseases-d-24-00032] [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: 04/16/2024] [Accepted: 04/22/2024] [Indexed: 10/15/2024]
Abstract
Fowl cholera, caused by Pasteurella multocida infection, poses challenges for prevention because of its many serotypes. Bacterins are currently widely used for vaccination against fowl cholera, but protection is limited to homologous strains. Live attenuated vaccines of P. multocida provide some heterologous protection, but side effects are considerable. More recently, protein-based antigens are promising subunit vaccines when their low immunogenicity has been addressed with effective adjuvants. Bacterial flagellin has been widely considered a promising adjuvant for vaccines. In this study, we tested the adjutancy of flagellin in a subunit vaccine against P. multocida in a mice and chicken models. For vaccine formulation, the antigen fPlpE (P. multocida liporotein E) was combined with fFliC (Salmonella Typhimurium flagellin). The recombinant proteins of fPlpE and fFliC were successfully expressed using the Escherichia coli system as the expected sizes of 55 kDa and 70 kDa, respectively. The fFliC elicited strong expression levels of proinflammatory cytokine (IL-1β, IL-8, and IL-6) when stimulated in native chicken peripheral blood mononuclear cells. Immunization of mice and chickens with the subunit vaccines containing fFliC accelerated the antibody response. In the challenge tests, fFliC increased vaccine protective efficacy against the heterologous strain P. multocida A1 and highly virulent strain Chu01 in mice and chickens, respectively. These data indicated potential possibilities of using fFliC as an immunostimulant adjuvant in developing a subunit vaccine against fowl cholera.
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Affiliation(s)
- Yao-Chi Chung
- Graduate Institute of Animal Vaccine Technology, College of Veterinary Medicine, National Pingtung University of Science and Technology, Neipu, Pingtung 91201, Taiwan
- International Degree Program in Animal Vaccine Technology, International College, National Pingtung University of Science and Technology, Pingtung, Taiwan
| | - Li-Ting Cheng
- Graduate Institute of Animal Vaccine Technology, College of Veterinary Medicine, National Pingtung University of Science and Technology, Neipu, Pingtung 91201, Taiwan
- International Degree Program in Animal Vaccine Technology, International College, National Pingtung University of Science and Technology, Pingtung, Taiwan
| | - Chun-Yen Chu
- Graduate Institute of Animal Vaccine Technology, College of Veterinary Medicine, National Pingtung University of Science and Technology, Neipu, Pingtung 91201, Taiwan
- International Degree Program in Animal Vaccine Technology, International College, National Pingtung University of Science and Technology, Pingtung, Taiwan
| | - Haroon Afzal
- International Degree Program in Animal Vaccine Technology, International College, National Pingtung University of Science and Technology, Pingtung, Taiwan
| | - Thu-Dung Doan
- Graduate Institute of Animal Vaccine Technology, College of Veterinary Medicine, National Pingtung University of Science and Technology, Neipu, Pingtung 91201, Taiwan,
- International Degree Program in Animal Vaccine Technology, International College, National Pingtung University of Science and Technology, Pingtung, Taiwan
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10
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Zhong K, Chen X, Zhang J, Jiang X, Zhang J, Huang M, Bi S, Ju C, Luo Y. Recent Advances in Oral Vaccines for Animals. Vet Sci 2024; 11:353. [PMID: 39195807 PMCID: PMC11360704 DOI: 10.3390/vetsci11080353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 07/29/2024] [Accepted: 08/02/2024] [Indexed: 08/29/2024] Open
Abstract
Compared to traditional injected vaccines, oral vaccines offer significant advantages for the immunization of livestock and wildlife due to their ease of use, high compliance, improved safety, and potential to stimulate mucosal immune responses and induce systemic immunity against pathogens. This review provides an overview of the delivery methods for oral vaccines, and the factors that influence their immunogenicity. We also highlight the global progress and achievements in the development and use of oral vaccines for animals, shedding light on potential future applications in this field.
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Affiliation(s)
- Kaining Zhong
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510640, China; (K.Z.); (X.C.); (J.Z.); (X.J.); (J.Z.); (M.H.)
| | - Xinting Chen
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510640, China; (K.Z.); (X.C.); (J.Z.); (X.J.); (J.Z.); (M.H.)
| | - Junhao Zhang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510640, China; (K.Z.); (X.C.); (J.Z.); (X.J.); (J.Z.); (M.H.)
| | - Xiaoyu Jiang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510640, China; (K.Z.); (X.C.); (J.Z.); (X.J.); (J.Z.); (M.H.)
| | - Junhui Zhang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510640, China; (K.Z.); (X.C.); (J.Z.); (X.J.); (J.Z.); (M.H.)
| | - Minyi Huang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510640, China; (K.Z.); (X.C.); (J.Z.); (X.J.); (J.Z.); (M.H.)
| | - Shuilian Bi
- School of Food Science, Guangdong Pharmaceutical University, Zhongshan 528458, China;
| | - Chunmei Ju
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510640, China; (K.Z.); (X.C.); (J.Z.); (X.J.); (J.Z.); (M.H.)
- Key Laboratory of Animal Vaccine Development of the Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou 510640, China
| | - Yongwen Luo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510640, China; (K.Z.); (X.C.); (J.Z.); (X.J.); (J.Z.); (M.H.)
- Key Laboratory of Animal Vaccine Development of the Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou 510640, China
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11
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Elguindy DAS, Ashour DS, Elmarhoumy SM, El-Guindy DM, Ismail HIH. The efficacy of cercarial antigen loaded on nanoparticles as a potential vaccine candidate in Schistosoma mansoni-infected mice. J Parasit Dis 2024; 48:381-399. [PMID: 38840868 PMCID: PMC11147980 DOI: 10.1007/s12639-024-01677-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Accepted: 04/21/2024] [Indexed: 06/07/2024] Open
Abstract
Schistosomiasis is one of the most common causes of morbidity and mortality from parasitic diseases. Mass treatment has proven to be insufficient because of repeated infection after treatment and the appearance of strains resistant to drug therapy. Hence, immunization is a new approach to control the disease and limit the pathological consequences of schistosomiasis. To evaluate the prophylactic effect of Cercarial antigen (CAP) loaded on chitosan nanoparticles (CSNPs) as a potential vaccine against Schistosoma mansoni-infected mice. 130 mice divided into 2 groups were used: Group I: Control groups (50 mice) subdivided into subgroup Ia (10 mice): Non-infected mice (normal control), subgroup Ib (20 mice): Schistosoma infected mice (infected control) and subgroup Ic (20 mice): Non-infected mice receiving NPs only. Group II: Vaccinated group (80 mice) subdivided equally into subgroup IIa (CAP): Received cercarial antigen and subgroup IIb (CAP + CSNP): Received cercarial antigen loaded on chitosan NPs then both vaccinated groups were infected with S. mansoni 3 weeks following the initial vaccination dose. CAP + CSNP and CAP groups showed significant reduction in adult worms count, hepatic egg count, hepatic granulomas number and size in comparison to the infected control group. Elevation of serum IgG and IgM levels, CD4+ and CD8+ T cell frequencies, IL-4, IL-10 and INF-γ levels was more significant in CAP + CSNP group than CAP group. CAP + CSNP is a promising new preparation of Schistosomal antigens that gave better results than immunization with CAP alone. CSNPs enhanced the immune and protective effect of CAP as validated by parasitological, histopathological and immunohistochemical studies.
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Affiliation(s)
- Dina A. S. Elguindy
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Dalia S. Ashour
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Sirria M. Elmarhoumy
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Dina M. El-Guindy
- Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Howaida I. H. Ismail
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
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12
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Pearson JA, Hu Y, Peng J, Wong FS, Wen L. TLR5-deficiency controls dendritic cell subset development in an autoimmune diabetes-susceptible model. Front Immunol 2024; 15:1333967. [PMID: 38482010 PMCID: PMC10935730 DOI: 10.3389/fimmu.2024.1333967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 02/06/2024] [Indexed: 03/17/2024] Open
Abstract
Introduction The incidence of the autoimmune disease, type 1 diabetes (T1D), has been increasing worldwide and recent studies have shown that the gut microbiota are associated with modulating susceptibility to T1D. Toll-like receptor 5 (TLR5) recognizes bacterial flagellin and is widely expressed on many cells, including dendritic cells (DCs), which are potent antigen-presenting cells (APCs). TLR5 modulates susceptibility to obesity and alters metabolism through gut microbiota; however, little is known about the role TLR5 plays in autoimmunity, especially in T1D. Methods To fill this knowledge gap, we generated a TLR5-deficient non-obese diabetic (NOD) mouse, an animal model of human T1D, for study. Results We found that TLR5-deficiency led to a reduction in CD11c+ DC development in utero, prior to microbial colonization, which was maintained into adulthood. This was associated with a bias in the DC populations expressing CD103, with or without CD8α co-expression, and hyper-secretion of different cytokines, both in vitro (after stimulation) and directly ex vivo. We also found that TLR5-deficient DCs were able to promote polyclonal and islet antigen-specific CD4+ T cell proliferation and proinflammatory cytokine secretion. Interestingly, only older TLR5-deficient NOD mice had a greater risk of developing spontaneous T1D compared to wild-type mice. Discussion In summary, our data show that TLR5 modulates DC development and enhances cytokine secretion and diabetogenic CD4+ T cell responses. Further investigation into the role of TLR5 in DC development and autoimmune diabetes may give additional insights into the pathogenesis of Type 1 diabetes.
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Affiliation(s)
- James Alexander Pearson
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, United States
- Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Youjia Hu
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, United States
| | - Jian Peng
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, United States
| | - F. Susan Wong
- Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Li Wen
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, United States
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13
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Tabynov K, Solomadin M, Turebekov N, Babayeva M, Fomin G, Yadagiri G, Sankar R, Yerubayev T, Petrovsky N, Renukaradhya GJ, Tabynov K. An intranasal vaccine comprising SARS-CoV-2 spike receptor-binding domain protein entrapped in mannose-conjugated chitosan nanoparticle provides protection in hamsters. Sci Rep 2023; 13:12115. [PMID: 37495639 PMCID: PMC10372096 DOI: 10.1038/s41598-023-39402-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 07/25/2023] [Indexed: 07/28/2023] Open
Abstract
We developed a novel intranasal SARS-CoV-2 subunit vaccine called NARUVAX-C19/Nano based on the spike protein receptor-binding domain (RBD) entrapped in mannose-conjugated chitosan nanoparticles (NP). A toll-like receptor 9 agonist, CpG55.2, was also added as an adjuvant to see if this would potentiate the cellular immune response to the NP vaccine. The NP vaccine was assessed for immunogenicity, protective efficacy, and ability to prevent virus transmission from vaccinated animals to naive cage-mates. The results were compared with a RBD protein vaccine mixed with alum adjuvant and administered intramuscularly. BALB/c mice vaccinated twice intranasally with the NP vaccines exhibited secretory IgA and a pronounced Th1-cell response, not seen with the intramuscular alum-adjuvanted RBD vaccine. NP vaccines protected Syrian hamsters against a wild-type SARS-CoV-2 infection challenge as indicated by significant reductions in weight loss, lung viral load and lung pathology. However, despite significantly reduced viral load in the nasal turbinates and oropharyngeal swabs from NP-vaccinated hamsters, virus transmission was not prevented to naïve cage-mates. In conclusion, intranasal RBD-based NP formulations induced mucosal and Th1-cell mediated immune responses in mice and protected Syrian hamsters against SARS-CoV-2 infection but not against viral transmission.
