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Wang Y, Ding Q, Ma G, Zhang Z, Wang J, Lu C, Xiang C, Qian K, Zheng J, Shan Y, Zhang P, Cheng Z, Gong P, Zhao Q. Mucus-Penetrable Biomimetic Nanoantibiotics for Pathogen-Induced Pneumonia Treatment. ACS NANO 2024; 18:31349-31359. [PMID: 39485232 DOI: 10.1021/acsnano.4c10837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Bacterial pneumonia has garnered significant attention in the realm of infectious diseases owing to a surge in the incidence of severe infections coupled with the growing scarcity of efficacious therapeutic modalities. Antibiotic treatment is still an irreplaceable method for bacterial pneumonia because of its strong bactericidal activity and good clinical efficacy. However, the mucus layer forming after a bacterial infection in the lungs has been considered as the "Achilles' heels" facing the clinical application of such treatment. Herein, traceable biomimetic nanoantibiotics (BioNanoCFPs) were developed by loading indacenodithieno[3,2-b]thiophene (ITIC) and cefoperazone (CFP) in nanoplatforms coated with natural killer (NK) cell membranes. The BioNanoCFP exhibited excellent demonstrated mucus-penetrating abilities, facilitating their arrival at the infection site. The presence of Toll-like receptors in the NK cell membrane rendered the BioNanoCFP with the capability to recognize pathogen-associated molecular patterns within bacteria, allowing precise targeting of bacterial colonization sites and achieving substantial therapeutic efficacy. Overall, our findings demonstrate the viability and desirability of using NK cell membrane-mediated drug delivery as a promising strategy for precision treatment.
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Affiliation(s)
- Yue Wang
- Cancer Center, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China
- Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, China
| | - Qihang Ding
- Department of Chemistry, Korea University, Seoul 02841, Korea
| | - Gongcheng Ma
- Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, China
| | - Zhiwei Zhang
- Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, China
| | - Jiaqi Wang
- Cancer Center, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China
| | - Chang Lu
- Cancer Center, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China
| | - Chunbai Xiang
- Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, China
| | - Kun Qian
- State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Jun Zheng
- Cancer Center, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China
| | - Yaming Shan
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin 130012, China
| | - Pengfei Zhang
- Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, China
- Sino-Euro Center of Biomedicine and Health, Luohu, Shenzhen 518024, China
| | - Zhen Cheng
- State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China
| | - Ping Gong
- Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, China
- Sino-Euro Center of Biomedicine and Health, Luohu, Shenzhen 518024, China
| | - Qi Zhao
- Cancer Center, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China
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Almutairi A, Alshehri NA, Al Subayyil A, Bahattab E, Alshabibi M, Abomaray F, Basmaeil YS, Khatlani T. Human decidua basalis mesenchymal stem/stromal cells enhance anticancer properties of human natural killer cells, in vitro. Front Cell Dev Biol 2024; 12:1435484. [PMID: 39539962 PMCID: PMC11557523 DOI: 10.3389/fcell.2024.1435484] [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: 05/20/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Introduction Mesenchymal stem cells/stromal cells from the Decidua Basalis of the human placenta (DBMSCs) express wide range of effector molecules that modulate the functions of their target cells. These properties make them potential candidate for use in cellular therapy. In this study, we have investigated the consequences of interaction between DBMSCs and natural killer (NK) cells for both cell types. Methods DBMSCs were cultured with IL-2-activated and resting non-activated NK cells isolated from healthy human peripheral blood and various functional assays were performed including, NK cell proliferation and cytolytic activities. Flow cytometry and microscopic studies were performed to examine the expression of NK cell receptors that mediate these cytolytic activities against DBMSCs. Moreover, the mechanism underlying these effects was also investigated. Results Our findings revealed that, co-culture of DBMSCs and NK cells resulted in inhibition of proliferation of resting NK cells, while proliferation of IL-2 activated NK cells was increased. Contrarily, treatment of DBMSC's with comparatively high numbers of IL-2 activated NK cells, resulted in their lysis, whereas treatment with low numbers resulted in reduction in their proliferation. Cytolytic activity of NK cells against DBMSCs was mediated by several activating NK cell receptors. In spite of the expression of HLA class I molecules by DBMSCs, they were still lysed by NK cells, excluding their involvement in cytolytic activity. In addition, preconditioning NK cells by DBMSCs, enhanced their ability to suppress tumor cell proliferation and in severe cases resulted in their partial lysis. Lysis and decrease of tumor cell proliferation is associated with increased expression of important molecules involved in anticancer activities. Discussion We conclude that DBMSCs exhibit dualfunctions on NK cells that enhance their anticancer therapeutic potential.
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Affiliation(s)
- Abdulaziz Almutairi
- College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- Stem Cells and Regenerative Medicine Unit, Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdul Aziz University for Medical Sciences (KSAU-HS), King Abdulaziz Medical City (KAMC), Ministry of National Guard Health Affairs (MNGHA), Riyadh, Saudi Arabia
| | - Najlaa A. Alshehri
- Stem Cells and Regenerative Medicine Unit, Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdul Aziz University for Medical Sciences (KSAU-HS), King Abdulaziz Medical City (KAMC), Ministry of National Guard Health Affairs (MNGHA), Riyadh, Saudi Arabia
- School of Education, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Abdullah Al Subayyil
- Stem Cells and Regenerative Medicine Unit, Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdul Aziz University for Medical Sciences (KSAU-HS), King Abdulaziz Medical City (KAMC), Ministry of National Guard Health Affairs (MNGHA), Riyadh, Saudi Arabia
| | - Eman Bahattab
- National Center for Stem Cell Technology, Life Sciences and Environment Research Institute, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Manal Alshabibi
- National Center for Stem Cell Technology, Life Sciences and Environment Research Institute, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Fawaz Abomaray
- Department of Clinical Science, Intervention and Technology, Division of Obstetrics and Gynecology, Karolinska Institutet, Stockholm, Sweden
- Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Yasser S. Basmaeil
- Stem Cells and Regenerative Medicine Unit, Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdul Aziz University for Medical Sciences (KSAU-HS), King Abdulaziz Medical City (KAMC), Ministry of National Guard Health Affairs (MNGHA), Riyadh, Saudi Arabia
| | - Tanvir Khatlani
- Stem Cells and Regenerative Medicine Unit, Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdul Aziz University for Medical Sciences (KSAU-HS), King Abdulaziz Medical City (KAMC), Ministry of National Guard Health Affairs (MNGHA), Riyadh, Saudi Arabia
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Nakashima Y, Onuki K, Hibi T, Ohno RI, Sugawa H, Tominaga Y, Yasuda S, Kinoshita H. Soymilk yogurt fermented using Pediococcus pentosaceus TOKAI 759 m improves mice gut microbiota and reduces pro-inflammatory cytokine production. Biosci Biotechnol Biochem 2024; 88:1349-1361. [PMID: 39134513 DOI: 10.1093/bbb/zbae112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 08/06/2024] [Indexed: 10/23/2024]
Abstract
This study aimed to determine the anti-inflammatory activities and bioactive compounds of soymilk yogurt prepared using Lactiplantibacillus plantarum TOKAI 17 or Pediococcus pentosaceus TOKAI 759 m. Mice were divided into five groups: normal diet (ND), soymilk, soymilk yogurt using L. plantarum TOKAI 17 (SY 17) or P. pentosaceus TOKAI 759 m (SY 759 m), and 0.5 × 109 cells of each starter strain (BC 17 or BC759m). In the SY 759 m group, the serum pro-inflammatory cytokine levels and the cytotoxicity of natural killer cells were attenuated compared to the ND group. In the cecum microbiota, the abundances of butyrate-producing bacteria increased in the SY 759 m and BC 17 groups. Furthermore, SY 759 m metabolites contained high levels of aglycone isoflavone, adenine and showed a significant decrease in CCL-2 and interleukin-6 production in lipopolysaccharide-induced macrophage. In conclusion, soymilk yogurt produced using P. pentosaceus TOKAI 759 m modulates the gut microbiota and can potentially prevent pro-inflammatory cytokine production.
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Affiliation(s)
- Yuki Nakashima
- Graduate School of Bioscience, Tokai University , Kamimashiki-gun, Kumamoto, Japan
- JSPS Research Fellowship for Young Scientists, Tokyo, Japan
| | - Kotone Onuki
- Graduate School of Agriculture, Tokai University , Kamimashiki-gun, Kumamoto, Japan
| | - Tomoyuki Hibi
- Graduate School of Bioscience, Tokai University , Kamimashiki-gun, Kumamoto, Japan
- Research Institute of Agriculture, Tokai University, Kumamoto, Japan
| | - Rei-Ichi Ohno
- Graduate School of Agriculture, Tokai University , Kamimashiki-gun, Kumamoto, Japan
| | - Hikari Sugawa
- Graduate School of Agriculture, Tokai University , Kamimashiki-gun, Kumamoto, Japan
| | - Yuki Tominaga
- Graduate School of Agriculture, Tokai University , Kamimashiki-gun, Kumamoto, Japan
| | - Shin Yasuda
- Graduate School of Bioscience, Tokai University , Kamimashiki-gun, Kumamoto, Japan
- Graduate School of Agriculture, Tokai University , Kamimashiki-gun, Kumamoto, Japan
| | - Hideki Kinoshita
- Graduate School of Bioscience, Tokai University , Kamimashiki-gun, Kumamoto, Japan
- Graduate School of Agriculture, Tokai University , Kamimashiki-gun, Kumamoto, Japan
- Research Institute of Agriculture, Tokai University, Kumamoto, Japan
- Probio Co., Ltd , Aso-gun, Kumamoto, Japan
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Devulder J, Barrier M, Carrard J, Amniai L, Plé C, Marquillies P, Ledroit V, Ryffel B, Tsicopoulos A, de Nadai P, Duez C. Pulmonary Administration of TLR2/6 Agonist after Allergic Sensitization Inhibits Airway Hyper-Responsiveness and Recruits Natural Killer Cells in Lung Parenchyma. Int J Mol Sci 2024; 25:9606. [PMID: 39273551 PMCID: PMC11394962 DOI: 10.3390/ijms25179606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 08/24/2024] [Accepted: 09/02/2024] [Indexed: 09/15/2024] Open
Abstract
Asthma is a chronic lung disease with persistent airway inflammation, bronchial hyper-reactivity, mucus overproduction, and airway remodeling. Antagonizing T2 responses by triggering the immune system with microbial components such as Toll-like receptors (TLRs) has been suggested as a therapeutic concept for allergic asthma. The aim of this study was to evaluate the effect of a TLR2/6 agonist, FSL-1 (Pam2CGDPKHPKSF), administered by intranasal instillation after an allergic airway reaction was established in the ovalbumin (OVA) mouse model and to analyze the role of natural killer (NK) cells in this effect. We showed that FSL-1 decreased established OVA-induced airway hyper-responsiveness and eosinophilic inflammation but did not reduce the T2 or T17 response. FSL-1 increased the recruitment and activation of NK cells in the lung parenchyma and modified the repartition of NK cell subsets in lung compartments. Finally, the transfer or depletion of NK cells did not modify airway hyper-responsiveness and eosinophilia after OVA and/or FSL-1 treatment. Thus, the administration of FSL-1 reduces airway hyper-responsiveness and bronchoalveolar lavage eosinophilia. However, despite modifications of their functions following OVA sensitization, NK cells play no role in OVA-induced asthma and its inhibition by FSL-1. Therefore, the significance of NK cell functions and localization in the airways remains to be unraveled in asthma.