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Affiliation(s)
- Kairat Tabynov
- International Center for Vaccinology, Kazakh National Agrarian Research University (KazNARU), Almaty, Kazakhstan
- Preclinical Research Laboratory with Vivarium, M. Aikimbayev National Research Center for Especially Dangerous Infections, Almaty, Kazakhstan
- T&TvaX LLC, Almaty, Kazakhstan
| | - Maxim Solomadin
- International Center for Vaccinology, Kazakh National Agrarian Research University (KazNARU), Almaty, Kazakhstan
- School of Pharmacy, Karaganda Medical University, Karaganda, Kazakhstan
| | - Nurkeldi Turebekov
- Central Reference Laboratory, M. Aikimbayev National Scientific Center for Especially Dangerous Infections, Almaty, Kazakhstan
| | - Meruert Babayeva
- International Center for Vaccinology, Kazakh National Agrarian Research University (KazNARU), Almaty, Kazakhstan
| | - Gleb Fomin
- International Center for Vaccinology, Kazakh National Agrarian Research University (KazNARU), Almaty, Kazakhstan
| | - Ganesh Yadagiri
- Center for Food Animal Health, College of Food Agricultural and Environmental Sciences, The Ohio State University (OSU), Wooster, OH, 44691, USA
| | - Renu Sankar
- Center for Food Animal Health, College of Food Agricultural and Environmental Sciences, The Ohio State University (OSU), Wooster, OH, 44691, USA
| | - Toktassyn Yerubayev
- Central Reference Laboratory, M. Aikimbayev National Scientific Center for Especially Dangerous Infections, Almaty, Kazakhstan
| | | | - Gourapura J Renukaradhya
- Center for Food Animal Health, College of Food Agricultural and Environmental Sciences, The Ohio State University (OSU), Wooster, OH, 44691, USA
| | - Kaissar Tabynov
- International Center for Vaccinology, Kazakh National Agrarian Research University (KazNARU), Almaty, Kazakhstan.
- T&TvaX LLC, Almaty, Kazakhstan.
- Republican Allergy Center, Research Institute of Cardiology and Internal Medicine, Almaty, Kazakhstan.
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14
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Chen S, Lei Q, Zou X, Ma D. The role and mechanisms of gram-negative bacterial outer membrane vesicles in inflammatory diseases. Front Immunol 2023; 14:1157813. [PMID: 37398647 PMCID: PMC10313905 DOI: 10.3389/fimmu.2023.1157813] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 06/05/2023] [Indexed: 07/04/2023] Open
Abstract
Outer membrane vesicles (OMVs) are spherical, bilayered, and nanosized membrane vesicles that are secreted from gram-negative bacteria. OMVs play a pivotal role in delivering lipopolysaccharide, proteins and other virulence factors to target cells. Multiple studies have found that OMVs participate in various inflammatory diseases, including periodontal disease, gastrointestinal inflammation, pulmonary inflammation and sepsis, by triggering pattern recognition receptors, activating inflammasomes and inducing mitochondrial dysfunction. OMVs also affect inflammation in distant organs or tissues via long-distance cargo transport in various diseases, including atherosclerosis and Alzheimer's disease. In this review, we primarily summarize the role of OMVs in inflammatory diseases, describe the mechanism through which OMVs participate in inflammatory signal cascades, and discuss the effects of OMVs on pathogenic processes in distant organs or tissues with the aim of providing novel insights into the role and mechanism of OMVs in inflammatory diseases and the prevention and treatment of OMV-mediated inflammatory diseases.
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15
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Bernal AM, Sosa FN, Todero MF, Montagna DR, Vermeulen ME, Fernández-Brando RJ, Ramos MV, Errea AJ, Rumbo M, Palermo MS. Nasal immunization with H7 flagellin protects mice against hemolytic uremic syndrome secondary to Escherichia coli O157:H7 gastrointestinal infection. Front Cell Infect Microbiol 2023; 13:1143918. [PMID: 37260706 PMCID: PMC10227447 DOI: 10.3389/fcimb.2023.1143918] [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: 01/13/2023] [Accepted: 04/26/2023] [Indexed: 06/02/2023] Open
Abstract
Introduction Shiga-toxin (Stx) producing Escherichia coli (STEC) O157:H7 is the most frequent serotype associated with hemolytic uremic syndrome (HUS) after gastrointestinal infections. Protection against HUS secondary to STEC infections has been experimentally assayed through the generation of different vaccine formulations. With focus on patients, the strategies have been mainly oriented to inhibit production of Stx or its neutralization. However, few approaches have been intended to block gastrointestinal phase of this disease, which is considered the first step in the pathogenic cascade of HUS. The aim of this work was to assay H7 flagellin as a mucosal vaccine candidate to prevent the systemic complications secondary to E. coli O157:H7 infections. Materials and methods The cellular and humoral immune response after H7 nasal immunization in mice were studied by the analysis of systemic and intestinal specific antibody production, as well as cytokine production and lymphocyte proliferation against H7 flagellin ex vivo. Results Immunized mice developed a strong and specific anti-H7 IgG and IgA response, at systemic and mucosal level, as well as a cellular Th1/Th2/Th17 response. H7 induced activation of bone marrow derived dendritic cells in vitro and a significant delayed-type hypersensitivity (DTH) response in immunized mice. Most relevant, immunized mice were completely protected against the challenge with an E. coli O157:H7 virulent strain in vivo, and surviving mice presented high titres of anti-H7 and Stx antibodies. Discussion These results suggest that immunization avoids HUS outcome and allows to elicit a specific immune response against other virulence factors.
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Affiliation(s)
- Alan Mauro Bernal
- Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental (IMEX), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Academia Nacional de Medicina, Buenos Aires, Argentina
| | - Fernando Nicolás Sosa
- Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental (IMEX), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Academia Nacional de Medicina, Buenos Aires, Argentina
| | - María Florencia Todero
- Laboratorio de Fisiología de Procesos Inflamatorios, IMEX CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina
| | - Daniela Romina Montagna
- Laboratorio de Oncología Experimental, IMEX CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina
| | - Mónica Elba Vermeulen
- Laboratorio de Células Presentadoras de Antígenos y Respuesta Inflamatoria, IMEX CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina
| | - Romina Jimena Fernández-Brando
- Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental (IMEX), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Academia Nacional de Medicina, Buenos Aires, Argentina
| | - María Victoria Ramos
- Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental (IMEX), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Academia Nacional de Medicina, Buenos Aires, Argentina
| | - Agustina Juliana Errea
- Instituto de Estudios Inmunológicos y Fisiopatológicos - CONICET - Universidad Nacional de La Plata, La Plata, Argentina
| | - Martin Rumbo
- Instituto de Estudios Inmunológicos y Fisiopatológicos - CONICET - Universidad Nacional de La Plata, La Plata, Argentina
| | - Marina Sandra Palermo
- Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental (IMEX), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Academia Nacional de Medicina, Buenos Aires, Argentina
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16
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Recombinant Domain of Flagellin Promotes In Vitro a Chemotactic Inflammatory Profile in Human Immune Cells Independently of a Dendritic Cell Phenotype. Molecules 2023; 28:molecules28052394. [PMID: 36903639 PMCID: PMC10005431 DOI: 10.3390/molecules28052394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Flagellin is the major component of the flagellum in gram-positive and -negative bacteria and is also the ligand for the Toll-like receptor 5 (TLR5). The activation of TLR5 promotes the expression of proinflammatory cytokines and chemokines and the subsequent activation of T cells. This study evaluated a recombinant domain from the amino-terminus D1 domain (rND1) of flagellin from Vibrio anguillarum, a fish pathogen, as an immunomodulator in human peripheral blood mononuclear cells (PBMCs) and monocyte-derived dendritic cells (MoDCs). We demonstrated that rND1 induced an upregulation of proinflammatory cytokines in PBMCs, characterized at the transcriptional level by an expression peak of 220-fold for IL-1β, 20-fold for IL-8, and 65-fold for TNF-α. In addition, at the protein level, 29 cytokines and chemokines were evaluated in the supernatant and were correlated with a chemotactic signature. MoDCs treated with rND1 showed low levels of co-stimulatory and HLA-DR molecules and kept an immature phenotype with a decreased phagocytosis of dextran. We probed that rND1 from a non-human pathogen promotes modulation in human cells, and it may be considered for further studies in adjuvant therapies based on pathogen-associated patterns (PAMPs).
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17
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Korpi F, Irajian G, Forouhi F, Mohammadian T. A chimeric vaccine targeting Pseudomonas aeruginosa virulence factors protects mice against lethal infection. Microb Pathog 2023; 178:106033. [PMID: 36813005 DOI: 10.1016/j.micpath.2023.106033] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 01/25/2023] [Accepted: 02/12/2023] [Indexed: 02/22/2023]
Abstract
Pseudomonas aeruginosa is an important and hazardous nosocomial pathogen in respiratory tract infections and rapidly achieves antibiotic resistance, so it is necessary to develop an effective vaccine to combat the infection. The Type III secretion system (T3SS) protein P. aeruginosa V-antigen (PcrV), outer membrane protein F (OprF), and two kinds of flagellins (FlaA and FlaB) all play important roles in the pathogenesis of P. aeruginosa lung infection and its spread into deeper tissues. In a mouse acute pneumonia model, the protective effects of a chimer vaccine including PcrV, FlaA, FlaB, and OprF (PABF) protein were investigated. PABF immunization prompted robust opsonophagocytic titer of IgG antibodies and decreased bacterial burden, and improved survival afterward intranasal challenge with ten times 50% lethal doses (LD50) of P. aeruginosa strains, indicating its broad-spectrum immunity. Moreover, these findings showed a promise chimeric vaccine candidate to treat and control P. aeruginosa infections.
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Affiliation(s)
- Fatemeh Korpi
- Department of Cell and Molecular Biology, Faculty of Basic Science, Islamic Azad University Shahre Qods Branch, Iran
| | - Gholamreza Irajian
- Department of Cell and Molecular Biology, Faculty of Basic Science, Islamic Azad University Shahre Qods Branch, Iran; Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Fatemeh Forouhi
- Department of Cell and Molecular Biology, Faculty of Basic Science, Islamic Azad University Shahre Qods Branch, Iran
| | - Taher Mohammadian
- Department of Cell and Molecular Biology, Faculty of Basic Science, Islamic Azad University Shahre Qods Branch, Iran
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18
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Azharuddin M, Zhu GH, Sengupta A, Hinkula J, Slater NKH, Patra HK. Nano toolbox in immune modulation and nanovaccines. Trends Biotechnol 2022; 40:1195-1212. [PMID: 35450779 PMCID: PMC10439010 DOI: 10.1016/j.tibtech.2022.03.011] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 03/18/2022] [Accepted: 03/25/2022] [Indexed: 12/23/2022]
Abstract
Despite the great success of vaccines over two centuries, the conventional strategy is based on attenuated/altered microorganisms. However, this is not effective for all microbes and often fails to elicit a protective immune response, and sometimes poses unexpected safety risks. The expanding nano toolbox may overcome some of the roadblocks in vaccine development given the plethora of unique nanoparticle (NP)-based platforms that can successfully induce specific immune responses leading to exciting and novel solutions. Nanovaccines necessitate a thorough understanding of the immunostimulatory effect of these nanotools. We present a comprehensive description of strategies in which nanotools have been used to elicit an immune response and provide a perspective on how nanotechnology can lead to future personalized nanovaccines.
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Affiliation(s)
- Mohammad Azharuddin
- Department of Biomedical and Clinical Sciences (BKV), Linköping University, Linköping, Sweden
| | - Geyunjian Harry Zhu
- Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
| | - Anirban Sengupta
- Department of Biomedical and Clinical Sciences (BKV), Linköping University, Linköping, Sweden
| | - Jorma Hinkula
- Department of Biomedical and Clinical Sciences (BKV), Linköping University, Linköping, Sweden
| | - Nigel K H Slater
- Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
| | - Hirak K Patra
- Department of Surgical Biotechnology, University College London, London, UK.
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19
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Díaz-Dinamarca DA, Salazar ML, Castillo BN, Manubens A, Vasquez AE, Salazar F, Becker MI. Protein-Based Adjuvants for Vaccines as Immunomodulators of the Innate and Adaptive Immune Response: Current Knowledge, Challenges, and Future Opportunities. Pharmaceutics 2022; 14:1671. [PMID: 36015297 PMCID: PMC9414397 DOI: 10.3390/pharmaceutics14081671] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/05/2022] [Accepted: 08/07/2022] [Indexed: 12/03/2022] Open
Abstract
New-generation vaccines, formulated with subunits or nucleic acids, are less immunogenic than classical vaccines formulated with live-attenuated or inactivated pathogens. This difference has led to an intensified search for additional potent vaccine adjuvants that meet safety and efficacy criteria and confer long-term protection. This review provides an overview of protein-based adjuvants (PBAs) obtained from different organisms, including bacteria, mollusks, plants, and humans. Notably, despite structural differences, all PBAs show significant immunostimulatory properties, eliciting B-cell- and T-cell-mediated immune responses to administered antigens, providing advantages over many currently adopted adjuvant approaches. Furthermore, PBAs are natural biocompatible and biodegradable substances that induce minimal reactogenicity and toxicity and interact with innate immune receptors, enhancing their endocytosis and modulating subsequent adaptive immune responses. We propose that PBAs can contribute to the development of vaccines against complex pathogens, including intracellular pathogens such as Mycobacterium tuberculosis, those with complex life cycles such as Plasmodium falciparum, those that induce host immune dysfunction such as HIV, those that target immunocompromised individuals such as fungi, those with a latent disease phase such as Herpes, those that are antigenically variable such as SARS-CoV-2 and those that undergo continuous evolution, to reduce the likelihood of outbreaks.
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Affiliation(s)
- Diego A. Díaz-Dinamarca
- Fundación Ciencia y Tecnología para el Desarrollo (FUCITED), Santiago 7750000, Chile
- Sección de Biotecnología, Departamento Agencia Nacional de Dispositivos Médicos, Innovación y Desarrollo, Instituto de Salud Pública de Chile, Santiago 7750000, Chile
| | - Michelle L. Salazar
- Fundación Ciencia y Tecnología para el Desarrollo (FUCITED), Santiago 7750000, Chile
| | - Byron N. Castillo
- Fundación Ciencia y Tecnología para el Desarrollo (FUCITED), Santiago 7750000, Chile
| | - Augusto Manubens
- Fundación Ciencia y Tecnología para el Desarrollo (FUCITED), Santiago 7750000, Chile
- Biosonda Corporation, Santiago 7750000, Chile
| | - Abel E. Vasquez
- Sección de Biotecnología, Departamento Agencia Nacional de Dispositivos Médicos, Innovación y Desarrollo, Instituto de Salud Pública de Chile, Santiago 7750000, Chile
- Facultad de Ciencias para el Cuidado de la Salud, Universidad San Sebastián, Providencia, Santiago 8320000, Chile
| | - Fabián Salazar
- Fundación Ciencia y Tecnología para el Desarrollo (FUCITED), Santiago 7750000, Chile
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter EX4 4QD, UK
| | - María Inés Becker
- Fundación Ciencia y Tecnología para el Desarrollo (FUCITED), Santiago 7750000, Chile
- Biosonda Corporation, Santiago 7750000, Chile
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Li XP, Sun JQ, Sui ZH, Zhang J, Feng JX. Membrane orthologs of TLR5 of tongue sole Cynoglossus semilaevis: Expression patterns, signaling pathway and antibacterial property. FISH & SHELLFISH IMMUNOLOGY 2022; 126:131-140. [PMID: 35618170 DOI: 10.1016/j.fsi.2022.05.031] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 05/05/2022] [Accepted: 05/16/2022] [Indexed: 06/15/2023]
Abstract
Mammalian toll-like receptor 5 (TLR5) is crucial for recognizing bacterial flagellin and initiating the inflammatory signaling cascades via myeloid differentiation factor 88 (MyD88) signaling pathway, which plays vital roles in innate immune against pathogenic bacteria. Herein, we reported the signaling pathway and antibacterial property of tongue sole (Cynoglossus semilaevis) membrane forms of TLR5 (i.e. CsTLR5M1and CsTLR5M2). CsTLR5M1/M2 contain 936 and 885 amino acid residues respectively. CsTLR5M1 shares 86.7% overall sequence identities with CsTLR5M2. CsTLR5M1/M2 possess the same extracellular domain (ECD) and transmembrane domain (TMD), but the different toll-interleukin-1 receptor (TIR) domain. CsTLR5M1/M2 expression occurred constitutively in multiple tissues and regulated by bacterial stimulation. Recombinant CsTLR5M1/M2 (rCsTLR5M) could bind to flagellin and Gram-negative/positive bacteria, which could suppress bacterial growth. Stimulation of the CsTLR5M pathway by flagellin resulted in increased expression of MyD88-dependent signaling molecules and inflammatory cytokines. Blocking rCsTLR5M by antibody markedly reduced the phagocytosis and ROS production of peripheral blood leukocytes (PBLs), which in turn in vivo promoted the dissemination of bacteria. Overall, these observations add new insights into the signaling pathway and immune function of teleost TLR5M.
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Affiliation(s)
- Xue-Peng Li
- School of Ocean, Yantai University, Yantai, China.
| | - Jia-Qi Sun
- School of Ocean, Yantai University, Yantai, China
| | - Zhi-Hai Sui
- School of Life Science, Linyi University, Linyi, China
| | - Jian Zhang
- School of Ocean, Yantai University, Yantai, China
| | - Ji-Xing Feng
- School of Ocean, Yantai University, Yantai, China
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21
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Lu Y, Liu Z, Li Y, Deng Z, Fang W, He F. The truncated form of flagellin (tFlic) provides the 2dCap subunit vaccine with better immunogenicity and protective effects in mice. ANIMAL DISEASES 2022; 2:11. [PMID: 35669451 PMCID: PMC9160859 DOI: 10.1186/s44149-022-00043-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 05/03/2022] [Indexed: 02/06/2023] Open
Abstract
Porcine circovirus type 2 (PCV2) is the main causative agent of porcine circovirus-associated diseases, and it causes substantial economic losses in the swine industry each year. It is crucial to develop an effective vaccine against the circulating strain PCV2d, which is prone to substantial degrees of mutation. In this study, a truncated form of flagellin (tFlic: 85-111 aa) was inserted into the C-terminal sequence of 2dCap, and Western blotting results showed that recombinant Cap-tFlic VLPs were successfully expressed. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) data indicated that purified recombinant Cap-tFlic fusion proteins existed in the form of polymers and that tFlic could not affect the formation and internalization of VLPs. Integrated Cap-tFlic VLPs induced the expression of antigen presentation-related factors (MHC-II and CD86) by bone marrow-derived dendritic cells (BM-DCs), and the expression of TLR5-related factors (TNF-α) was dramatically elevated. Mice intramuscularly immunized with Cap-tFlic VLPs exhibited significantly higher levels of Cap-specific antibodies and neutralizing antibodies than mice immunized with wild-type Cap VLPs. The data obtained in the current study indicate that Cap-tFlic may be a candidate for a subunit vaccine against PCV2 in the future.
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Affiliation(s)
- Ying Lu
- Department of Veterinary Medicine, Institute of Preventive Veterinary Medicine & Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, 866 Yuhangtang road, Hangzhou, 310058 China
| | - Zehui Liu
- Department of Veterinary Medicine, Institute of Preventive Veterinary Medicine & Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, 866 Yuhangtang road, Hangzhou, 310058 China
| | - Yingxiang Li
- Department of Veterinary Medicine, Institute of Preventive Veterinary Medicine & Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, 866 Yuhangtang road, Hangzhou, 310058 China
| | - Zhuofan Deng
- Department of Veterinary Medicine, Institute of Preventive Veterinary Medicine & Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, 866 Yuhangtang road, Hangzhou, 310058 China
| | - Weihuan Fang
- Department of Veterinary Medicine, Institute of Preventive Veterinary Medicine & Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, 866 Yuhangtang road, Hangzhou, 310058 China
| | - Fang He
- Department of Veterinary Medicine, Institute of Preventive Veterinary Medicine & Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, 866 Yuhangtang road, Hangzhou, 310058 China
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22
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Emerging Trends in Botulinum Neurotoxin A Resistance: An International Multidisciplinary Review and Consensus. PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN 2022; 10:e4407. [PMID: 35747253 PMCID: PMC9208887 DOI: 10.1097/gox.0000000000004407] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 05/11/2022] [Indexed: 11/26/2022]
Abstract
Botulinum neurotoxin A (BoNT-A) injection is the most widely performed aesthetic procedure and a first-line therapeutic option for various medical conditions. The potential for BoNT-A immunoresistance and secondary nonresponse related to neutralizing antibody (NAb) formation warrants attention as the range of BoNT-A aesthetic applications continues to expand. Methods An international multidisciplinary panel reviewed published evidence on BoNT-A immunoresistance in aesthetic and therapeutic applications and discussed best practices integrating clinical, ethical, and aesthetic considerations. Consensus statements relating to awareness, assessment, and management of the risk of NAb-related secondary nonresponse in aesthetic practice were developed. Results There was a consensus that, as doses used in aesthetic practice become like those in therapeutics, rates of NAb formation may be expected to increase. However, the true extent of NAb formation in aesthetics is likely underestimated due to limitations of published evidence and variability in treatment patterns of aesthetic patients. Since BoNT-A therapy is often lifelong, practitioners need to recognize immunogenicity as a potential complication that might affect future therapeutic use and strive to minimize modifiable risk factors. The selection and use of a BoNT-A product with the least immunogenic potential from the beginning may thus be advantageous, especially when treatment with high doses is planned. Conclusions In view of current trends in BoNT-A aesthetic use, it is essential for practitioners to conduct thorough clinical assessments, inform patients of treatment risks, and develop BoNT-A treatment plans to minimize immunogenicity. This can help preserve the option of continued or future BoNT-A treatment with satisfactory outcomes.
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23
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Kang X, Jiao Y, Zhou Y, Meng C, Zhou X, Song L, Jiao X, Pan Z. MicroRNA-5112 Targets IKKγ to Dampen the Inflammatory Response and Improve Clinical Symptoms in Both Bacterial Infection and DSS-Induced Colitis. Front Immunol 2022; 13:779770. [PMID: 35222370 PMCID: PMC8866336 DOI: 10.3389/fimmu.2022.779770] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 01/20/2022] [Indexed: 11/13/2022] Open
Abstract
Inflammation is a double-edged sword that can be induced by various PAMPs, resulting in the control of infection by invading pathogens or injuries. The inflammatory response requires strict and precise control and regulation. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression via translational inhibition or mRNA degradation. However, the role of miRNAs in inflammation induced by flagellin (ligand of TLR5) has yet to be fully determined. In this study, we identified differentially expressed miRNAs in murine bone marrow-derived dendritic cells (BMDCs) between flagellin treatment and medium alone using miRNA microarray. We found that flagellin stimulation downregulated miR-5112 expression in BMDCs and spleen DCs in vitro and in vivo. The overexpression of miR-5112 decreased inflammatory cytokine production, accompanied by a reduction of IKKγ in flagellin-stimulated BMDCs. We demonstrated that miR-5112 could directly target IKKγ to inhibit inflammatory cytokine production. Furthermore, miR-5112 inhibited the inflammatory response induced by flagellin or Salmonella infection in vivo. Interestingly, miR-5112 could also dampen the inflammatory response and alleviate dextran sulfate sodium (DSS)-induced colitis in C57BL/6 mice. These results suggest that miR-5112 could be a novel therapeutic target for both bacterial infection and DSS-induced colitis model.