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Affiliation(s)
- Justine Devulder
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL—Center for Infection and Immunity of Lille, F-59000 Lille, France; (J.D.); (A.T.); (P.d.N.)
| | - Mathieu Barrier
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL—Center for Infection and Immunity of Lille, F-59000 Lille, France; (J.D.); (A.T.); (P.d.N.)
| | - Julie Carrard
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL—Center for Infection and Immunity of Lille, F-59000 Lille, France; (J.D.); (A.T.); (P.d.N.)
| | - Latiffa Amniai
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL—Center for Infection and Immunity of Lille, F-59000 Lille, France; (J.D.); (A.T.); (P.d.N.)
| | - Coline Plé
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL—Center for Infection and Immunity of Lille, F-59000 Lille, France; (J.D.); (A.T.); (P.d.N.)
| | - Philippe Marquillies
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL—Center for Infection and Immunity of Lille, F-59000 Lille, France; (J.D.); (A.T.); (P.d.N.)
| | - Valérie Ledroit
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL—Center for Infection and Immunity of Lille, F-59000 Lille, France; (J.D.); (A.T.); (P.d.N.)
| | - Bernhard Ryffel
- CNRS and University Orleans—INEM (Immuno-Neuro Modulation), UMR7355 INEM, 45071 Orleans , France;
| | - Anne Tsicopoulos
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL—Center for Infection and Immunity of Lille, F-59000 Lille, France; (J.D.); (A.T.); (P.d.N.)
| | - Patricia de Nadai
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL—Center for Infection and Immunity of Lille, F-59000 Lille, France; (J.D.); (A.T.); (P.d.N.)
| | - Catherine Duez
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL—Center for Infection and Immunity of Lille, F-59000 Lille, France; (J.D.); (A.T.); (P.d.N.)
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Mohammad Taheri M, Javan F, Poudineh M, Athari SS. Beyond CAR-T: The rise of CAR-NK cell therapy in asthma immunotherapy. J Transl Med 2024; 22:736. [PMID: 39103889 PMCID: PMC11302387 DOI: 10.1186/s12967-024-05534-8] [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: 05/12/2024] [Accepted: 07/23/2024] [Indexed: 08/07/2024] Open
Abstract
Asthma poses a major public health burden. While existing asthma drugs manage symptoms for many, some patients remain resistant. The lack of a cure, especially for severe asthma, compels exploration of novel therapies. Cancer immunotherapy successes with CAR-T cells suggest its potential for asthma treatment. Researchers are exploring various approaches for allergic diseases including membrane-bound IgE, IL-5, PD-L2, and CTLA-4 for asthma, and Dectin-1 for fungal asthma. NK cells offer several advantages over T cells for CAR-based immunotherapy. They offer key benefits: (1) HLA compatibility, meaning they can be used in a wider range of patients without the need for matching tissue types. (2) Minimal side effects (CRS and GVHD) due to their limited persistence and cytokine profile. (3) Scalability for "off-the-shelf" production from various sources. Several strategies have been introduced that highlight the superiority and challenges of CAR-NK cell therapy for asthma treatment including IL-10, IFN-γ, ADCC, perforin-granzyme, FASL, KIR, NCRs (NKP46), DAP, DNAM-1, TGF-β, TNF-α, CCL, NKG2A, TF, and EGFR. Furthermore, we advocate for incorporating AI for CAR design optimization and CRISPR-Cas9 gene editing technology for precise gene manipulation to generate highly effective CAR constructs. This review will delve into the evolution and production of CAR designs, explore pre-clinical and clinical studies of CAR-based therapies in asthma, analyze strategies to optimize CAR-NK cell function, conduct a comparative analysis of CAR-T and CAR-NK cell therapy with their respective challenges, and finally present established novel CAR designs with promising potential for asthma treatment.
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Affiliation(s)
| | - Fatemeh Javan
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohadeseh Poudineh
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Seyed Shamseddin Athari
- Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran.
- Department of Immunology, Zanjan School of Medicine, Zanjan University of Medical Sciences, 12th Street, Shahrake Karmandan, Zanjan, 45139-561111, Iran.
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Hu X, Li B, Lu B, Yu H, Du Y, Chen J. Identification and functional analysis of perforin 1 from largemouth bass (Micropterus salmoides). FISH & SHELLFISH IMMUNOLOGY 2024; 149:109531. [PMID: 38604479 DOI: 10.1016/j.fsi.2024.109531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 03/24/2024] [Accepted: 03/28/2024] [Indexed: 04/13/2024]
Abstract
In this study, we present the first cloning and identification of perforin (MsPRF1) in largemouth bass (Micropterus salmoides). The full-length cDNA of MsPRF1 spans 1572 base pairs, encoding a 58.88 kDa protein consisting of 523 amino acids. Notably, the protein contains MACPF and C2 structural domains. To evaluate the expression levels of MsPRF1 in various healthy largemouth bass tissues, real-time quantitative PCR was employed, revealing the highest expression in the liver and gut. After the largemouth bass were infected by Nocardia seriolae, the mRNA levels of MsPRF1 generally increased within 48 h. Remarkably, the recombinant protein MsPRF1 exhibits inhibitory effects against both Gram-negative and Gram-positive bacteria. Additionally, the largemouth bass showed a higher survival rate in the N. seriolae challenge following the intraperitoneal injection of rMsPRF1, with observed reductions in the tissue bacterial loads. Moreover, rMsPRF1 demonstrated a significant impact on the phagocytic and bactericidal activities of largemouth bass MO/MΦ cells, concurrently upregulating the expression of pro-inflammatory factors. These results demonstrate that MsPRF1 has a potential role in the immune response of largemouth bass against N. seriolae infection.
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Affiliation(s)
- Xiaoman Hu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315211, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Ningbo University, Ningbo, 315211, China
| | - Bin Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315211, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Ningbo University, Ningbo, 315211, China
| | - Bowen Lu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315211, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Ningbo University, Ningbo, 315211, China
| | - Hui Yu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315211, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Ningbo University, Ningbo, 315211, China
| | - Yang Du
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315211, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Ningbo University, Ningbo, 315211, China.
| | - Jiong Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315211, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Ningbo University, Ningbo, 315211, China.
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Landolina N, Ricci B, Veneziani I, Alicata C, Mariotti FR, Pelosi A, Quatrini L, Mortari EP, Carsetti R, Vacca P, Tumino N, Azzarone B, Moretta L, Maggi E. TLR2/4 are novel activating receptors for SARS-CoV-2 spike protein on NK cells. Front Immunol 2024; 15:1368946. [PMID: 38881905 PMCID: PMC11176535 DOI: 10.3389/fimmu.2024.1368946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 05/03/2024] [Indexed: 06/18/2024] Open
Abstract
Background In early infected or severe coronavirus disease 2019 (COVID-19) patients, circulating NK cells are consistently reduced, despite being highly activated or exhausted. The aim of this paper was to establish whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (SP) may directly trigger NK cells and through which receptor(s). Methods SP-stimulated human NK cells have been evaluated for the expression of activation markers, cytokine release, and cytotoxic activity, as well as for gene expression profiles and NF-kB phosphorylation, and they have been silenced with specific small interfering RNAs. Results SPs from the Wuhan strain and other variants of concern (VOCs) directly bind and stimulate purified NK cells by increasing activation marker expression, cytokine release, and cytolytic activity, prevalently in the CD56brightNK cell subset. VOC-SPs differ in their ability to activate NK cells, G614, and Delta-Plus strains providing the strongest activity in the majority of donors. While VOC-SPs do not trigger ACE2, which is not expressed on NK cells, or other activating receptors, they directly and variably bind to both Toll-like receptor 2 (TLR2) and TLR4. Moreover, SP-driven NK cell functions are inhibited upon masking such receptors or silencing the relative genes. Lastly, VOC-SPs upregulate CD56dimNK cell functions in COVID-19 recovered, but not in non-infected, individuals. Conclusions TLR2 and TLR4 are novel activating receptors for SP in NK cells, suggesting a new role of these cells in orchestrating the pathophysiology of SARS-CoV-2 infection. The pathogenic relevance of this finding is highlighted by the fact that free SP providing NK cell activation is frequently detected in a SARS-CoV-2 inflamed environment and in plasma of infected and long-COVID-19 subjects.
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Affiliation(s)
- Nadine Landolina
- Tumor Immunology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Biancamaria Ricci
- Tumor Immunology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Irene Veneziani
- Tumor Immunology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Claudia Alicata
- Tumor Immunology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | | | - Andrea Pelosi
- Tumor Immunology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Linda Quatrini
- Innate Lymphoid Cells Unit, Immunology Research Area, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Eva Piano Mortari
- B cell Unit, Immunology Research Area, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Rita Carsetti
- B cell Unit, Immunology Research Area, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Paola Vacca
- Innate Lymphoid Cells Unit, Immunology Research Area, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Nicola Tumino
- Innate Lymphoid Cells Unit, Immunology Research Area, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Bruno Azzarone
- Tumor Immunology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Lorenzo Moretta
- Tumor Immunology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Enrico Maggi
- Tumor Immunology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
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Joshi VR, Altfeld M. Harnessing natural killer cells to target HIV-1 persistence. Curr Opin HIV AIDS 2024; 19:141-149. [PMID: 38457230 DOI: 10.1097/coh.0000000000000848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2024]
Abstract
PURPOSE OF REVIEW The purpose of this article is to review recent advances in the role of natural killer (NK) cells in approaches aimed at reducing the latent HIV-1 reservoir. RECENT FINDINGS Multiple approaches to eliminate cells harboring latent HIV-1 are being explored, but have been met with limited success so far. Recent studies have highlighted the role of NK cells and their potential in HIV-1 cure efforts. Anti-HIV-1 NK cell function can be optimized by enhancing NK cell activation, antibody dependent cellular cytotoxicity, reversing inhibition of NK cells as well as by employing immunotherapeutic complexes to enable HIV-1 specificity of NK cells. While NK cells alone do not eliminate the HIV-1 reservoir, boosting NK cell function might complement other strategies involving T cell and B cell immunity towards an HIV-1 functional cure. SUMMARY Numerous studies focusing on targeting latently HIV-1-infected cells have emphasized a potential role of NK cells in these strategies. Our review highlights recent advances in harnessing NK cells in conjunction with latency reversal agents and other immunomodulatory therapeutics to target HIV-1 persistence.