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Affiliation(s)
- Xilong Kang
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.,Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China (MOA), Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou University, Yangzhou, China
| | - Yang Jiao
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.,Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China (MOA), Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou University, Yangzhou, China
| | - Yingying Zhou
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.,Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China (MOA), Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou University, Yangzhou, China
| | - Chuang Meng
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.,Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China (MOA), Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou University, Yangzhou, China
| | - Xiaohui Zhou
- Pathobiology and Veterinary Science, College of Agriculture, Health and Natural Resources, University of Connecticut, Storrs, CT, United States
| | - Li Song
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.,Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China (MOA), Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou University, Yangzhou, China
| | - Xinan Jiao
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.,Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China (MOA), Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou University, Yangzhou, China
| | - Zhiming Pan
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.,Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China (MOA), Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou University, Yangzhou, China
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24
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Tabynov K, Babayeva M, Nurpeisov T, Fomin G, Nurpeisov T, Saltabayeva U, Renu S, Renukaradhya GJ, Petrovsky N, Tabynov K. Evaluation of a Novel Adjuvanted Vaccine for Ultrashort Regimen Therapy of Artemisia Pollen-Induced Allergic Bronchial Asthma in a Mouse Model. Front Immunol 2022; 13:828690. [PMID: 35371056 PMCID: PMC8965083 DOI: 10.3389/fimmu.2022.828690] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 02/15/2022] [Indexed: 12/25/2022] Open
Abstract
Wormwood (Artemisia) pollen is among the top 10 aeroallergens globally that cause allergic rhinitis and bronchial asthma. Allergen-specific immunotherapy (ASIT) is the gold standard for treating patients with allergic rhinitis, conjunctivitis, and asthma. A significant disadvantage of today's ASIT methods is the long duration of therapy and multiplicity of allergen administrations. The goal of this study was to undertake a pilot study in mice of a novel ultrashort vaccine immunotherapy regimen incorporating various adjuvants to assess its ability to treat allergic bronchial asthma caused by wormwood pollen. We evaluated in a mouse model of wormwood pollen allergy candidates comprising recombinant Art v 1 wormwood pollen protein formulated with either newer (Advax, Advax-CpG, ISA-51) or more traditional [aluminum hydroxide, squalene water emulsion (SWE)] adjuvants administered by the intramuscular or subcutaneous route vs. intranasal administration of a mucosal vaccine formulation using chitosan-mannose nanoparticle entrapped with Art v 1 protein. The vaccine formulations were administered to previously wormwood pollen-sensitized animals, four times at weekly intervals. Desensitization was determined by measuring decreases in immunoglobulin E (IgE), cellular immunity, ear swelling test, and pathological changes in the lungs of animals after aeroallergen challenge. Art v 1 protein formulation with Advax, Advax-CpG, SWE, or ISA-51 adjuvants induced a significant decrease in both total and Art v 1-specific IgE with a concurrent increase in Art v 1-specific IgG compared to the positive control group. There was a shift in T-cell cytokine secretion toward a Th1 (Advax-CpG, ISA-51, and Advax) or a balanced Th1/Th2 (SWE) pattern. Protection against lung inflammatory reaction after challenge was seen with ISA-51, Advax, and SWE Art v 1 formulations. Overall, the ISA-51-adjuvanted vaccine group induced the largest reduction of allergic ear swelling and protection against type 2 and non-type 2 lung inflammation in challenged animals. This pilot study shows the potential to develop an ultrashort ASIT regimen for wormwood pollen-induced bronchial asthma using appropriately adjuvanted recombinant Art v 1 protein. The data support further preclinical studies with the ultimate goal of advancing this therapy to human clinical trials.
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Affiliation(s)
- Kairat Tabynov
- International Center for Vaccinology, Kazakh National Agrarian Research University (KazNARU), Almaty, Kazakhstan.,Preclinical Research Laboratory With Vivarium, M. Aikimbayev National Research Center for Especially Dangerous Infections, Almaty, Kazakhstan.,T&TvaX LLC, Almaty, Kazakhstan
| | - Meruert Babayeva
- International Center for Vaccinology, Kazakh National Agrarian Research University (KazNARU), Almaty, Kazakhstan.,Department of General Immunology, Asfendiyarov Kazakh National Medical University (KazNMU), Almaty, Kazakhstan
| | - Tair Nurpeisov
- Department of General Immunology, Asfendiyarov Kazakh National Medical University (KazNMU), Almaty, Kazakhstan.,Republican Allergy Center, Research Institute of Cardiology and Internal Medicine, Almaty, Kazakhstan
| | - Gleb Fomin
- International Center for Vaccinology, Kazakh National Agrarian Research University (KazNARU), Almaty, Kazakhstan
| | - Temirzhan Nurpeisov
- Department of General Immunology, Asfendiyarov Kazakh National Medical University (KazNMU), Almaty, Kazakhstan
| | | | - Sankar Renu
- Center for Food Animal Health, Ohio Agricultural Research and Development Center, The Ohio State University (OSU), Wooster, OH, United States
| | - Gourapura J Renukaradhya
- Center for Food Animal Health, Ohio Agricultural Research and Development Center, The Ohio State University (OSU), Wooster, OH, United States
| | | | - Kaissar Tabynov
- International Center for Vaccinology, Kazakh National Agrarian Research University (KazNARU), Almaty, Kazakhstan.,T&TvaX LLC, Almaty, Kazakhstan.,Republican Allergy Center, Research Institute of Cardiology and Internal Medicine, Almaty, Kazakhstan
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25
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Nanotechnology for making a paradigm shift in COVID-19 vaccine. CLINICAL COMPLEMENTARY MEDICINE AND PHARMACOLOGY 2022; 2:100017. [PMID: 37520497 PMCID: PMC8884076 DOI: 10.1016/j.ccmp.2021.100017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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26
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Choe Y, Lee D, Seong M, Yoon JB, Yang JH, Yang JY, Moon KH, Kang HY. Characterization of Edwardsiella piscicida CK108 flagellin genes and evaluation of their potential as vaccine targets in the zebrafish model. JOURNAL OF FISH DISEASES 2022; 45:249-259. [PMID: 34843109 DOI: 10.1111/jfd.13550] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/20/2021] [Accepted: 10/21/2021] [Indexed: 06/13/2023]
Abstract
The control of bacterial pathogens, including Edwardsiella piscicida, in the aquaculture industry has high economic importance. This study aimed to identify a potential live vaccine candidate against E. piscicida infection to minimize the side effects and elicit immunity in the host. This study evaluated the virulence factors of E. piscicida CK108, with a special focus on the flagella. E. piscicida has two important homologous flagellin genes, namely flagellin-associated protein (fap) and flagellin domain-containing protein (fdp). CK226 (Δfap), CK247 (Δfdp) and CK248 (Δfap, fdp) mutant strains were constructed. Both CK226 and CK247 displayed decreased length and thickness of flagellar filaments, resulting in reduced bacterial swimming motility, while CK248 was non-motile as it lacked flagella. The loss of flagella and decreased motility was expected to decrease the pathogenicity of CK248. However, the median lethal dose (LD50 ) of CK248 against zebrafish was lower than those of the wild-type, CK226 and CK247 strains. The protective immunity and cytokine gene expression levels in the CK248-infected zebrafish were lower than those in the wild type-infected zebrafish. In conclusion, Fap and Fdp are essential for flagella formation and motility, and for stimulating fish immune response, which can be utilized as a potential adjuvants for E. piscicida vaccination.
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Affiliation(s)
- Yunjeong Choe
- Department of Microbiology, Pusan National University, Busan, Korea
- Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea
| | - Donghee Lee
- Department of Microbiology, Pusan National University, Busan, Korea
- Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina, USA
| | - Minji Seong
- Department of Microbiology, Pusan National University, Busan, Korea
- Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea
- Mucosal Immunology Lab., Department of Biological Sciences, Pusan National University, Busan, Korea
| | - Ju Bin Yoon
- Department of Convergence Study on the Ocean Science and Technology, Korea Maritime & Ocean University, Busan, Korea
- Lab. of Marine Microbiology, Division of Convergence on Marine Science, Korea Maritime & Ocean University, Busan, Korea
| | - Jun Hyeok Yang
- Lab. of Marine Microbiology, Division of Convergence on Marine Science, Korea Maritime & Ocean University, Busan, Korea
- Department of Marine Bioscience and Environment, Korea Maritime & Ocean University, Busan, Korea
| | - Jin-Young Yang
- Mucosal Immunology Lab., Department of Biological Sciences, Pusan National University, Busan, Korea
| | - Ki Hwan Moon
- Department of Convergence Study on the Ocean Science and Technology, Korea Maritime & Ocean University, Busan, Korea
- Lab. of Marine Microbiology, Division of Convergence on Marine Science, Korea Maritime & Ocean University, Busan, Korea
- Department of Marine Bioscience and Environment, Korea Maritime & Ocean University, Busan, Korea
| | - Ho Young Kang
- Department of Microbiology, Pusan National University, Busan, Korea
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27
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Zhao BR, Wang XX, Wang XW. Shoc2 recognizes bacterial flagellin and mediates antibacterial Erk/Stat signaling in an invertebrate. PLoS Pathog 2022; 18:e1010253. [PMID: 35073369 PMCID: PMC8812994 DOI: 10.1371/journal.ppat.1010253] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 02/03/2022] [Accepted: 01/06/2022] [Indexed: 11/18/2022] Open
Abstract
Flagellin is a key bacterial virulence factor that can stimulate molecular immune signaling in both animals and plants. The detailed mechanisms of recognizing flagellin and mounting an efficient immune response have been uncovered in vertebrates; however, whether invertebrates can discriminate flagellin remains largely unknown. In the present study, the homolog of human SHOC2 leucine rich repeat scaffold protein in kuruma shrimp (Marsupenaeus japonicus), designated MjShoc2, was found to interact with Vibrio anguillarum flagellin A (FlaA) using yeast two-hybrid and pull-down assays. MjShoc2 plays a role in antibacterial response by mediating the FlaA-induced expression of certain antibacterial effectors, including lectin and antimicrobial peptide. FlaA challenge, via MjShoc2, led to phosphorylation of extracellular regulated kinase (Erk), and the subsequent activation of signal transducer and activator of transcription (Stat), ultimately inducing the expression of effectors. Therefore, by establishing the FlaA/MjShoc2/Erk/Stat signaling axis, this study revealed a new antibacterial strategy in shrimp, and provides insights into the flagellin sensing mechanism in invertebrates. Flagellin sensing has been proven as a general antibacterial strategy. Recognition of bacterial flagellin by the transmembrane receptor toll like receptor 5 (TLR5) leads to the activation of nuclear factor kappa B (NF-κB) pathway and induction of proinflammatory cytokines, while recognition by the intracellular nucleotide-binding leucine-rich (NLR) receptor leads to caspase-activation and cytokines-expression. Although flagellin is an effective immune stimulator that induces antimicrobial peptides in Drosophila and in crustaceans, how an invertebrate host senses flagellin and mounts an immune response is poorly understood. Here, we used the flagellin (FlaA) from Vibrio anguillarum, a pathogen of shrimp, as a bait protein to screen a yeast two-hybrid library derived from kuruma shrimp (Marsupenaeus japonicus). We found a scaffold protein, MjShoc2, able to interact with FlaA. We also found that FlaA could effectively induce the expression of certain recognized antibacterial effectors in shrimp depending on MjShoc2. We revealed that extracellular regulated kinase (Erk) phosphorylation occurred downstream of FlaA/MjShoc2, and led to signal transducer and activator of transcription (Stat) activation, resulting in transcription of certain effectors. Therefore our study provides new insights into the FlaA-induced molecular immunity in invertebrates.
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Affiliation(s)
- Bao-Rui Zhao
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China
| | - Xin-Xin Wang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China
| | - Xian-Wei Wang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
- * E-mail:
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28
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Ijaz A, Veldhuizen EJA, Broere F, Rutten VPMG, Jansen CA. The Interplay between Salmonella and Intestinal Innate Immune Cells in Chickens. Pathogens 2021; 10:1512. [PMID: 34832668 PMCID: PMC8618210 DOI: 10.3390/pathogens10111512] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/15/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open
Abstract
Salmonellosis is a common infection in poultry, which results in huge economic losses in the poultry industry. At the same time, Salmonella infections are a threat to public health, since contaminated poultry products can lead to zoonotic infections. Antibiotics as feed additives have proven to be an effective prophylactic option to control Salmonella infections, but due to resistance issues in humans and animals, the use of antimicrobials in food animals has been banned in Europe. Hence, there is an urgent need to look for alternative strategies that can protect poultry against Salmonella infections. One such alternative could be to strengthen the innate immune system in young chickens in order to prevent early life infections. This can be achieved by administration of immune modulating molecules that target innate immune cells, for example via feed, or by in-ovo applications. We aimed to review the innate immune system in the chicken intestine; the main site of Salmonella entrance, and its responsiveness to Salmonella infection. Identifying the most important players in the innate immune response in the intestine is a first step in designing targeted approaches for immune modulation.
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Affiliation(s)
- Adil Ijaz
- Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands; (A.I.); (E.J.A.V.); (F.B.); (V.P.M.G.R.)
| | - Edwin J. A. Veldhuizen
- Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands; (A.I.); (E.J.A.V.); (F.B.); (V.P.M.G.R.)
| | - Femke Broere
- Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands; (A.I.); (E.J.A.V.); (F.B.); (V.P.M.G.R.)
| | - Victor P. M. G. Rutten
- Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands; (A.I.); (E.J.A.V.); (F.B.); (V.P.M.G.R.)
- Department of Veterinary Tropical Diseases, Faculty of Veterinary Science, University of Pretoria, Onderstepoort, Pretoria 0110, South Africa
| | - Christine A. Jansen
- Cell Biology and Immunology Group, Department of Animal Sciences, Wageningen University & Research, De Elst 1, 6708 PB Wageningen, The Netherlands
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29
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Pogostin BH, McHugh KJ. Novel Vaccine Adjuvants as Key Tools for Improving Pandemic Preparedness. Bioengineering (Basel) 2021; 8:155. [PMID: 34821721 PMCID: PMC8615241 DOI: 10.3390/bioengineering8110155] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/20/2021] [Accepted: 10/22/2021] [Indexed: 02/07/2023] Open
Abstract
Future infectious disease outbreaks are inevitable; therefore, it is critical that we maximize our readiness for these events by preparing effective public health policies and healthcare innovations. Although we do not know the nature of future pathogens, antigen-agnostic platforms have the potential to be broadly useful in the rapid response to an emerging infection-particularly in the case of vaccines. During the current COVID-19 pandemic, recent advances in mRNA engineering have proven paramount in the rapid design and production of effective vaccines. Comparatively, however, the development of new adjuvants capable of enhancing vaccine efficacy has been lagging. Despite massive improvements in our understanding of immunology, fewer than ten adjuvants have been approved for human use in the century since the discovery of the first adjuvant. Modern adjuvants can improve vaccines against future pathogens by reducing cost, improving antigen immunogenicity, and increasing antigen stability. In this perspective, we survey the current state of adjuvant use, highlight potentially impactful preclinical adjuvants, and propose new measures to accelerate adjuvant safety testing and technology sharing to enable the use of "off-the-shelf" adjuvant platforms for rapid vaccine testing and deployment in the face of future pandemics.
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Affiliation(s)
| | - Kevin J. McHugh
- Department of Bioengineering, Rice University, Houston, TX 77030, USA;
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30
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Anik MI, Mahmud N, Al Masud A, Hasan M. Gold nanoparticles (GNPs) in biomedical and clinical applications: A review. NANO SELECT 2021. [DOI: 10.1002/nano.202100255] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Affiliation(s)
- Muzahidul I. Anik
- Department of Chemical Engineering University of Rhode Island South Kingstown Rhode Island USA
| | - Niaz Mahmud
- Department of Biomedical Engineering Military Institute of Science and Technology Dhaka Bangladesh
| | - Abdullah Al Masud
- Department of Chemical Engineering Bangladesh University of Engineering and Technology Dhaka Bangladesh
| | - Maruf Hasan
- Department of Biomedical Engineering Military Institute of Science and Technology Dhaka Bangladesh
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31
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Xia F, Wen LP, Ge BC, Li YX, Li FP, Zhou BJ. Gut microbiota as a target for prevention and treatment of type 2 diabetes: Mechanisms and dietary natural products. World J Diabetes 2021; 12:1146-1163. [PMID: 34512884 PMCID: PMC8394227 DOI: 10.4239/wjd.v12.i8.1146] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/10/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is among the most remarkable public health concerns globally. Accumulating research evidence documents that alteration of gut microbiota has an indispensable role in the onset and progression of obesity and T2DM. A reduced microbial diversity is linked to insulin resistance and energy metabolism, especially for the rise of the Firmicutes/Bacteroidetes ratio. Changes in metabolites followed by the gut dysbacteriosis are linked to the presence of T2DM. Moreover, endotoxin leakage and gut permeability caused by gut dysbacteriosis is more of a trigger for the onset and progression of T2DM. Research documents that natural products are remarkable arsenals of bioactive agents for the discovery of anti-T2DM drugs. Many studies have elucidated that the possible mechanisms of the anti-T2DM effects of natural products are remarkably linked to its regulation on the composition of gut microflora and the successive changes in metabolites directly or indirectly. This review presents a brief overview of the gut microbiota in T2DM and several relevant mechanisms, including short-chain fatty acids, biosynthesis and metabolism of branched-chain fatty acids, trimethylamine N-oxide, bile acid signaling, endotoxin leakage, and gut permeability, and describes how dietary natural products can improve T2DM via the gut microbiota.
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Affiliation(s)
- Fan Xia
- Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, Guangdong Province, China
| | - Lu-Ping Wen
- Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, Guangdong Province, China
| | - Bing-Chen Ge
- Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, Guangdong Province, China
| | - Yu-Xin Li
- Department of Pharmacology, Guangdong Medical University, Zhanjiang 524023, Guangdong Province, China
| | - Fang-Ping Li
- Department of Endocrinology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, Guangdong Province, China
| | - Ben-Jie Zhou
- Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, Guangdong Province, China
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32
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Zeng XY, Li M. Looking into key bacterial proteins involved in gut dysbiosis. World J Methodol 2021; 11:130-143. [PMID: 34322365 PMCID: PMC8299906 DOI: 10.5662/wjm.v11.i4.130] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/11/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal microbiota plays a pivotal role in health and has been linked to many diseases. With the rapid accumulation of pyrosequencing data of the bacterial composition, the causal-effect relationship between specific dysbiosis features and diseases is now being explored. The aim of this review is to describe the key functional bacterial proteins and antigens in the context of dysbiosis related-diseases. We subjectively classify the key functional proteins into two categories: Primary key proteins and secondary key proteins. The primary key proteins mainly act by themselves and include biofilm inhibitors, toxin degraders, oncogene degraders, adipose metabolism modulators, anti-inflammatory peptides, bacteriocins, host cell regulators, adhesion and invasion molecules, and intestinal barrier regulators. The secondary key proteins mainly act by eliciting host immune responses and include flagellin, outer membrane proteins, and other autoantibody-related antigens. Knowledge of key bacterial proteins is limited compared to the rich microbiome data. Understanding and focusing on these key proteins will pave the way for future mechanistic level cause-effect studies of gut dysbiosis and diseases.
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Affiliation(s)
- Xin-Yu Zeng
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Ming Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
- Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumors, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
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Abdelbaky SB, Ibrahim MT, Samy H, Mohamed M, Mohamed H, Mustafa M, Abdelaziz MM, Forrest ML, Khalil IA. Cancer immunotherapy from biology to nanomedicine. J Control Release 2021; 336:410-432. [PMID: 34171445 DOI: 10.1016/j.jconrel.2021.06.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/16/2021] [Accepted: 06/19/2021] [Indexed: 02/06/2023]
Abstract
With the significant drawbacks of conventional cancer chemotherapeutics, cancer immunotherapy has demonstrated the ability to eradicate cancer cells and circumvent multidrug resistance (MDR) with fewer side effects than traditional cytotoxic therapies. Various immunotherapeutic agents have been investigated for that purpose including checkpoint inhibitors, cytokines, monoclonal antibodies and cancer vaccines. All these agents aid immune cells to recognize and engage tumor cells by acting on tumor-specific pathways, antigens or cellular targets. However, immunotherapeutics are still associated with some concerns such as off-target side effects and poor pharmacokinetics. Nanomedicine may resolve some limitations of current immunotherapeutics such as localizing delivery, controlling release and enhancing the pharmacokinetic profile. Herein, we discuss recent advances of immunotherapeutic agents with respect to their development and biological mechanisms of action, along with the advantages that nanomedicine strategies lend to immunotherapeutics by possibly improving therapeutic outcomes and minimizing side effects.
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Affiliation(s)
- Salma B Abdelbaky
- University of Science and Technology, Zewail City, 6th of October City, Giza 12578, Egypt; Molecular, Cellular, and Developmental Biology, College of Arts and Sciences, The Ohio State University, Columbus, OH 43210, United States of America
| | - Mayar Tarek Ibrahim
- University of Science and Technology, Zewail City, 6th of October City, Giza 12578, Egypt; Department of Chemistry, Center for Scientific Computation, Center for Drug Discovery, Design, and Delivery (CD4), Southern Methodist University, Dallas, Texas 75275, United States of America
| | - Hebatallah Samy
- University of Science and Technology, Zewail City, 6th of October City, Giza 12578, Egypt; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec H3C 3J7, Canada
| | - Menatalla Mohamed
- University of Science and Technology, Zewail City, 6th of October City, Giza 12578, Egypt; Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario L8S 4M1, Canada
| | - Hebatallah Mohamed
- University of Science and Technology, Zewail City, 6th of October City, Giza 12578, Egypt; Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario L8S 4M1, Canada
| | - Mahmoud Mustafa
- University of Science and Technology, Zewail City, 6th of October City, Giza 12578, Egypt
| | - Moustafa M Abdelaziz
- Department of Bioengineering, School of Engineering, The University of Kansas, Lawrence, KS 66045, USA
| | - M Laird Forrest
- Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, KS 66047, USA.
| | - Islam A Khalil
- Department of Pharmaceutics, College of Pharmacy and Drug Manufacturing, Misr University of Science and Technology (MUST), 6th of October, Giza 12582, Egypt.
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Molecular cloning and functional studies on magang goose toll-like receptor 5. Vet Immunol Immunopathol 2021; 236:110236. [PMID: 33892385 DOI: 10.1016/j.vetimm.2021.110236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 02/05/2021] [Accepted: 03/30/2021] [Indexed: 11/22/2022]
Abstract
Disease outbreaks heavily impact the economic viability of animal industries. Little is known about the mechanisms of immune system-related diseases in geese. Toll-like receptors (TLRs) play a major role in the anti-inflammatory immunity process in most animal species, but they have not been studied in the Magang goose. To elucidate the role of TLRs, reverse transcription polymerase chain reaction (RT-PCR) and PCR amplification of cDNA ends (Smart RACE) were used to clone the Magang goose TLR5 gene (mgTLR5). The full-length cDNA of mgTLR5 was 2967 bp in length, including a 5'-terminal untranslated region (UTR) of 215 bp, a 3'-terminal UTR of 384 bp, and an open reading frame of 2583 bp that encodes a protein of 860 amino acids. Structurally, mgTLR5 has a toll/interleukin-receptor (TIR) domain, a transmembrane domain, and seven leucine-rich repeats (LRRs) domains. Homology alignment of TLR5 and its TIR domains with other species revealed that mgTLR5 shared 98 % and 81.3 % of sequence similarity with white goose TLR5 and chicken TLR5, respectively. Quantitative RT-PCR showed that the mgTLR5 gene of the goose is widely expressed in all tested tissues, with the highest expression in the kidney and spleen. The increase in NF-κB promoter activity stimulated by flagellin was dependent on mgTLR5 expression in 293 T cells. Salmonella pullorum and flagellin significantly upregulated the expression of TLR5, IL-8, and IL-1 mRNA in peripheral blood mononucleotide cells of Magang goose cultured in vitro. Stimulation by S. pullorum for 24 h upregulated mgTLR5 expression in the cecum and kidney. We conclude that Magang goose TLR5 is a functional TLR5 homologue of the protein in other species and plays an important role in bacterial recognition.