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Affiliation(s)
- Vinita R Joshi
- Department of Virus Immunology, Leibniz Institute of Virology
| | - Marcus Altfeld
- Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Mahapatra S, Ganguly B, Pani S, Saha A, Samanta M. A comprehensive review on the dynamic role of toll-like receptors (TLRs) in frontier aquaculture research and as a promising avenue for fish disease management. Int J Biol Macromol 2023; 253:126541. [PMID: 37648127 DOI: 10.1016/j.ijbiomac.2023.126541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/23/2023] [Accepted: 08/24/2023] [Indexed: 09/01/2023]
Abstract
Toll-like receptors (TLRs) represent a conserved group of germline-encoded pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) and play a crucial role in inducing the broadly acting innate immune response against pathogens. In recent years, the detection of 21 different TLR types in various fish species has sparked interest in exploring the potential of TLRs as targets for boosting immunity and disease resistance in fish. This comprehensive review offers the latest insights into the diverse facets of fish TLRs, highlighting their history, classification, architectural insights through 3D modelling, ligands recognition, signalling pathways, crosstalk, and expression patterns at various developmental stages. It provides an exhaustive account of the distinct TLRs induced during the invasion of specific pathogens in various fish species and delves into the disparities between fish TLRs and their mammalian counterparts, highlighting the specific contribution of TLRs to the immune response in fish. Although various facets of TLRs in some fish, shellfish, and molluscs have been described, the role of TLRs in several other aquatic organisms still remained as potential gaps. Overall, this article outlines frontier aquaculture research in advancing the knowledge of fish immune systems for the proper management of piscine maladies.
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Affiliation(s)
- Smruti Mahapatra
- Immunology Laboratory, Fish Health Management Division, ICAR-Central Institute of Freshwater Aquaculture (ICAR-CIFA), Kausalyaganga, Bhubaneswar 751002, Odisha, India
| | - Bristy Ganguly
- Immunology Laboratory, Fish Health Management Division, ICAR-Central Institute of Freshwater Aquaculture (ICAR-CIFA), Kausalyaganga, Bhubaneswar 751002, Odisha, India
| | - Saswati Pani
- Immunology Laboratory, Fish Health Management Division, ICAR-Central Institute of Freshwater Aquaculture (ICAR-CIFA), Kausalyaganga, Bhubaneswar 751002, Odisha, India
| | - Ashis Saha
- Reproductive Biology and Endocrinology Laboratory, Fish Nutrition and Physiology Division, ICAR-Central Institute of Freshwater Aquaculture (ICAR-CIFA), Kausalyaganga, Bhubaneswar 751002, Odisha, India
| | - Mrinal Samanta
- Immunology Laboratory, Fish Health Management Division, ICAR-Central Institute of Freshwater Aquaculture (ICAR-CIFA), Kausalyaganga, Bhubaneswar 751002, Odisha, India.
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Karandikar K, Bhonde G, Palav H, Padwal V, Velhal S, Pereira J, Meshram H, Goel A, Shah I, Patel V, Bhor VM. A novel gut microbiome-immune axis influencing pathology in HCMV infected infants with neonatal cholestasis. Microbes Infect 2023; 25:105165. [PMID: 37247806 DOI: 10.1016/j.micinf.2023.105165] [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: 12/16/2022] [Revised: 05/02/2023] [Accepted: 05/24/2023] [Indexed: 05/31/2023]
Abstract
The interplay of active HCMV infection with gut dysbiosis in the immunopathology of cholestasis in neonates and infants remains unexplored. In this study, we evaluated gut microbiome profiles and immune dysfunction in a cohort of HCMV infected cholestatic infants (IgM positive, N = 21; IgM negative, N = 25) compared to healthy infants, N = 10. HCMV infected IgM positive individuals exhibited increased clinical severity in terms of liver dysfunction, altered CD4+: CD8+ ratio, and elevated Granzyme B levels in cellular immune subsets. Gut microbiome analysis revealed distinct and differential diversity and composition within infected groups aligned with clinical severity reflected through the increased abundance of Gammaproteobacteria, reduced Bifidobacteria, and a unique signature mapping to the HCMV infected IgM negative group. Correlation analyses revealed associations between Bifidobacterium breve, Gammaproteobacteria, Firmicutes, Clostridia, Finegoldia magna, Veillonella dispar, and Granzyme B expressing immune cell subsets. Our study describes a novel gut microbiome-immune axis that may influence disease severity in cholestatic infants with active HCMV infection.
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Affiliation(s)
- Kalyani Karandikar
- Department of Molecular Immunology and Microbiology, ICMR-NIRRCH, Mumbai, India
| | - Gauri Bhonde
- Department of Molecular Immunology and Microbiology, ICMR-NIRRCH, Mumbai, India
| | - Harsha Palav
- Department of Viral Immunopathogenesis, ICMR-NIRRCH, Mumbai, India
| | - Varsha Padwal
- Department of Viral Immunopathogenesis, ICMR-NIRRCH, Mumbai, India
| | - Shilpa Velhal
- Department of Viral Immunopathogenesis, ICMR-NIRRCH, Mumbai, India
| | - Jacintha Pereira
- Department of Viral Immunopathogenesis, ICMR-NIRRCH, Mumbai, India
| | - Himali Meshram
- Pediatric Infectious Diseases and Pediatric GI, Hepatology, Bai Jerbai Wadia Hospital for Children, Mumbai, India
| | - Akshat Goel
- Pediatric Infectious Diseases and Pediatric GI, Hepatology, Bai Jerbai Wadia Hospital for Children, Mumbai, India
| | - Ira Shah
- Pediatric Infectious Diseases and Pediatric GI, Hepatology, Bai Jerbai Wadia Hospital for Children, Mumbai, India
| | - Vainav Patel
- Department of Viral Immunopathogenesis, ICMR-NIRRCH, Mumbai, India.
| | - Vikrant M Bhor
- Department of Molecular Immunology and Microbiology, ICMR-NIRRCH, Mumbai, India.
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Veneziani I, Alicata C, Moretta L, Maggi E. Human toll-like receptor 8 (TLR8) in NK cells: Implication for cancer immunotherapy. Immunol Lett 2023; 261:13-16. [PMID: 37451320 DOI: 10.1016/j.imlet.2023.07.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/06/2023] [Accepted: 07/08/2023] [Indexed: 07/18/2023]
Abstract
Toll-like receptors (TLR)s are homo- or heterodimeric proteins, whose structure and function were widely described in the antigen presenting cells (APC), such as Dendritic cells (DC). Recently, the expression and the role of TLRs in fighting against pathogens, was described also in NK cells. Their activation and functional properties can be directly and indirectly modulated by agonists for TLRs. In particular CD56bright NK cells subset, that is the most abundant NK cell subset in tissues and tumor microenvironment (TME), was mostly activated in terms of pro-inflammatory cytokine production, proliferation and cytotoxicity, by agonists specific for endosomal TLR8. The interplay between DC and NK, that depends on both cell-to-cell contact and soluble factors such as cytokines, promote both DC maturation and NK cell activation. Based on this concept, a TLR based immunotherapy aimed to activate NK-DC axis, may modulate TME by inducing a pro-inflammatory phenotype, thus improving DC ability to present tumor-associated antigens to T cells, and NK cell cytotoxicity against tumor cells. In this mini-review, we report data of recent literature about TLRs on human NK cells and their application as adjuvant in cancer vaccines or in combined tumor immunotherapy.
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Affiliation(s)
- Irene Veneziani
- Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Claudia Alicata
- Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Lorenzo Moretta
- Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
| | - Enrico Maggi
- Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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Li Q, Liu Q, Wang Z, Zhang X, Ma R, Hu X, Mei J, Su Z, Zhu W, Zhu C. Biofilm Homeostasis Interference Therapy via 1 O 2 -Sensitized Hyperthermia and Immune Microenvironment Re-Rousing for Biofilm-Associated Infections Elimination. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2300592. [PMID: 36850031 DOI: 10.1002/smll.202300592] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/10/2023] [Indexed: 06/02/2023]
Abstract
The recurrence of biofilm-associated infections (BAIs) remains high after implant-associated surgery. Biofilms on the implant surface reportedly shelter bacteria from antibiotics and evade innate immune defenses. Moreover, little is currently known about eliminating residual bacteria that can induce biofilm reinfection. Herein, novel "interference-regulation strategy" based on bovine serum albumin-iridium oxide nanoparticles (BIONPs) as biofilm homeostasis interrupter and immunomodulator via singlet oxygen (1 O2 )-sensitized mild hyperthermia for combating BAIs is reported. The catalase-like BIONPs convert abundant H2 O2 inside the biofilm-microenvironment (BME) to sufficient oxygen gas (O2 ), which can efficiently enhance the generation of 1 O2 under near-infrared irradiation. The 1 O2 -induced biofilm homeostasis disturbance (e.g., sigB, groEL, agr-A, icaD, eDNA) can disrupt the sophisticated defense system of biofilm, further enhancing the sensitivity of biofilms to mild hyperthermia. Moreover, the mild hyperthermia-induced bacterial membrane disintegration results in protein leakage and 1 O2 penetration to kill bacteria inside the biofilm. Subsequently, BIONPs-induced immunosuppressive microenvironment re-rousing successfully re-polarizes macrophages to pro-inflammatory M1 phenotype in vivo to devour residual biofilm and prevent biofilm reconstruction. Collectively, this 1 O2 -sensitized mild hyperthermia can yield great refractory BAIs treatment via biofilm homeostasis interference, mild-hyperthermia, and immunotherapy, providing a novel and effective anti-biofilm strategy.
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Affiliation(s)
- Qianming Li
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, P. R. China
| | - Quan Liu
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, P. R. China
| | - Zhengxi Wang
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, P. R. China
| | - Xianzuo Zhang
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, P. R. China
| | - Ruixiang Ma
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, P. R. China
| | - Xianli Hu
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, P. R. China
| | - Jiawei Mei
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, P. R. China
| | - Zheng Su
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, P. R. China
| | - Wanbo Zhu
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, 200233, P. R. China
| | - Chen Zhu
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, P. R. China
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13
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Qin Y, Wang Q, Shi J. Immune checkpoint modulating T cells and NK cells response to Mycobacterium tuberculosis infection. Microbiol Res 2023; 273:127393. [PMID: 37182283 DOI: 10.1016/j.micres.2023.127393] [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: 11/12/2022] [Revised: 04/07/2023] [Accepted: 04/22/2023] [Indexed: 05/16/2023]
Abstract
Many subversive mechanisms promote the occurrence and development of chronic infectious diseases and cancer, among which the down-regulated expression of immune-activating receptors and the enhanced expression of immune-inhibitory receptors accelerate the occurrence and progression of the disease. Recently, the use of immune checkpoint inhibitors has shown remarkable efficacy in the treatment of tumors in multiple organs. However, the expression of immune checkpoint molecules on natural killer (NK) cells by Mycobacterium tuberculosis (Mtb) infection and its impact on NK cell effector functions have been poorly studied. In this review, we focus on what is currently known about the expression of various immune checkpoints in NK cells following Mtb infection and how it alters NK cell-mediated host cytotoxicity and cytokine secretion. Unraveling the function of NK cells after the infection of host cells by Mtb is crucial for a comprehensive understanding of the innate immune mechanism of NK cells involved in tuberculosis and the evaluation of the efficacy of immunotherapies using immune checkpoint inhibitors to treat tuberculosis. In view of some similarities in the immune characteristics of T cells and NK cells, we reviewed the molecular mechanism of the interaction between T cells and Mtb, which can help us to further understand and explore the specific interaction mechanism between NK cells and Mtb.