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Huang X, Pan J, Xu F, Shao B, Wang Y, Guo X, Zhou S. Bacteria-Based Cancer Immunotherapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2003572. [PMID: 33854892 PMCID: PMC8025040 DOI: 10.1002/advs.202003572] [Citation(s) in RCA: 156] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 11/03/2020] [Indexed: 05/24/2023]
Abstract
In the past decade, bacteria-based cancer immunotherapy has attracted much attention in the academic circle due to its unique mechanism and abundant applications in triggering the host anti-tumor immunity. One advantage of bacteria lies in their capability in targeting tumors and preferentially colonizing the core area of the tumor. Because bacteria are abundant in pathogen-associated molecular patterns that can effectively activate the immune cells even in the tumor immunosuppressive microenvironment, they are capable of enhancing the specific immune recognition and elimination of tumor cells. More attractively, during the rapid development of synthetic biology, using gene technology to enable bacteria to be an efficient producer of immunotherapeutic agents has led to many creative immunotherapy paradigms. The combination of bacteria and nanomaterials also displays infinite imagination in the multifunctional endowment for cancer immunotherapy. The current progress report summarizes the recent advances in bacteria-based cancer immunotherapy with specific foci on the applications of naive bacteria-, engineered bacteria-, and bacterial components-based cancer immunotherapy, and at the same time discusses future directions in this field of research based on the present developments.
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Affiliation(s)
- Xuehui Huang
- Key Laboratory of Advanced Technologies of MaterialsMinistry of EducationSchool of Materials Science and EngineeringSouthwest Jiaotong UniversityChengdu610031China
| | - Jingmei Pan
- Key Laboratory of Advanced Technologies of MaterialsMinistry of EducationSchool of Materials Science and EngineeringSouthwest Jiaotong UniversityChengdu610031China
| | - Funeng Xu
- Key Laboratory of Advanced Technologies of MaterialsMinistry of EducationSchool of Materials Science and EngineeringSouthwest Jiaotong UniversityChengdu610031China
| | - Binfen Shao
- School of Life Science and EngineeringSouthwest Jiaotong UniversityChengdu610031China
| | - Yi Wang
- School of Life Science and EngineeringSouthwest Jiaotong UniversityChengdu610031China
| | - Xing Guo
- Key Laboratory of Advanced Technologies of MaterialsMinistry of EducationSchool of Materials Science and EngineeringSouthwest Jiaotong UniversityChengdu610031China
| | - Shaobing Zhou
- Key Laboratory of Advanced Technologies of MaterialsMinistry of EducationSchool of Materials Science and EngineeringSouthwest Jiaotong UniversityChengdu610031China
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Lei X, Palomero J, de Rink I, de Wit T, van Baalen M, Xiao Y, Borst J. Flagellin/TLR5 Stimulate Myeloid Progenitors to Enter Lung Tissue and to Locally Differentiate Into Macrophages. Front Immunol 2021; 12:621665. [PMID: 33815375 PMCID: PMC8017192 DOI: 10.3389/fimmu.2021.621665] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 02/24/2021] [Indexed: 11/30/2022] Open
Abstract
Toll-like receptor 5 (TLR5) is the receptor of bacterial Flagellin. Reportedly, TLR5 engagement helps to combat infections, especially at mucosal sites, by evoking responses from epithelial cells and immune cells. Here we report that TLR5 is expressed on a previously defined bipotent progenitor of macrophages (MΦs) and osteoclasts (OCs) that resides in the mouse bone marrow (BM) and circulates at low frequency in the blood. In vitro, Flagellin promoted the generation of MΦs, but not OCs from this progenitor. In vivo, MΦ/OC progenitors were recruited from the blood into the lung upon intranasal inoculation of Flagellin, where they rapidly differentiated into MΦs. Recruitment of the MΦ/OC progenitors into the lung was likely promoted by the CCL2/CCR2 axis, since the progenitors expressed CCR2 and type 2 alveolar epithelial cells (AECs) produced CCL2 upon stimulation by Flagellin. Moreover, CCR2 blockade reduced migration of the MΦ/OC progenitors toward lung lavage fluid (LLF) from Flagellin-inoculated mice. Our study points to a novel role of the Flagellin/TLR5 axis in recruiting circulating MΦ/OC progenitors into infected tissue and stimulating these progenitors to locally differentiate into MΦs. The progenitor pathway to produce MΦs may act, next to monocyte recruitment, to fortify host protection against bacterial infection at mucosal sites.
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Affiliation(s)
- Xin Lei
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, Netherlands.,Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, Netherlands
| | - Jara Palomero
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Iris de Rink
- Genomics Facility, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Tom de Wit
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, Netherlands.,Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, Netherlands
| | - Martijn van Baalen
- Flow Cytometry Facility, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Yanling Xiao
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, Netherlands.,Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, Netherlands
| | - Jannie Borst
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, Netherlands.,Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, Netherlands
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Vijayan A, Van Maele L, Fougeron D, Cayet D, Sirard JC. The GM-CSF Released by Airway Epithelial Cells Orchestrates the Mucosal Adjuvant Activity of Flagellin. THE JOURNAL OF IMMUNOLOGY 2020; 205:2873-2882. [PMID: 33008952 DOI: 10.4049/jimmunol.2000746] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 09/09/2020] [Indexed: 01/15/2023]
Abstract
The TLR5 agonist flagellin is a potent adjuvant and is currently being developed for use in vaccines. The mechanisms that drive flagellin's activity are influenced by its administration route. Previous studies showed that lung structural cells (especially epithelial cells lining the conducting airways) are pivotal for the efficacy of intranasally administered flagellin-containing vaccines. In this study, we looked at how the airway epithelial cells (AECs) regulate the flagellin-dependent stimulation of Ag-specific CD4+ T cells and the Ab response in mice. Our results demonstrate that after sensing flagellin, AECs trigger the release of GM-CSF in a TLR5-dependent fashion and the doubling of the number of activated type 2 conventional dendritic cells (cDC2s) in draining lymph nodes. Furthermore, the neutralization of GM-CSF reduced cDC2s activation. This resulted in lower of Ag-specific CD4+ T cell count and Ab titers in mice. Our data indicate that during pulmonary immunization, the GM-CSF released by AECs orchestrates the cross-talk between cDC2s and CD4+ T cells and thus drives flagellin's adjuvant effect.
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Affiliation(s)
- Aneesh Vijayan
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France
| | - Laurye Van Maele
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France
| | - Delphine Fougeron
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France
| | - Delphine Cayet
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France
| | - Jean-Claude Sirard
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France
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Ifuku M, Hinkelmann L, Kuhrt LD, Efe IE, Kumbol V, Buonfiglioli A, Krüger C, Jordan P, Fulde M, Noda M, Kettenmann H, Lehnardt S. Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injury. Acta Neuropathol Commun 2020; 8:159. [PMID: 32912327 PMCID: PMC7488138 DOI: 10.1186/s40478-020-01031-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 08/29/2020] [Indexed: 12/12/2022] Open
Abstract
Microglia are the primary immune-competent cells of the central nervous system (CNS) and sense both pathogen- and host-derived factors through several receptor systems including the Toll-like receptor (TLR) family. Although TLR5 has previously been implicated in different CNS disorders including neurodegenerative diseases, its mode of action in the brain remained largely unexplored. We sought to determine the expression and functional consequences of TLR5 activation in the CNS. Quantitative real-time PCR and immunocytochemical analysis revealed that microglia is the major CNS cell type that constitutively expresses TLR5. Using Tlr5−/− mice and inhibitory TLR5 antibody we found that activation of TLR5 in microglial cells by its agonist flagellin, a principal protein component of bacterial flagella, triggers their release of distinct inflammatory molecules, regulates chemotaxis, and increases their phagocytic activity. Furthermore, while TLR5 activation does not affect tumor growth in an ex vivo GL261 glioma mouse model, it triggers microglial accumulation and neuronal apoptosis in the cerebral cortex in vivo. TLR5-mediated microglial function involves the PI3K/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway, as specific inhibitors of this signaling pathway abolish microglial activation. Taken together, our findings establish TLR5 as a modulator of microglial function and indicate its contribution to inflammatory and injurious processes in the CNS.
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Bromley SK, Akbaba H, Mani V, Mora-Buch R, Chasse AY, Sama A, Luster AD. CD49a Regulates Cutaneous Resident Memory CD8 + T Cell Persistence and Response. Cell Rep 2020; 32:108085. [PMID: 32877667 PMCID: PMC7520726 DOI: 10.1016/j.celrep.2020.108085] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 06/15/2020] [Accepted: 08/07/2020] [Indexed: 12/12/2022] Open
Abstract
CD8+ tissue-resident memory T cells (TRM) persist at sites of previous infection, where they provide rapid local protection against pathogen challenge. CD8+ TRM expressing the α1 chain (CD49a) of integrin VLA-1 have been identified within sites of resolved skin infection and in vitiligo lesions. We demonstrate that CD49a is expressed early following T cell activation in vivo, and TGF-β and IL-12 induce CD49a expression by CD8+ T cells in vitro. Despite this rapid expression, CD49a is not required for the generation of a primary CD8+ T cell response to cutaneous herpes simplex virus (HSV) infection, migration of CD8+ T cells across the epidermal basement membrane, or positioning of TRM within basal epidermis. Rather, CD49a supports CD8+ TRM persistence within skin, regulates epidermal CD8+ TRM dendritic extensions, and increases the frequency of IFN-γ+ CD8+ TRM following local antigen challenge. Our results suggest that CD49a promotes optimal cutaneous CD8+ TRM-mediated immunity.
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Affiliation(s)
- Shannon K Bromley
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| | - Hasan Akbaba
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Pharmaceutical Biotechnology Faculty of Pharmacy, Ege University, 35100, Bornova, Izmir, Turkey
| | - Vinidhra Mani
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Immunology Graduate Program, Harvard Medical School, Boston, MA, USA
| | - Rut Mora-Buch
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Alexandra Y Chasse
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Andrea Sama
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Andrew D Luster
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Gauthier L, Babych M, Segura M, Bourgault S, Archambault D. Identification of a novel TLR5 agonist derived from the P97 protein of Mycoplasma hyopneumoniae. Immunobiology 2020; 225:151962. [PMID: 32747018 DOI: 10.1016/j.imbio.2020.151962] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/22/2020] [Accepted: 05/15/2020] [Indexed: 02/08/2023]
Abstract
By modulating specific immune responses against antigens, adjuvants are used in many vaccine preparations to enhance protective immunity. The C-terminal domain of the protein P97 (P97c) of Mycoplasma hyopneumoniae, which is the etiologic agent of porcine enzootic pneumonia, has been shown to increase the specific humoral response against an antigen when this antigen is merged with P97c and delivered by adenovectors. However, the immunostimulating mechanism of this protein remains unknown. In the present study, recombinantly expressed P97c triggered a concentration-dependent TLR5 activation and stimulates the production of interleukin-8 from HEK-Blue mTLR5 cells. Circular dichroism spectroscopy and prediction of 3-dimensional conformation exposed a relevant secondary and tertiary structural homology between P97c and flagellin, the known potent TLR5 agonist. P97c adjuvanticity was evaluated by fusing the conserved epitope of the ectodomain matrix 2 protein (M2e) of the influenza A virus to the protein. Mice immunized with P97c-3M2e revealed a high antibody titer against the M2e epitope associated with a mixed Th1/Th2 immune response. Overall, this study identifies a novel agonist of the pattern recognition receptor TLR5 and reveals that P97c is a potential adjuvant through the activation of the innate immune system.