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Affiliation(s)
- Yongwei Qin
- Department of Pathogen Biology, Medical College, Nantong University, No. 19 Qixiu Road, Nantong 226001, China.
| | - Qinglan Wang
- Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Jiahai Shi
- Department of Thoracic Surgery, Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, and Research Institution of Translational Medicine in Cardiothoracic Diseases in Affiliated Hospital of Nantong University, No. 20 Xisi Road, Nantong 226001, China
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Guo M, Yang K, Lin S, Tang J, Liu M, Zhou H, Lin H, Fan H. Coinfection with porcine circovirus type 2 and Glaesserella parasuis serotype 4 enhances pathogenicity in piglets. Vet Microbiol 2023; 278:109663. [PMID: 36680971 DOI: 10.1016/j.vetmic.2023.109663] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 01/11/2023] [Accepted: 01/13/2023] [Indexed: 01/18/2023]
Abstract
Coinfection of Porcine circovirus type 2 (PCV2) and Glaesserella parasuis type 4 (GPS4) is widespread clinically, resulting in high morbidity and mortality, however, interactions between the two pathogens during coinfection and the coinfection pathogenesis are poorly understood. In this study, a piglet model coinfected with PCV2 and GPS4 was established; coinfection of the piglets' group showed more obvious symptoms, such as high fever and emaciation, and more severe histological lesions appeared in various organs. Importantly, piglets in the coinfection group produced lower levels of PCV2 and GPS4 antibodies, and showed high levels of inflammatory cytokines, TLR2, and TLR4, while the levels of CD4, CD8, MHC II, costimulatory molecules, and IL-12p40 were decreased. In addition, a model of macrophage 3D4/21 cells coinfection with PCV2 and GPS4 was established, coinfected cells exhibited increased expression of the cytokines IL-6, IL-8, TNF-α, IL-1β, and the receptors TLR2, TLR4, while decreased MHC II. We further demonstrate that cytokine production is associated with the activation of NF-κB and NLRP3 inflammasome signaling pathways, and TLR4 is also involved. Altogether, our findings suggest that coinfection with PCV2 and GPS4 exacerbates the inflammatory response, resulting in severe tissue damage, and probably impaired macrophage antigen presentation and T cell activation, resulting in immune dysregulation, aggravating host infection.
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Affiliation(s)
- Mengru Guo
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Kaiyue Yang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Shaojie Lin
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Jinsheng Tang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Mingxing Liu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Hong Zhou
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Huixing Lin
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Hongjie Fan
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China.
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Mandour MF, Soe PP, Castonguay AS, Van Snick J, Coutelier JP. Inhibition of IL-12 heterodimers impairs TLR9-mediated prevention of early mouse plasmacytoma cell growth. Front Med (Lausanne) 2023; 9:1057252. [PMID: 36714124 PMCID: PMC9880182 DOI: 10.3389/fmed.2022.1057252] [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: 09/29/2022] [Accepted: 12/21/2022] [Indexed: 01/15/2023] Open
Abstract
Introduction Natural prevention of cancer development depends on an efficient immunosurveillance that may be modulated by environmental factors, including infections. Innate lymphoid cytotoxic cells have been shown to play a major role in this immunosurveillance. Interleukin-12 (IL-12) has been suggested to be a key factor in the activation of innate cytotoxic cells after infection, leading to the enhancement of cancer immunosurveillance. Methods The aim of this work was to analyze in mouse experimental models by which mechanisms the interaction between infectious agent molecules and the early innate responses could enhance early inhibition of cancer growth and especially to assess the role of IL-12 by using novel antibodies specific for IL-12 heterodimers. Results Ligation of toll-like receptor (TLR)9 by CpG-protected mice against plasmacytoma TEPC.1033.C2 cell early growth. This protection mediated by innate cytolytic cells was strictly dependent on IL-12 and partly on gamma-interferon. Moreover, the protective effect of CpG stimulation, and to a lesser extent of TLR3 and TLR7/8, and the role of IL-12 in this protection were confirmed in a model of early mesothelioma AB1 cell growth. Discussion These results suggest that modulation of the mouse immune microenvironment by ligation of innate receptors deeply modifies the efficiency of cancer immunosurveillance through the secretion of IL-12, which may at least partly explain the inhibitory effect of previous infections on the prevalence of some cancers.
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Affiliation(s)
- Mohamed F. Mandour
- Unit of Experimental Medicine, Université catholique de Louvain, Brussels, Belgium,Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Pyone Pyone Soe
- Unit of Experimental Medicine, Université catholique de Louvain, Brussels, Belgium,Department of Pathology, University of Medicine (1) Yangon, Yangon, Myanmar
| | - Anne-Sophie Castonguay
- Unit of Experimental Medicine, Université catholique de Louvain, Brussels, Belgium,Département de Pharmacologie et de Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
| | - Jacques Van Snick
- Unit of Experimental Medicine, Université catholique de Louvain, Brussels, Belgium,Ludwig Institute, de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Jean-Paul Coutelier
- Unit of Experimental Medicine, Université catholique de Louvain, Brussels, Belgium,de Duve Institute, Université catholique de Louvain, Woluwe-Saint-Lambert, Belgium,*Correspondence: Jean-Paul Coutelier,
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Mestre-Durán C, Martín-Cortázar C, García-Solís B, Pernas A, Pertíñez L, Galán V, Sisinni L, Clares-Villa L, Navarro-Zapata A, Al-Akioui K, Escudero A, Ferreras C, Pérez-Martínez A. Ruxolitinib does not completely abrogate the functional capabilities of TLR4/9 ligand-activated NK cells. Front Immunol 2023; 13:1045316. [PMID: 36685552 PMCID: PMC9851469 DOI: 10.3389/fimmu.2022.1045316] [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: 09/15/2022] [Accepted: 12/16/2022] [Indexed: 01/06/2023] Open
Abstract
Introduction Natural killer (NK) cells are lymphocytes from the innate immune system part of the first defense barrier against infected and transformed cells, representing 5%-15% of peripheral blood lymphocytes. The cytotoxic capacity of NK cells is controlled by a balance between inhibitory and activating NK receptors expressed on their surface, which recognize and interact with the ligands on stressed cells. The cytokines involved in NK cell activation, proliferation, survival, and cytotoxicity are signaled mainly through the Janus kinase and signal transducer and activator of transcription proteins (JAK/STAT) pathway. NK cells are also activated in response to pathogens through Toll-like receptors (TLRs) expressed on their surface. Ruxolitinib is a specific JAK1/2 inhibitor approved for treating myelofibrosis and for steroid-refractory acute and chronic graft-versus-host disease (SR-GvHD). Methods Purified NK cells from healthy donors were stimulated with two TOLL-like receptor ligands, LPS and CpG, in the presence of different concentrations of Ruxolitinib. Results This study showed the effects of ruxolitinib on TLR4 and TLR9 ligand-activated NK cells from healthy donors. Ruxolitinib did not completely inhibit STAT3 phosphorylation and had a moderate effect on NK cell cytokine activation via the TLR pathway. Only the highest doses of ruxolitinib led to a decrease in the pro-inflammatory cytokines tumor necrosis factor α, interferon-γ, interleukin-6, and interleukin-1β. The cytotoxic capacity of stimulated NK cells versus K562, SEM, and MV-4-11 cell lines was reduced by increasing doses of ruxolitinib, but it was not completely abolished and we observed no major changes in degranulation capacity. Phenotypic changes were observed in activated NK cells in the presence of ruxolitinib. In a small cohort of pediatric patients treated with ruxolitinib for SR-GvHD, we observed no decrease in NK cell counts; however, further prospective studies with larger cohorts are necessary to confirm this finding. Discussion In summary, our results showed that the functional capabilities and phenotype of NK cells activated through TLR4/9 agonists were not completely abolished by the inhibition of the JAK-STAT pathway by ruxolitinib.
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Affiliation(s)
- Carmen Mestre-Durán
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
| | - Carla Martín-Cortázar
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
| | - Blanca García-Solís
- Laboratory of Immunogenetics of Human Diseases, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
| | - Alicia Pernas
- Department of Genetics, Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain
| | - Lidia Pertíñez
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
| | - Víctor Galán
- Pediatric Hemato-Oncology Department, La Paz University Hospital, Madrid, Spain
| | - Luisa Sisinni
- Pediatric Hemato-Oncology Department, La Paz University Hospital, Madrid, Spain
| | - Laura Clares-Villa
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
| | - Alfonso Navarro-Zapata
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
| | - Karima Al-Akioui
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
| | - Adela Escudero
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
- Department of Genetics, Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain
| | - Cristina Ferreras
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
| | - Antonio Pérez-Martínez
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
- Pediatric Hemato-Oncology Department, La Paz University Hospital, Madrid, Spain
- Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain
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Chen PC, Kaur K, Ko MW, Huerta-Yepez S, Jain Y, Jewett A. Regulation of Cytotoxic Immune Effector Function by AJ3 Probiotic Bacteria in Amyotrophic Lateral Sclerosis (ALS). Crit Rev Immunol 2023; 43:13-26. [PMID: 37522558 DOI: 10.1615/critrevimmunol.2023047231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Our recent studies indicated that amyotrophic lateral sclerosis (ALS) patients suffer from significantly elevated levels of interferon-gamma (IFN-γ) secretion by natural killer (NK) and CD8+ T cells, which may be responsible for the immune-pathologies seen in central nervous system and in peripheral organs of the patients. In order to counter such elevated induction of IFN-γ in patients we designed a treatment strategy to increase anti-inflammatory cytokine interleukin-10 (IL-10) by the use of probiotic strains which significantly increase the levels of IL-10. Therefore, in this paper we demonstrate disease specific functions of Al-Pro (AJ3) formulated for the adjunct treatment of auto-immune diseases including ALS, and compared the function with CA/I-Pro (AJ4) for the treatment of cancer and viral diseases, and NK-CLK (AJ2) for maintenance of immune balance and promotion of disease prevention. The three different formulations of probiotic bacteria have distinct profiles of activation of peripheral blood mononuclear cells (PBMCs), NK, and CD8+ T cells, and their induced activation is different from those mediated by either IL-2 or IL-2 + anti-CD16 monoclonal antibodies (mAbs) or IL-2 + anti-CD3/CD28 mAbs. IL-2 + anti-CD16 mAb activation of PBMCs and NK cells had the highest IFN-γ/IL-10 ratio, whereas IL-2 combination with sAJ4 had the next highest followed by IL-2 + sAJ2 and the lowest was seen with IL-2 + sAJ3. Accordingly, the highest secretion of IFN-γ was seen when the PBMCs and NK cells were treated with IL-2 + sAJ4, intermediate for IL-2 + sAJ2 and the lowest with IL-2 + sAJ3. The levels of IFN-γ induction and the ratio of IFN-γ to IL-10 induced by different probiotic bacteria formulation in the absence of IL-2 treatment remained much lower when compared to those treated in the presence of IL-2. Of note is the difference between NK cells and CD8+ T cells in which synergistic induction of IFN-y by IL-2 + sAJ4 was significantly higher in NK cells than those seen by CD8+ T cells. Based on these results, sAJ3 should be effective in alleviating auto-immunity seen in ALS since it will greatly regulate the levels and function of IFN-γ negatively, decreasing overactivation of cytotoxic immune effectors and prevention of death in motor neurons.
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Affiliation(s)
- Po-Chun Chen
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA
| | - Kawaljit Kaur
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA
| | - Meng-Wei Ko
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA
| | - Sara Huerta-Yepez
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, Los Angeles, CA 90095, USA
| | - Yash Jain
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, Los Angeles, CA 90095, USA
| | - Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA; The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA
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18
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Song Y, Zheng X, Hu J, Ma S, Li K, Chen J, Xu X, Lu X, Wang X. Recent advances of cell membrane-coated nanoparticles for therapy of bacterial infection. Front Microbiol 2023; 14:1083007. [PMID: 36876074 PMCID: PMC9981803 DOI: 10.3389/fmicb.2023.1083007] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 02/01/2023] [Indexed: 02/19/2023] Open
Abstract
The rapid evolution of antibiotic resistance and the complicated bacterial infection microenvironments are serious obstacles to traditional antibiotic therapy. Developing novel antibacterial agents or strategy to prevent the occurrence of antibiotic resistance and enhance antibacterial efficiency is of the utmost importance. Cell membrane-coated nanoparticles (CM-NPs) combine the characteristics of the naturally occurring membranes with those of the synthetic core materials. CM-NPs have shown considerable promise in neutralizing toxins, evading clearance by the immune system, targeting specific bacteria, delivering antibiotics, achieving responsive antibiotic released to the microenvironments, and eradicating biofilms. Additionally, CM-NPs can be utilized in conjunction with photodynamic, sonodynamic, and photothermal therapies. In this review, the process for preparing CM-NPs is briefly described. We focus on the functions and the recent advances in applications of several types of CM-NPs in bacterial infection, including CM-NPs derived from red blood cells, white blood cells, platelet, bacteria. CM-NPs derived from other cells, such as dendritic cells, genetically engineered cells, gastric epithelial cells and plant-derived extracellular vesicles are introduced as well. Finally, we place a novel perspective on CM-NPs' applications in bacterial infection, and list the challenges encountered in this field from the preparation and application standpoint. We believe that advances in this technology will reduce threats posed by bacteria resistance and save lives from infectious diseases in the future.
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Affiliation(s)
- Yue Song
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, China
| | - Xia Zheng
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Juan Hu
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Subo Ma
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Kun Li
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Junyao Chen
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Xiaoling Xu
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Xiaoyang Lu
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaojuan Wang
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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19
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Veneziani I, Alicata C, Moretta L, Maggi E. The Latest Approach of Immunotherapy with Endosomal TLR Agonists Improving NK Cell Function: An Overview. Biomedicines 2022; 11:biomedicines11010064. [PMID: 36672572 PMCID: PMC9855813 DOI: 10.3390/biomedicines11010064] [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: 10/06/2022] [Revised: 12/05/2022] [Accepted: 12/08/2022] [Indexed: 12/29/2022] Open
Abstract
Toll-like receptors (TLRs) are the most well-defined pattern recognition receptors (PRR) of several cell types recognizing pathogens and triggering innate immunity. TLRs are also expressed on tumor cells and tumor microenvironment (TME) cells, including natural killer (NK) cells. Cell surface TLRs primarily recognize extracellular ligands from bacteria and fungi, while endosomal TLRs recognize microbial DNA or RNA. TLR engagement activates intracellular pathways leading to the activation of transcription factors regulating gene expression of several inflammatory molecules. Endosomal TLR agonists may be considered as new immunotherapeutic adjuvants for dendritic cell (DC) vaccines able to improve anti-tumor immunity and cancer patient outcomes. The literature suggests that endosomal TLR agonists modify TME on murine models and human cancer (clinical trials), providing evidence that locally infused endosomal TLR agonists may delay tumor growth and induce tumor regression. Recently, our group demonstrated that CD56bright NK cell subset is selectively responsive to TLR8 engagement. Thus, TLR8 agonists (loaded or not to nanoparticles or other carriers) can be considered a novel strategy able to promote anti-tumor immunity. TLR8 agonists can be used to activate and expand in vitro circulating or intra-tumoral NK cells to be adoptively transferred into patients.
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Affiliation(s)
- Irene Veneziani
- Translational Immunology Unit, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy
| | - Claudia Alicata
- Tumor Immunology Unit, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy
| | - Lorenzo Moretta
- Tumor Immunology Unit, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy
| | - Enrico Maggi
- Translational Immunology Unit, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy
- Correspondence:
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20
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Liu B, Zhang X, Ding X, Bin P, Zhu G. The vertical transmission of Salmonella Enteritidis in a One-Health context. One Health 2022; 16:100469. [PMID: 36507074 PMCID: PMC9731862 DOI: 10.1016/j.onehlt.2022.100469] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 12/01/2022] [Accepted: 12/01/2022] [Indexed: 12/07/2022] Open
Abstract
Salmonella enterica serovar Enteritidis (S. Enteritidis, SE) is a foodborne zoonotic pathogen, causing economic losses in animal husbandry and large numbers of human deaths and critically threatening economic development and public health. Human infection with SE has complex transmission routes, involving the environment, animal reservoirs, and water in a One-Health context. Food-producing animals, particularly poultry and livestock, are regarded as the most common sources of SE infection in humans. However, there is little known about the vertical transmission of SE in a One-Health context. In this review, we analyze the ecological significance of SE in a One-Health context. Importantly, we focus on the difference in vertical transmission of SE in poultry, livestock, and humans. We introduce the transmission pathway, describe the immune mechanisms, and discuss the models that could be used for studying the vertical transmission of SE and the strategy that prevention and control for vertical transmission of SE into the future from a One-Health perspective. Together, considering the vertical transmission of SE, it is helpful to provide important insights into the control and decontamination pathways of SE in animal husbandry and enhance knowledge about the prevention of fetal infection in human pregnancy.
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Affiliation(s)
- Baobao Liu
- College of Veterinary Medicine (Institute of comparative medicine), Yangzhou University, Yangzhou 225009, China,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China,Joint Laboratory of International Cooperation on Prevention and Control Technology of Important Animal Diseases and Zoonoses of Jiangsu Higher Education Institutions, Yangzhou 225009, China,Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Xiaojie Zhang
- College of Veterinary Medicine (Institute of comparative medicine), Yangzhou University, Yangzhou 225009, China,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China,Joint Laboratory of International Cooperation on Prevention and Control Technology of Important Animal Diseases and Zoonoses of Jiangsu Higher Education Institutions, Yangzhou 225009, China,Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Xueyan Ding
- College of Veterinary Medicine (Institute of comparative medicine), Yangzhou University, Yangzhou 225009, China,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China,Joint Laboratory of International Cooperation on Prevention and Control Technology of Important Animal Diseases and Zoonoses of Jiangsu Higher Education Institutions, Yangzhou 225009, China,Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Peng Bin
- College of Veterinary Medicine (Institute of comparative medicine), Yangzhou University, Yangzhou 225009, China,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China,Joint Laboratory of International Cooperation on Prevention and Control Technology of Important Animal Diseases and Zoonoses of Jiangsu Higher Education Institutions, Yangzhou 225009, China,Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Guoqiang Zhu
- College of Veterinary Medicine (Institute of comparative medicine), Yangzhou University, Yangzhou 225009, China,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China,Joint Laboratory of International Cooperation on Prevention and Control Technology of Important Animal Diseases and Zoonoses of Jiangsu Higher Education Institutions, Yangzhou 225009, China,Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China,Corresponding author at: College of Veterinary Medicine (Institute of comparative medicine), Yangzhou University, Yangzhou 225009, China.
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21
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A Narrative Review on the Bioactivity and Health Benefits of Alpha-Phellandrene. Sci Pharm 2022. [DOI: 10.3390/scipharm90040057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Aromatic essential oils play a significant role in pharmaceuticals, food additives, cosmetics, and perfumery. Essential oils mostly comprise aliphatic hydrocarbons, monoterpenoids, sesquiterpenoids and diterpenes. Plant extracts comprise a complex mixture of terpenes, terpenoids, aliphatic and phenol-derived aromatic components. Terpenes are a significant class of hydrocarbons with numerous health benefits. These biological functions of essential oil components are examined in vitro and in vivo studies. Some studies evaluated the properties and functions of α-phellandrene (α-PHE). Detailed evaluation to determine the functions of α-PHE over a spectrum of health care domains needs to be initiated. Its possible mechanism of action in a biological system could reveal the future opportunities and challenges in using α-PHE as a pharmaceutical candidate. The biological functions of α-PHE are reported, including anti-microbial, insecticidal, anti-inflammatory, anti-cancer, wound healing, analgesic, and neuronal responses. The present narrative review summarizes the synthesis, biotransformation, atmospheric emission, properties, and biological activities of α-PHE. The literature review suggests that extended pre-clinical studies are necessary to develop α-PHE-based adjuvant therapeutic approaches.
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22
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Sanche S, Cassidy T, Chu P, Perelson AS, Ribeiro RM, Ke R. A simple model of COVID-19 explains disease severity and the effect of treatments. Sci Rep 2022; 12:14210. [PMID: 35988008 PMCID: PMC9392071 DOI: 10.1038/s41598-022-18244-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 08/08/2022] [Indexed: 12/23/2022] Open
Abstract
Considerable effort has been made to better understand why some people suffer from severe COVID-19 while others remain asymptomatic. This has led to important clinical findings; people with severe COVID-19 generally experience persistently high levels of inflammation, slower viral load decay, display a dysregulated type-I interferon response, have less active natural killer cells and increased levels of neutrophil extracellular traps. How these findings are connected to the pathogenesis of COVID-19 remains unclear. We propose a mathematical model that sheds light on this issue by focusing on cells that trigger inflammation through molecular patterns: infected cells carrying pathogen-associated molecular patterns (PAMPs) and damaged cells producing damage-associated molecular patterns (DAMPs). The former signals the presence of pathogens while the latter signals danger such as hypoxia or lack of nutrients. Analyses show that SARS-CoV-2 infections can lead to a self-perpetuating feedback loop between DAMP expressing cells and inflammation, identifying the inability to quickly clear PAMPs and DAMPs as the main contributor to hyperinflammation. The model explains clinical findings and reveal conditions that can increase the likelihood of desired clinical outcome from treatment administration. In particular, the analysis suggest that antivirals need to be administered early during infection to have an impact on disease severity. The simplicity of the model and its high level of consistency with clinical findings motivate its use for the formulation of new treatment strategies.