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Affiliation(s)
- Laurie Gauthier
- Department of Biological Sciences, Université du Québec à Montréal, Montréal, Canada; Department of Chemistry, Université du Québec à Montréal, Montréal, Canada; The Swine and Poultry Infectious Diseases Research Centre (CRIPA), Saint-Hyacinthe, Canada; Quebec Network for Research on Protein Function, Engineering, and Applications, PROTEO, Québec, Canada; Centre d'Excellence en Recherche sur les Maladies Orphelines-Fondation Courtois (CERMO-FC), Université du Québec à Montréal, Montréal, Canada
| | - Margaryta Babych
- Department of Chemistry, Université du Québec à Montréal, Montréal, Canada; Quebec Network for Research on Protein Function, Engineering, and Applications, PROTEO, Québec, Canada; Centre d'Excellence en Recherche sur les Maladies Orphelines-Fondation Courtois (CERMO-FC), Université du Québec à Montréal, Montréal, Canada
| | - Mariela Segura
- The Swine and Poultry Infectious Diseases Research Centre (CRIPA), Saint-Hyacinthe, Canada; Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Canada
| | - Steve Bourgault
- Department of Chemistry, Université du Québec à Montréal, Montréal, Canada; The Swine and Poultry Infectious Diseases Research Centre (CRIPA), Saint-Hyacinthe, Canada; Quebec Network for Research on Protein Function, Engineering, and Applications, PROTEO, Québec, Canada; Centre d'Excellence en Recherche sur les Maladies Orphelines-Fondation Courtois (CERMO-FC), Université du Québec à Montréal, Montréal, Canada.
| | - Denis Archambault
- Department of Biological Sciences, Université du Québec à Montréal, Montréal, Canada; The Swine and Poultry Infectious Diseases Research Centre (CRIPA), Saint-Hyacinthe, Canada; Centre d'Excellence en Recherche sur les Maladies Orphelines-Fondation Courtois (CERMO-FC), Université du Québec à Montréal, Montréal, Canada.
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Dewangan HK. Rational application of nanoadjuvant for mucosal vaccine delivery system. J Immunol Methods 2020; 481-482:112791. [PMID: 32387695 DOI: 10.1016/j.jim.2020.112791] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 03/20/2020] [Accepted: 04/24/2020] [Indexed: 12/11/2022]
Abstract
The surface of the mucosa is the biggest path through which pathogens enter the human body. We need an understanding of mucosal immune systems to use vaccines that generate protective mucosal and systemic immunity to regulate the outbreak of various infectious diseases. The better impact of the mucosal vaccine over traditional injectable vaccines are that not only do they induce efficient immune reactions to the mucosa but they are also comfortable in physical aspect & psychological aspect. The material of the vaccine includes pathogens antigens and adjuvants, which enable vaccination to be effective. Vaccines are classified into different criteria, including the used vaccine material and method of administration. Vaccines have traditionally been injected through a needle. However, as most of the pathogens first infect the mucosal surfaces, and growing interest is expressed in establishing protective immunity from the mucosa, which is accomplished through mucosal paths through vaccinosis. To improve the existing vaccines further, innovative strategies derived from interdisciplinary scientific research will need to develop new vaccine production, storage, and delivery systems. A distinctive & vast research and development platform has been set up for the growth of the next generation of mucosal vaccinations. The latest science and technological advancement in the areas of molecular biology, bio and chemical engineering, genome and system biology has provided accumulated understanding of the inborn and acquired multi-dimensional immune system. This review summarizes recent developments in the use of mucosal vaccines and their associated nanoadjuvants for the control of infectious diseases.
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Affiliation(s)
- Hitesh Kumar Dewangan
- Institute of Pharmaceutical Research (IPR), GLA University, Mathura, NH-2, Mathura Delhi Road, Chaumuhan Mathura, Uttar Pradesh 281406, India.
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Zhao Y, Li Z, Zhu X, Cao Y, Chen X. Improving immunogenicity and safety of flagellin as vaccine carrier by high-density display on virus-like particle surface. Biomaterials 2020; 249:120030. [PMID: 32315864 DOI: 10.1016/j.biomaterials.2020.120030] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 03/30/2020] [Accepted: 04/03/2020] [Indexed: 12/17/2022]
Abstract
Flagellin is a protein-based adjuvant that activates toll-like receptor (TLR) 5. Flagellin has been actively explored as vaccine adjuvants and carriers. Preclinical and clinical studies find flagellin-based vaccines have a risk to induce systemic adverse reactions potentially due to its overt activation of TLR5. To improve safety and immunogenicity of flagellin as vaccine carriers, FljB was displayed at high densities on hepatitis b core (HBc) virus-like particle (VLP) surface upon c/e1 loop insertion. FljB-HBc (FH) VLPs showed significantly reduced ability to activate TLR5 or induce systemic interleukin-6 release as compared to FljB. FH VLPs also failed to significantly increase rectal temperature of mice, while FljB could significantly increase rectal temperature of mice. These data indicated systemic safety of FljB could be significantly improved by high-density display on HBc VLP surface. Besides improved safety, FH VLPs and FljB similarly boosted co-administered ovalbumin immunization and FH VLPs were found to induce two-fold higher anti-FljB antibody titer than FljB. These data indicated preserved adjuvant potency and improved immunogenicity after high-density display of FljB on HBc VLP surface. Consistent with the high immunogenicity, FH VLPs were found to be more efficiently taken up by bone marrow-derived dendritic cells and stimulate more potent dendritic cell maturation than FljB. Lastly, FH VLPs were found to be a more immunogenic carrier than FljB, HBc VLPs, or the widely used keyhole limpet hemocyanin for nicotine vaccine development with a good local and systemic safety. Our data support FH VLPs to be a potentially safer and more immunogenic carrier than FljB for vaccine development.
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Affiliation(s)
- Yiwen Zhao
- Biomedical & Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, USA
| | - Zhuofan Li
- Biomedical & Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, USA
| | - Xiaoyue Zhu
- Biomedical & Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, USA
| | - Yan Cao
- Biomedical & Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, USA
| | - Xinyuan Chen
- Biomedical & Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, USA.
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Kang W, Park A, Huh JW, You G, Jung DJ, Song M, Lee HK, Kim YM. Flagellin-Stimulated Production of Interferon-β Promotes Anti-Flagellin IgG2c and IgA Responses. Mol Cells 2020; 43:251-263. [PMID: 32131150 PMCID: PMC7103879 DOI: 10.14348/molcells.2020.2300] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 12/25/2019] [Accepted: 12/30/2019] [Indexed: 12/14/2022] Open
Abstract
Flagellin, a major structural protein of the flagellum found in all motile bacteria, activates the TLR5- or NLRC4 inflammasomedependent signaling pathway to induce innate immune responses. Flagellin can also serve as a specific antigen for the adaptive immune system and stimulate anti-flagellin antibody responses. Failure to recognize commensal-derived flagellin in TLR5-deficient mice leads to the reduction in antiflagellin IgA antibodies at steady state and causes microbial dysbiosis and mucosal barrier breach by flagellated bacteria to promote chronic intestinal inflammation. Despite the important role of anti-flagellin antibodies in maintaining the intestinal homeostasis, regulatory mechanisms underlying the flagellin-specific antibody responses are not well understood. In this study, we show that flagellin induces interferon-β (IFN-β) production and subsequently activates type I IFN receptor signaling in a TLR5- and MyD88-dependent manner in vitro and in vivo . Internalization of TLR5 from the plasma membrane to the acidic environment of endolysosomes was required for the production of IFN-β, but not for other proinflammatory cytokines. In addition, we found that antiflagellin IgG2c and IgA responses were severely impaired in interferon-alpha receptor 1 (IFNAR1)-deficient mice, suggesting that IFN-β produced by the flagellin stimulation regulates anti-flagellin antibody class switching. Our findings shed a new light on the regulation of flagellin-mediated immune activation and may help find new strategies to promote the intestinal health and develop mucosal vaccines.
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Affiliation(s)
- Wondae Kang
- Division of Integrative Biosciences & Biotechnology, Pohang University of Science and Technology, Pohang 37673, Korea
| | - Areum Park
- Division of Integrative Biosciences & Biotechnology, Pohang University of Science and Technology, Pohang 37673, Korea
| | - Ji-Won Huh
- Division of Integrative Biosciences & Biotechnology, Pohang University of Science and Technology, Pohang 37673, Korea
| | - Gihoon You
- Division of Integrative Biosciences & Biotechnology, Pohang University of Science and Technology, Pohang 37673, Korea
| | - Da-Jung Jung
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
| | - Manki Song
- International Vaccine Institute, Seoul 08826, Korea
| | - Heung Kyu Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
| | - You-Me Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
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Incorporation of a truncated form of flagellin (TFlg) into porcine circovirus type 2 virus-like particles enhances immune responses in mice. BMC Vet Res 2020; 16:45. [PMID: 32028949 PMCID: PMC7006081 DOI: 10.1186/s12917-020-2253-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Accepted: 01/22/2020] [Indexed: 02/07/2023] Open
Abstract
Background Porcine circovirus type 2 (PCV2) is an economically important pathogen in the swine industry worldwide. Vaccination remains the principal tool to control PCV2-associated diseases (PCVADs). Current vaccines do not eliminate viral shedding in the environment. To enhance the efficacy of PCV2 vaccines, recombinant virus-like particles (VLPs) of PCV2 were generated by fusing a truncated form of flagellin FliC (TFlg: 85-111aa) with the PCV2 capsid protein (Cap). Results The recombinant proteins were expressed in Escherichia coli and detected using Western blotting. The abilities of the recombinant proteins to assemble into VLPs were observed under transmission electron microscopy (TEM). The protective immune responses of recombinant VLPs were further evaluated by immunization of mice. The results showed that insertion of TFlg into C terminal of the Cap protein did not affect the formation of VLPs and boosted both humoral and cellular immune responses in mice. After a challenge with PCV2, in the Cap-TFlg vaccinated group, viremia was milder and viral loads were lower as compared with those in the Cap vaccinated group. Conclusion These results suggest that recombinant VLPs of PCV2 containing a TFlg adjuvant can be used as a promising PCV2 vaccine candidate.
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Ahmed Z, Lysek M, Zhang N, Malik TA. Association Between Serological Markers and Crohn's Disease Activity. J Clin Med Res 2020; 12:6-12. [PMID: 32010416 PMCID: PMC6968925 DOI: 10.14740/jocmr4016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 11/20/2019] [Indexed: 11/20/2022] Open
Abstract
Background The aim was to study the association between six serological markers and Crohn’s disease (CD) activity at an inflammatory bowel disease (IBD) referral center. Methods We designed a retrospective cohort study using adults (> 18 years) with CD followed for at least 1 year at University of Alabama at Birmingham. Baseline serological markers ASCA-IgA, ASCA-IgG, anti-OmpC IgA, anti-CBir1 IgG, anti-A4Fla2 IgG and anti-FlaX IgG were drawn at initial visit. Poisson regression was used to assess the longitudinal relationship between these markers drawn at baseline and rate of active clinical disease during follow-up. Results Each marker, from 135 patients, was categorized into high vs. low. A Poisson regression model adjusted for age, gender, race, duration of disease, obesity, proton pump inhibitor; steroid and thiopurine use, and disease location demonstrated that CD patients with high anti-CBir1 IgG at baseline were approximately twice more likely to have active clinical disease (incidence rate ratio (IRR) 2.06, 95% confidence interval (CI) 1.28 - 3.33, P = 0.0032). The unadjusted Poisson regression model for A4Fla2 IgG antibody level did suggest that a high A4Fla2 IgG at baseline was associated with a higher likelihood of active CD (IRR 1.64, 95% CI 1.07, 2.53, P = 0.0238) which however, upon adjustment based on effect size, was not significant. The other four antibodies did not appear to predict clinical course. Conclusions High levels of anti-CBir1 IgG appear to be associated with a greater likelihood of active CD. Whether routine baseline testing for anti-CBir1 IgG to predict a more active clinical course is warranted needs more research.
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Affiliation(s)
- Zunirah Ahmed
- Department of Medicine, University of Alabama at Birmingham Montgomery, AL 36116, USA
| | - Michael Lysek
- Department of Medicine, University of South Alabama, Mobile, AL 36617, USA
| | - Nan Zhang
- Department of Biostatistics, Mayo Clinic, Scottsdale, AZ 85259, USA
| | - Talha A Malik
- Department of Medicine-Gastroenterology, Mayo Clinic, Scottsdale, AZ 85259, USA
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Okay S, Özge Özcan Ö, Karahan M. Nanoparticle-based delivery platforms for mRNA vaccine development. AIMS BIOPHYSICS 2020. [DOI: 10.3934/biophy.2020023] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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Park JY, Sunga O, Wanitphakdeedecha R, Frevert J. Neurotoxin Impurities: A Review of Threats to Efficacy. PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN 2020; 8:e2627. [PMID: 32095419 PMCID: PMC7015620 DOI: 10.1097/gox.0000000000002627] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 12/09/2019] [Indexed: 01/04/2023]
Abstract
Recently launched esthetic botulinum toxin serotype A (BoNT/A) products include Nabota/Jeuveau, Meditoxin/Neuronox, and Botulax, which contain nontoxic accessory proteins and excipients. Clinical evidence supporting these formulations, including their purity and potential immunogenicity or their link to treatment failures, is limited. Any nonhuman protein, including nontoxin accessory proteins, can initiate immune reactions, especially if administered repeatedly, yet the issue of BoNT/A-induced immunogenicity is widely contested. However, there have been multiple reports of treatment failures and observations of BoNT/A-induced neutralizing antibodies. Compared with the purified formulation in Xeomin, these recently launched toxins contain higher total neurotoxin quantities, much of which is inactive and exposes patients to potentially immunogenic nontoxin proteins or inactive neurotoxins that increase their risk of developing treatment failure. Well-established products [especially abobotulinumtoxinA (Dysport), onabotulinumtoxinA (Botox) and Xeomin] are accompanied by comprehensive and long-ranging clinical evidence on safety and efficacy in esthetic facial indications, which still remains undisclosed for many of the recently introduced toxins. Clinicians need this information as patients will require repeated BoNT treatments and may be unnecessarily but cumulatively exposed to potential immunogens. To underscore the need for caution and further evidence, we review some of the issues surrounding BoNT/A-induced immunogenicity and antibody-induced treatment failures and argue that using highly purified toxins that do not negatively impact patient outcomes is a prudent clinical decision.
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Affiliation(s)
- Je-Young Park
- From the Apkoo-Jung Department, Oracle Dermatology Center, Seoul, Korea
| | - Owen Sunga
- Merz Aesthetics Asia Pacific Pte Ltd, Singapore
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Cook L, Lisko DJ, Wong MQ, Garcia RV, Himmel ME, Seidman EG, Bressler B, Levings MK, Steiner TS. Analysis of Flagellin-Specific Adaptive Immunity Reveals Links to Dysbiosis in Patients With Inflammatory Bowel Disease. Cell Mol Gastroenterol Hepatol 2019; 9:485-506. [PMID: 31790809 PMCID: PMC7036547 DOI: 10.1016/j.jcmgh.2019.11.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 11/21/2019] [Accepted: 11/22/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Bacterial flagellin is an important antigen in inflammatory bowel disease, but the role of flagellin-specific CD4+ T cells in disease pathogenesis remains unclear. Also unknown is how changes in intestinal microbiome intersect with those in microbiota-specific CD4+ T cells. We aimed to quantify and characterize flagellin-specific CD4+ T cells in Crohn's disease (CD) and ulcerative colitis (UC) patients and study their relationship with intestinal microbiome diversity. METHODS Blood was collected from 3 cohorts that included CD patients, UC patients, and healthy controls. Flow cytometry analyzed CD4+ T cells specific for Lachnospiraceae-derived A4-Fla2 and Escherichia coli H18 FliC flagellins, or control vaccine antigens. Serum antiflagellin IgG and IgA antibodies were detected by enzyme-linked immunosorbent assay and stool samples were collected and subjected to 16S ribosomal DNA sequencing. RESULTS Compared with healthy controls, CD and UC patients had lower frequencies of vaccine-antigen-specific CD4+ T cells and, as a proportion of vaccine-specific cells, higher frequencies of flagellin-specific CD4+ T cells. The proportion of flagellin-specific CD4+ T cells that were CXCR3negCCR4+CCR6+ Th17 cells was reduced in CD and UC patients, with increased proportions of CD39+, PD-1+, and integrin β7+ cells. Microbiome analysis showed differentially abundant bacterial species in patient groups that correlated with immune responses to flagellin. CONCLUSIONS Both CD and UC patients have relative increases in the proportion of circulating Fla2-specific CD4+ T cells, which may be associated with changes in the intestinal microbiome. Evidence that the phenotype of these cells strongly correlate with disease severity provides insight into the potential roles of flagellin-specific CD4+ T cells in inflammatory bowel disease.
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Affiliation(s)
- Laura Cook
- Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada,British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Daniel J. Lisko
- Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada,British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - May Q. Wong
- Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada,British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Rosa V. Garcia
- British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada,Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Megan E. Himmel
- British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Ernest G. Seidman
- Division of Gastroenterology, McGill University, Montréal, Quebec, Canada
| | - Brian Bressler
- Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada,Gastrointestinal Research Institute, Vancouver, British Columbia, Canada
| | - Megan K. Levings
- British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada,Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada,School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada
| | - Theodore S. Steiner
- Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada,British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada,Correspondence Address correspondence to: Ted Steiner, MD, British Columbia Children’s Hospital Research Institute, 950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4. fax: (604) 875-2373.
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Yang F, Kosten TR. Psychopharmacology: neuroimmune signaling in psychiatric disease-developing vaccines against abused drugs using toll-like receptor agonists. Psychopharmacology (Berl) 2019; 236:2899-2907. [PMID: 30726515 DOI: 10.1007/s00213-019-5176-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Accepted: 01/16/2019] [Indexed: 01/05/2023]
Abstract
RATIONALE Since substance use disorders have few or no effective pharmacotherapies, researchers have developed vaccines as immune-therapies against nicotine, cocaine, methamphetamine, and opioids including fentanyl. OBJECTIVES We focus on enhancing antibody (AB) production through stimulation of toll-like receptor-5 (TLR5) during active vaccination. The stimulating adjuvant is Entolimod, a novel protein derivative of flagellin. We review the molecular and cellular mechanisms underlying Entolimod's actions on TLR5. RESULTS Entolimod shows excellent efficacy for increasing AB levels to levels well beyond those produced by anti-addiction vaccines alone in animal models and humans. These ABs also significantly block the behavioral effects of the targeted drug of abuse. The TLR5 stimulation involves a wide range of immune cell types such as dendritic, antigen presenting, T and B cells. Entolimod binding to TLR5 initiates an intracellular signaling cascade that stimulates cytokine production of tumor necrosis factor and two interleukins (IL-6 and IL-12). While cytokine release can be catastrophic in cytokine storm, Entolimod produces a modulated release with few side effects even at doses 30 times greater than doses needed in these vaccine studies. Entolimod has markedly increased AB responses to all of our anti-addiction vaccines in rodent models, and in normal humans. CONCLUSIONS Entolimod and TLR5 stimulation has broad application to vaccines and potentially to other psychiatric disorders like depression, which has critical inflammatory contributions that Entolimod could reduce.
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Affiliation(s)
- Fang Yang
- Department of Psychiatry, Baylor College of Medicine, 1977 Butler Blvd, Suite E4.207, Houston, TX, 77030, USA
| | - Thomas R Kosten
- Department of Psychiatry, Baylor College of Medicine, 1977 Butler Blvd, Suite E4.207, Houston, TX, 77030, USA.
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Dos Reis EC, Leal VNC, Soares JLDS, Fernandes FP, Souza de Lima D, de Alencar BC, Pontillo A. Flagellin/NLRC4 Pathway Rescues NLRP3-Inflammasome Defect in Dendritic Cells From HIV-Infected Patients: Perspective for New Adjuvant in Immunocompromised Individuals. Front Immunol 2019; 10:1291. [PMID: 31244842 PMCID: PMC6579915 DOI: 10.3389/fimmu.2019.01291] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 05/21/2019] [Indexed: 12/27/2022] Open
Abstract
Introduction: NLRP3 inflammasome plays a key role in dendritic cells (DC) activation in response to vaccine adjuvants, however we previously showed that it is not properly activated in DC from HIV-infected patients (HIV-DC), explaining, at least in part, the poor response to immunization of these patients. Taking in account that several cytoplasmic receptors are able to activate inflammasome, and that bacterial components are considered as a novel and efficient adjuvant, we postulated that bacterial flagellin (FLG), a natural ligand of NAIP/NLRC4 inflammasome, could rescue the activation of the complex in HIV-DC. Objective: Demonstrate that FLG is able to activate monocyte-derived dendritic cells from HIV-infected individuals better than LPS, and to what extent the entity of inflammasome activation differs between DC from HIV-infected patients and healthy donors. Methods: Monocyte-derived dendritic cells from HIV-infected patients (HIV-DC) and healthy donors (HD-DC) were stimulated with FLG, and inflammasome as well as DC activation (phenotypic profile, cytokine production, autologous lymphocytes activation) were compared. Chemical and genetic inhibitors were used to depict the relative contribution of NLRC4 and NLRP3 in HIV/HD-DC response to FLG. Results: FLG properly activates HD-DC and HIV-DC. FLG induces higher inflammasome activation than LPS in HIV-DC. FLG acts through NLRC4 and NLRP3 in HD-DC, but at a lesser extent in HIV-DC due to intrinsic NLRP3 defect. Conclusions: FLG by-passes NLRP3 defect in HIV-DC, through the activation of NAIP/NLRC4 inflammasome, indicating possible future use of the bacterial component as an efficient adjuvant in immunocompromised individuals.
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Affiliation(s)
- Edione Cristina Dos Reis
- Laboratory of Immunogenetics, Department of Immunology, Institute of Biomedical Sciences/ICB, University of São Paulo/USP, São Paulo, Brazil
| | - Vinícius Nunes Cordeiro Leal
- Laboratory of Immunogenetics, Department of Immunology, Institute of Biomedical Sciences/ICB, University of São Paulo/USP, São Paulo, Brazil
| | - Jaíne Lima da Silva Soares
- Laboratory of Immunogenetics, Department of Immunology, Institute of Biomedical Sciences/ICB, University of São Paulo/USP, São Paulo, Brazil
| | - Fernanda Pereira Fernandes
- Laboratory of Immunogenetics, Department of Immunology, Institute of Biomedical Sciences/ICB, University of São Paulo/USP, São Paulo, Brazil
| | - Dhêmerson Souza de Lima
- Laboratory of Immunogenetics, Department of Immunology, Institute of Biomedical Sciences/ICB, University of São Paulo/USP, São Paulo, Brazil
| | - Bruna Cunha de Alencar
- Laboratory of Immune System Cell Biology, Department of Immunology, Institute of Biomedical Sciences/ICB, University of São Paulo/USP, São Paulo, Brazil
| | - Alessandra Pontillo
- Laboratory of Immunogenetics, Department of Immunology, Institute of Biomedical Sciences/ICB, University of São Paulo/USP, São Paulo, Brazil
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