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23
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Jalbert E, Ghosh T, Smith C, Amaral FR, Mussi-Pinhata MM, Weinberg A. Impaired functionality of antigen presenting cells in HIV- exposed uninfected infants in the first six months of life. Front Immunol 2022; 13:960313. [PMID: 36032106 PMCID: PMC9411519 DOI: 10.3389/fimmu.2022.960313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 07/21/2022] [Indexed: 11/13/2022] Open
Abstract
HIV-exposed uninfected infants (HEU) have increased morbidity and mortality due to infections in the first 6 months of life that tapers down to 2 years of life. The underlying immunologic defects remain undefined. We investigated antigen-presenting cells (APC) by comparing the phenotype of unstimulated APC, responses to toll-like receptor (TLR) stimulation, and ability to activate natural killer (NK) cells in 24 HEU and 64 HIV-unexposed infants (HUU) at 1-2 days of life (birth) and 28 HEU and 45 HUU at 6 months of life. At birth, unstimulated APC showed higher levels of activation and cytokine production in HEU than HUU and stimulation with TLR agonists revealed lower expression of inflammatory cytokines and activation markers, but similar expression of IL10 regulatory cytokine, in APC from HEU compared to HUU. Differences were still present at 6 months of life. From birth to 6 months, APC underwent extensive phenotypic and functional changes in HUU and minimal changes in HEU. TLR stimulation also generated lower NK cell expression of CD69 and/or IFNγ in HEU compared with HUU at birth and 6 months. In vitro experiments showed that NK IFNγ expression depended on APC cytokine secretion in response to TLR stimulation. Ex vivo IL10 supplementation decreased APC-mediated NK cell activation measured by IFNγ expression. We conclude that APC maturation was stunted or delayed in the first 6 months of life in HEU compared with HUU. Deficient inflammatory APC responses and/or the imbalance between inflammatory and regulatory responses in HEU may play an important role in their increased susceptibility to severe infections.
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Affiliation(s)
- Emilie Jalbert
- Department of Pediatrics, University of Colorado-Denver Anschutz Medical Campus, Aurora, CO, United States
| | - Tusharkanti Ghosh
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado-Denver Anschutz Medical Campus, Aurora, CO, United States
| | - Christiana Smith
- Department of Pediatrics, University of Colorado-Denver Anschutz Medical Campus, Aurora, CO, United States
| | - Fabiana R. Amaral
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Marisa M. Mussi-Pinhata
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Adriana Weinberg
- Department of Pediatrics, University of Colorado-Denver Anschutz Medical Campus, Aurora, CO, United States
- Department of Medicine and Pathology, University of Colorado-Denver Anschutz Medical Campus, Aurora, CO, United States
- *Correspondence: Adriana Weinberg,
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24
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Alarcon NO, Jaramillo M, Mansour HM, Sun B. Therapeutic Cancer Vaccines—Antigen Discovery and Adjuvant Delivery Platforms. Pharmaceutics 2022; 14:pharmaceutics14071448. [PMID: 35890342 PMCID: PMC9325128 DOI: 10.3390/pharmaceutics14071448] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/28/2022] [Accepted: 06/30/2022] [Indexed: 12/15/2022] Open
Abstract
For decades, vaccines have played a significant role in protecting public and personal health against infectious diseases and proved their great potential in battling cancers as well. This review focused on the current progress of therapeutic subunit vaccines for cancer immunotherapy. Antigens and adjuvants are key components of vaccine formulations. We summarized several classes of tumor antigens and bioinformatic approaches of identification of tumor neoantigens. Pattern recognition receptor (PRR)-targeting adjuvants and their targeted delivery platforms have been extensively discussed. In addition, we emphasized the interplay between multiple adjuvants and their combined delivery for cancer immunotherapy.
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Affiliation(s)
- Neftali Ortega Alarcon
- Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (N.O.A.); (M.J.); (H.M.M.)
| | - Maddy Jaramillo
- Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (N.O.A.); (M.J.); (H.M.M.)
| | - Heidi M. Mansour
- Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (N.O.A.); (M.J.); (H.M.M.)
- The University of Arizona Cancer Center, Tucson, AZ 85721, USA
- Department of Medicine, College of Medicine, The University of Arizona, Tucson, AZ 85724, USA
- BIO5 Institute, The University of Arizona, Tucson, AZ 85721, USA
| | - Bo Sun
- Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (N.O.A.); (M.J.); (H.M.M.)
- The University of Arizona Cancer Center, Tucson, AZ 85721, USA
- BIO5 Institute, The University of Arizona, Tucson, AZ 85721, USA
- Correspondence: ; Tel.: +1-520-621-6420
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25
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The Immunology of Zoonotic Infection. Trop Med Infect Dis 2022; 7:tropicalmed7070127. [PMID: 35878139 PMCID: PMC9320632 DOI: 10.3390/tropicalmed7070127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 06/30/2022] [Accepted: 07/05/2022] [Indexed: 11/30/2022] Open
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26
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Microbial-Derived Toll-like Receptor Agonism in Cancer Treatment and Progression. Cancers (Basel) 2022; 14:cancers14122923. [PMID: 35740589 PMCID: PMC9221178 DOI: 10.3390/cancers14122923] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/02/2022] [Accepted: 06/13/2022] [Indexed: 01/05/2023] Open
Abstract
Simple Summary Toll like receptors (TLRs) are a group of transmembrane receptors belonging to the class of pattern recognition receptors (PRR), which are involved in recognition of pathogen associated molecular patterns (PAMPs), inducing immune response. During the past decade, a number of preclinical and clinical breakthroughs in the field of TLR agonists has immerged in cancer research and some of these agents have performed exceptionally well in clinical trials. Based on evidence from scientific studies, we draw attention to several microbial based TLR agonists and discuss their relevance in various cancer and explore various microbial based TLR agonists for developing effective immunotherapeutic strategies against cancer. Abstract Toll-like receptors (TLRs) are typical transmembrane proteins, which are essential pattern recognition receptors in mediating the effects of innate immunity. TLRs recognize structurally conserved molecules derived from microbes and damage-associated molecular pattern molecules that play an important role in inflammation. Since the first discovery of the Toll receptor by the team of J. Hoffmann in 1996, in Drosophila melanogaster, numerous TLRs have been identified across a wide range of invertebrate and vertebrate species. TLR stimulation leads to NF-κB activation and the subsequent production of pro-inflammatory cytokines and chemokines, growth factors and anti-apoptotic proteins. The expression of TLRs has also been observed in many tumors, and their stimulation results in tumor progression or regression, depending on the TLR and tumor type. The anti-tumoral effects can result from the activation of anti-tumoral immune responses and/or the direct induction of tumor cell death. The pro-tumoral effects may be due to inducing tumor cell survival and proliferation or by acting on suppressive or inflammatory immune cells in the tumor microenvironment. The aim of this review is to draw attention to the effects of TLR stimulation in cancer, the activation of various TLRs by microbes in different types of tumors, and, finally, the role of TLRs in anti-cancer immunity and tumor rejection.
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Exploring the Utility of NK Cells in COVID-19. Biomedicines 2022; 10:biomedicines10051002. [PMID: 35625739 PMCID: PMC9138257 DOI: 10.3390/biomedicines10051002] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/22/2022] [Accepted: 04/25/2022] [Indexed: 02/07/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) can manifest as acute respiratory distress syndrome and is associated with substantial morbidity and mortality. Extensive data now indicate that immune responses to SARS-CoV-2 infection determine the COVID-19 disease course. A wide range of immunomodulatory agents have been tested for the treatment of COVID-19. Natural killer (NK) cells play an important role in antiviral innate immunity, and anti-SARS-CoV-2 activity and antifibrotic activity are particularly critical for COVID-19 control. Notably, SARS-CoV-2 clearance rate, antibody response, and disease progression in COVID-19 correlate with NK cell status, and NK cell dysfunction is linked with increased SARS-CoV-2 susceptibility. Thus, NK cells function as the key element in the switch from effective to harmful immune responses in COVID-19. However, dysregulation of NK cells has been observed in COVID-19 patients, exhibiting depletion and dysfunction, which correlate with COVID-19 severity; this dysregulation perhaps contributes to disease progression. Given these findings, NK-cell-based therapies with anti-SARS-CoV-2 activity, antifibrotic activity, and strong safety profiles for cancers may encourage the rapid application of functional NK cells as a potential therapeutic strategy to eliminate SARS-CoV-2-infected cells at an early stage, facilitate immune–immune cell interactions, and favor inflammatory processes that prevent and/or reverse over-inflammation and inhibit fibrosis progression, thereby helping in the fight against COVID-19. However, our understanding of the role of NK cells in COVID-19 remains incomplete, and further research on the involvement of NK cells in the pathogenesis of COVID-19 is needed. The rationale of NK-cell-based therapies for COVID-19 has to be based on the timing of therapeutic interventions and disease severity, which may be determined by the balance between beneficial antiviral and potential detrimental pathologic actions. NK cells would be more effective early in SARS-CoV-2 infection and prevent the progression of COVID-19. Immunomodulation by NK cells towards regulatory functions could be useful as an adjunct therapy to prevent the progression of COVID-19.
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28
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Duan S, Liu S. Targeting NK Cells for HIV-1 Treatment and Reservoir Clearance. Front Immunol 2022; 13:842746. [PMID: 35371060 PMCID: PMC8967654 DOI: 10.3389/fimmu.2022.842746] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 02/07/2022] [Indexed: 12/31/2022] Open
Abstract
Combined antiretroviral therapy (cART) can inhibit the replication of human immunodeficiency virus type 1 (HIV-1) and reduce viral loads in the peripheral blood to undetectable levels. However, the presence of latent HIV-1 reservoirs prevents complete HIV-1 eradication. Several drugs and strategies targeting T cells are now in clinical trials, but their effectiveness in reducing viral reservoirs has been mixed. Interestingly, innate immune natural killer (NK) cells, which are promising targets for cancer therapy, also play an important role in HIV-1 infection. NK cells are a unique innate cell population with features of adaptive immunity that can regulate adaptive and innate immune cell populations; therefore, they can be exploited for HIV-1 immunotherapy and reservoir eradication. In this review, we highlight immunotherapy strategies for HIV infection that utilize the beneficial properties of NK cells.
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Affiliation(s)
- Siqin Duan
- Department of Clinical Laboratory, Guangzhou Women and Children Medical Center, Guangzhou Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Shuwen Liu
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou, China
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29
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Steffen BT, Pankow JS, Lutsey PL, Demmer RT, Misialek JR, Guan W, Cowan LT, Coresh J, Norby FL, Tang W. Proteomic profiling identifies novel proteins for genetic risk of severe COVID-19: the Atherosclerosis Risk in Communities Study. Hum Mol Genet 2022; 31:2452-2461. [PMID: 35212764 PMCID: PMC9307314 DOI: 10.1093/hmg/ddac024] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 01/10/2022] [Accepted: 01/19/2022] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Genome-wide association studies have identified six genetic variants associated with severe COVID-19, yet the mechanisms through which they may affect disease remains unclear. We investigated proteomic signatures related to COVID-19 risk variants rs657152 (ABO), rs10735079 (OAS1/OAS2/OAS3), rs2109069 (DPP9), rs74956615 (TYK2), rs2236757 (IFNAR2) and rs11385942 (SLC6A20/LZTFL1/CCR9/FYCO1/CXCR6/XCR1) as well as their corresponding downstream pathways that may promote severe COVID-19 in risk allele carriers and their potential relevancies to other infection outcomes. METHODS A DNA aptamer-based array measured 4870 plasma proteins among 11 471 participants. Linear regression estimated associations between the COVID-19 risk variants and proteins with correction for multiple comparisons, and canonical pathway analysis was conducted. Cox regression assessed associations between proteins identified in the main analysis and risk of incident hospitalized respiratory infections (2570 events) over a 20.7-year follow-up. RESULTS The ABO variant rs657152 was associated with 84 proteins in 7241 white participants with 24 replicated in 1671 Black participants. The TYK2 variant rs74956615 was associated with ICAM-1 and -5 in white participants with ICAM-5 replicated in Black participants. Of the 84 proteins identified in the main analysis, seven were significantly associated with incident hospitalized respiratory infections including Ephrin type-A receptor 4 (hazard ratio (HR): 0.87; P = 2.3 × 10-11) and von Willebrand factor type A (HR: 1.17; P = 1.6x10-13). CONCLUSIONS Novel proteomics signatures and pathways for COVID-19-related risk variants TYK2 and ABO were identified. A subset of these proteins predicted greater risk of incident hospitalized pneumonia and respiratory infections. Further studies to examine these proteins in COVID-19 patients are warranted.
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Affiliation(s)
- Brian T Steffen
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55455, USA
| | - James S Pankow
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55455, USA
| | - Pamela L Lutsey
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55455, USA
| | - Ryan T Demmer
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55455, USA,Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
| | - Jeffrey R Misialek
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55455, USA
| | - Weihua Guan
- Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, MN 55455, USA
| | - Logan T Cowan
- Department of Biostatistics, Epidemiology, and Environmental Health Sciences, Jiann Ping-Hsu College of Public Health, Statesboro, GA 30458, USA
| | - Josef Coresh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD 21218, USA
| | - Faye L Norby
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55455, USA,Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Health System, Los Angeles 90048, CA
| | - Weihong Tang
- To whom correspondence should be addressed: Division of Epidemiology and Community Health, University of Minnesota, 1300 S. 2nd St., Suite 300, Minneapolis, MN 55454, USA. Tel: 6 126269140;
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30
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Feng Y, Wassie T, Gan R, Wu X. Structural characteristics and immunomodulatory effects of sulfated polysaccharides derived from marine algae. Crit Rev Food Sci Nutr 2022; 63:7180-7196. [PMID: 35193454 DOI: 10.1080/10408398.2022.2043823] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Marine algae are becoming an important source of valuable candidates of functional food that remain unexplored. Compositional analysis showed that marine algae contain essential nutrients, such as carbohydrates, proteins, fats, and minerals, of which polysaccharides are the main bioactive component. Depending on the source, marine algae polysaccharides are sulfated, which have diverse structures and compositions that influence their biological activities. A growing body of evidence has demonstrated that sulfated polysaccharides derived from marine algae (SPs) exhibit various bioactivities, especially immunomodulation. This review aims at summarizing the structural characteristics of SPs, their immunomodulatory effects, and the structural-immunomodulatory activity relationships between them from articles in recent decade, in order to provide a theoretical basis for the further applications of SPs as promising food or feed additives and possible health products to modulate the immune response.
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Affiliation(s)
- Yingying Feng
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China
| | - Teketay Wassie
- Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences; National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Changsha, Hunan, China
| | - Renyou Gan
- Research Center for Plants and Human Health, Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences, Chengdu National Agricultural Science and Technology Center, Chengdu, China
- Key Laboratory of Coarse Cereal Processing (Ministry of Agriculture and Rural Affairs), Sichuan Engineering & Technology Research Center of Coarse Cereal Industralization, School of Food and Biological Engineering, Chengdu University, Chengdu, China
| | - Xin Wu
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China
- Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences; National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Changsha, Hunan, China
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31
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Ghasemzadeh M, Ghasemzadeh A, Hosseini E. Exhausted NK cells and cytokine storms in COVID-19: Whether NK cell therapy could be a therapeutic choice. Hum Immunol 2022; 83:86-98. [PMID: 34583856 PMCID: PMC8423992 DOI: 10.1016/j.humimm.2021.09.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/17/2021] [Accepted: 09/04/2021] [Indexed: 02/08/2023]
Abstract
The global outbreak of coronavirus-2019 (COVID-19) still claims more lives daily around the world due to the lack of a definitive treatment and the rapid tendency of virus to mutate, which even jeopardizes vaccination efficacy. At the forefront battle against SARS-CoV-2, an effective innate response to the infection has a pivotal role in the initial control and treatment of disease. However, SARS-CoV-2 subtly interrupts the equations of immune responses, disrupting the cytolytic antiviral effects of NK cells, while seriously activating infected macrophages and other immune cells to induce an unleashed "cytokine storm", a dangerous and uncontrollable inflammatory response causing life-threatening symptoms in patients. Notably, the NK cell exhaustion with ineffective cytolytic function against the sources of exaggerated cytokine release, acts as an Achilles' heel which exacerbates the severity of COVID-19. Given this, approaches that improve NK cell cytotoxicity may benefit treatment protocols. As a suggestion, adoptive transfer of NK or CAR-NK cells with proper cytotolytic potentials and the lowest capacity of cytokine-release (for example CD56dim NK cells brightly express activating receptors), to severe COVID-19 patients may provide an effective cure especially in cases suffering from cytokine storms. More intriguingly, the ongoing evidence for persistent clonal expansion of NK memory cells characterized by an activating phenotype in response to viral infections, can benefit the future studies on vaccine development and adoptive NK cell therapy in COVID-19. Whether vaccinated volunteers or recovered patients can also be considered as suitable candidates for cell donation could be the subject of future research.
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Affiliation(s)
- Mehran Ghasemzadeh
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | | | - Ehteramolsadat Hosseini
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran; Department of Immunology, Alfred Medical Research and Education Precinct, Monash University, Melbourne, Victoria, Australia; Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia.
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32
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Abstract
Ensuring the maximum standards of quality and welfare in animal production requires developing effective tools to halt and prevent the spread of the high number of infectious diseases affecting animal husbandry. Many of these diseases are caused by pathogens of viral etiology. To date, one of the best strategies is to implement preventive vaccination policies whenever possible. However, many of the currently manufactured animal vaccines still rely in classical vaccine technologies (killed or attenuated vaccines). Under some circumstances, these vaccines may not be optimal in terms of safety and immunogenicity, nor adequate for widespread application in disease-free countries at risk of disease introduction. One step ahead is needed to improve and adapt vaccine manufacturing to the use of new generation vaccine technologies already tested in experimental settings. In the context of viral diseases of veterinary interest, we overview current vaccine technologies that can be approached, with a brief insight in the type of immunity elicited.
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Affiliation(s)
- Alejandro Brun
- Centro de Investigación en Sanidad Animal (CISA), Instituto de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC), Valdeolmos, Madrid, Spain.
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33
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Todberg T, Loft N, Møller DL, Ostrowski SR, Nielsen SD, Skov L. Impact of methotrexate and adalimumab on immune function of patients with psoriasis. Dermatol Ther 2021; 35:e15284. [PMID: 34953013 DOI: 10.1111/dth.15284] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/01/2021] [Accepted: 12/16/2021] [Indexed: 11/26/2022]
Abstract
Patients with psoriasis are commonly treated with methotrexate or biologics. We examined the immune response in a whole blood assay (TruCulture®) to assess the effect of methotrexate and adalimumab. Twenty patients with psoriasis were included and cytokine levels following stimulation with LPS, R848, HKCA, PolyIC, or a blank were investigated before and after 3-6 months of treatment with methotrexate or adalimumab and in patients who had received adalimumab > 5 years. Methotrexate only induced minor changes in the cytokine responses, whereas adalimumab affected a wide range of cytokines important for the immune defense towards microorganisms. In the long-term adalimumab treated group, the cytokine levels were almost equivalent to the short-term adalimumab-treated group. Overall, methotrexate was not associated with cytokine suppression. Short and long-term treatment with adalimumab lowered multiple cytokines involved in the immune defense equally emphasizing the need to continuously be aware of the risk of infections in these patients. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Tanja Todberg
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, DK-2900, Hellerup, Denmark.,Copenhagen Research Group for Inflammatory Skin (CORGIS), Hellerup, Denmark
| | - Nikolai Loft
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, DK-2900, Hellerup, Denmark.,Copenhagen Research Group for Inflammatory Skin (CORGIS), Hellerup, Denmark
| | - Dina Leth Møller
- Viro-immonology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, Copenhagen University Hospital
| | - Sisse Rye Ostrowski
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen
| | - Susanne Dam Nielsen
- Viro-immonology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, Copenhagen University Hospital.,Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet
| | - Lone Skov
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, DK-2900, Hellerup, Denmark.,Copenhagen Research Group for Inflammatory Skin (CORGIS), Hellerup, Denmark.,Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet
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34
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Choudhury SM, Ma X, Dang W, Li Y, Zheng H. Recent Development of Ruminant Vaccine Against Viral Diseases. Front Vet Sci 2021; 8:697194. [PMID: 34805327 PMCID: PMC8595237 DOI: 10.3389/fvets.2021.697194] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 10/04/2021] [Indexed: 01/21/2023] Open
Abstract
Pathogens of viral origin produce a large variety of infectious diseases in livestock. It is essential to establish the best practices in animal care and an efficient way to stop and prevent infectious diseases that impact animal husbandry. So far, the greatest way to combat the disease is to adopt a vaccine policy. In the fight against infectious diseases, vaccines are very popular. Vaccination's fundamental concept is to utilize particular antigens, either endogenous or exogenous to induce immunity against the antigens or cells. In light of how past emerging and reemerging infectious diseases and pandemics were handled, examining the vaccination methods and technological platforms utilized for the animals may provide some useful insights. New vaccine manufacturing methods have evolved because of developments in technology and medicine and our broad knowledge of immunology, molecular biology, microbiology, and biochemistry, among other basic science disciplines. Genetic engineering, proteomics, and other advanced technologies have aided in implementing novel vaccine theories, resulting in the discovery of new ruminant vaccines and the improvement of existing ones. Subunit vaccines, recombinant vaccines, DNA vaccines, and vectored vaccines are increasingly gaining scientific and public attention as the next generation of vaccines and are being seen as viable replacements to conventional vaccines. The current review looks at the effects and implications of recent ruminant vaccine advances in terms of evolving microbiology, immunology, and molecular biology.
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Affiliation(s)
- Sk Mohiuddin Choudhury
- State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Disease Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - XuSheng Ma
- State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Disease Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Wen Dang
- State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Disease Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - YuanYuan Li
- Gansu Agricultural University, Lanzhou, China
| | - HaiXue Zheng
- State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Disease Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
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35
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Elemam NM, Ramakrishnan RK, Hundt JE, Halwani R, Maghazachi AA, Hamid Q. Innate Lymphoid Cells and Natural Killer Cells in Bacterial Infections: Function, Dysregulation, and Therapeutic Targets. Front Cell Infect Microbiol 2021; 11:733564. [PMID: 34804991 PMCID: PMC8602108 DOI: 10.3389/fcimb.2021.733564] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 10/19/2021] [Indexed: 12/12/2022] Open
Abstract
Infectious diseases represent one of the largest medical challenges worldwide. Bacterial infections, in particular, remain a pertinent health challenge and burden. Moreover, such infections increase over time due to the continuous use of various antibiotics without medical need, thus leading to several side effects and bacterial resistance. Our innate immune system represents our first line of defense against any foreign pathogens. This system comprises the innate lymphoid cells (ILCs), including natural killer (NK) cells that are critical players in establishing homeostasis and immunity against infections. ILCs are a group of functionally heterogenous but potent innate immune effector cells that constitute tissue-resident sentinels against intracellular and extracellular bacterial infections. Being a nascent subset of innate lymphocytes, their role in bacterial infections is not clearly understood. Furthermore, these pathogens have developed methods to evade the host immune system, and hence permit infection spread and tissue damage. In this review, we highlight the role of the different ILC populations in various bacterial infections and the possible ways of immune evasion. Additionally, potential immunotherapies to manipulate ILC responses will be briefly discussed.
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Affiliation(s)
- Noha Mousaad Elemam
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Rakhee K Ramakrishnan
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Jennifer E Hundt
- Lübeck Institute for Experimental Dermatology, University of Lübeck, Lübeck, Germany
| | - Rabih Halwani
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Prince Abdullah Ben Khaled Celiac Disease Chair, Department of Pediatrics, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Azzam A Maghazachi
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Qutayba Hamid
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada
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36
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Nouri Y, Weinkove R, Perret R. T-cell intrinsic Toll-like receptor signaling: implications for cancer immunotherapy and CAR T-cells. J Immunother Cancer 2021; 9:jitc-2021-003065. [PMID: 34799397 PMCID: PMC8606765 DOI: 10.1136/jitc-2021-003065] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2021] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) are evolutionarily conserved molecules that specifically recognize common microbial patterns, and have a critical role in innate and adaptive immunity. Although TLRs are highly expressed by innate immune cells, particularly antigen-presenting cells, the very first report of a human TLR also described its expression and function within T-cells. Gene knock-out models and adoptive cell transfer studies have since confirmed that TLRs function as important costimulatory and regulatory molecules within T-cells themselves. By acting directly on T-cells, TLR agonists can enhance cytokine production by activated T-cells, increase T-cell sensitivity to T-cell receptor stimulation, promote long-lived T-cell memory, and reduce the suppressive activity of regulatory T-cells. Direct stimulation of T-cell intrinsic TLRs may be a relevant mechanism of action of TLR ligands currently under clinical investigation as cancer immunotherapies. Finally, chimeric antigen receptor (CAR) T-cells afford a new opportunity to specifically exploit T-cell intrinsic TLR function. This can be achieved by expressing TLR signaling domains, or domains from their signaling partner myeloid differentiation primary response 88 (MyD88), within or alongside the CAR. This review summarizes the expression and function of TLRs within T-cells, and explores the relevance of T-cell intrinsic TLR expression to the benefits and risks of TLR-stimulating cancer immunotherapies, including CAR T-cells.
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Affiliation(s)
- Yasmin Nouri
- Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand
| | - Robert Weinkove
- Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand.,Department of Pathology & Molecular Medicine, University of Otago, Wellington, Wellington, New Zealand.,Wellington Blood & Cancer Centre, Capital and Coast District Health Board, Wellington, New Zealand
| | - Rachel Perret
- Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand
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37
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Hvilsom CT, Søgaard OS. TLR-Agonist Mediated Enhancement of Antibody-Dependent Effector Functions as Strategy For an HIV-1 Cure. Front Immunol 2021; 12:704617. [PMID: 34630386 PMCID: PMC8495198 DOI: 10.3389/fimmu.2021.704617] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 09/03/2021] [Indexed: 11/29/2022] Open
Abstract
Background The current treatment for HIV-1 is based on blocking various stages in the viral replication cycle using combination antiretroviral therapy (ART). Even though ART effectively controls the infection, it is not curative, and patients must therefore continue treatment life-long. Aim Here we review recent literature investigating the single or combined effect of toll-like receptor (TLR) agonists and broadly neutralizing antibodies (bNAbs) with the objective to evaluate the evidence for this combination as a means towards an HIV-1 cure. Results Multiple preclinical studies found significantly enhanced killing of HIV-1 infected cells by TLR agonist-induced innate immune activation or by Fc-mediated effector functions following bNAb administration. However, monotherapy with either agent did not lead to sustained HIV-1 remission in clinical trials among individuals on long-term ART. Notably, findings in non-human primates suggest that a combination of TLR agonists and bNAbs may be able to induce long-term remission after ART cessation and this approach is currently being further investigated in clinical trials. Conclusion Preclinical findings show beneficial effects of either TLR agonist or bNAb administration for enhancing the elimination of HIV-1 infected cells. Further, TLR agonist-mediated stimulation of innate effector functions in combination with bNAbs may enhance antibody-dependent cellular cytotoxicity and non-human primate studies have shown promising results for this combination strategy. Factors such as immune exhaustion, proviral bNAb sensitivity and time of intervention might impact the clinical success.
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Affiliation(s)
| | - Ole Schmeltz Søgaard
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.,Department of Infectious Disease, Aarhus University Hospital, Aarhus, Denmark
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38
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NK Cell Subpopulation Is Altered and the Expression of TLR1 and TLR9 Is Decreased in Patients with Acute Lymphoblastic Leukemia. JOURNAL OF ONCOLOGY 2021; 2021:5528378. [PMID: 34567117 PMCID: PMC8457960 DOI: 10.1155/2021/5528378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 04/28/2021] [Accepted: 08/05/2021] [Indexed: 11/20/2022]
Abstract
NK cells represent a heterogeneous subpopulation of lymphocytes of the innate immune system, which possess powerful antitumor activity. NK cells exhibit their function through a complex collection of receptors that act synergistically to recognize, regulate, or amplify the immune response. TLRs allow cells to detect PAMPs, MAMPs, or DAMPs, which are essential for the initiation of the immune response. Studies on the different subpopulations of NK cells and their expression profile of innate immune receptors in hematological cancers are limited. In this study, the specific subpopulations of NK cells in pediatric patients with acute lymphoblastic leukemia (ALL) and the repertoire and level of expression of TLRs in cytotoxic NK cells were assessed. The results suggested that pediatric patients with ALL exhibited a significant decrease in NK cells in peripheral blood and bone marrow, in addition to alterations in the distribution of the subpopulations of cells. Regulatory and cytotoxic NK cells were diminished, whereas dysfunctional phenotype was considerably increased. Cytotoxic NK cells from children with ALL expressed all 10 TLRs, and expression of TLR1 and TLR9 was decreased compared with the controls. Interestingly, cytotoxic NK cells exhibited a higher expression of TLR1 in the bone marrow than in the peripheral blood of patients with ALL. The present study is the first to show that TLR10 was expressed in the cytotoxic NK cells and the first to assess the profile and levels of the 10 known TLRs in cytotoxic NK cells from patients with ALL. The alterations in expression levels and cellular distribution may be involved in the immune response.
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39
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Probiotics and Trained Immunity. Biomolecules 2021; 11:biom11101402. [PMID: 34680035 PMCID: PMC8533468 DOI: 10.3390/biom11101402] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/09/2021] [Accepted: 09/15/2021] [Indexed: 12/17/2022] Open
Abstract
The characteristics of innate immunity have recently been investigated in depth in several research articles, and original findings suggest that innate immunity also has a memory capacity, which has been named “trained immunity”. This notion has revolutionized our knowledge of the innate immune response. Thus, stimulation of trained immunity represents a therapeutic alternative that is worth exploring. In this context, probiotics, live microorganisms which when administered in adequate amounts confer a health benefit on the host, represent attractive candidates for the stimulation of trained immunity; however, although numerous studies have documented the beneficial proprieties of these microorganisms, their mechanisms of action are not yet fully understood. In this review, we propose to explore the putative connection between probiotics and stimulation of trained immunity.
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40
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Gallardo-Zapata J, Maldonado-Bernal C. Role of Toll-like receptors in natural killer cell function in acute lymphoblastic leukemia. Oncol Lett 2021; 22:748. [PMID: 34539852 PMCID: PMC8436356 DOI: 10.3892/ol.2021.13009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 12/22/2020] [Indexed: 11/25/2022] Open
Abstract
Natural killer (NK) cells are specialized lymphocytes primarily involved in the response to infection and tumors. NK cells are characterized by the presence of specific surface molecules, as well as a wide repertoire of receptors that impart microenvironment-dependent effector functions. Among these receptors, Toll-like receptors (TLRs) can be activated to condition the NK response to either a cytotoxic or immunoregulatory phenotype. However, cellular function is frequently impaired during disorders such as cancer. In the last decade, it has become increasingly evident that the stimulation of NK cells is a requirement for their increased cytotoxic activity. TLR activation has been suggested as an alternative route for reestablishing the antitumor activity of NK cells. The present review summarizes the characteristics of NK cells, their receptors, the expression and function of NK cell TLRs, and their functional status in cancer, primarily acute lymphoblastic leukemia.
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Affiliation(s)
- Janet Gallardo-Zapata
- Immunology and Proteomics Research Unit, Children's Hospital of Mexico Federico Gómez, Mexico City 06720, Mexico.,Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
| | - Carmen Maldonado-Bernal
- Immunology and Proteomics Research Unit, Children's Hospital of Mexico Federico Gómez, Mexico City 06720, Mexico
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41
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Zhang W, An EK, Park HB, Hwang J, Dhananjay Y, Kim SJ, Eom HY, Oda T, Kwak M, Lee PCW, Jin JO. Ecklonia cava fucoidan has potential to stimulate natural killer cells in vivo. Int J Biol Macromol 2021; 185:111-121. [PMID: 34119543 DOI: 10.1016/j.ijbiomac.2021.06.045] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 05/27/2021] [Accepted: 06/07/2021] [Indexed: 12/12/2022]
Abstract
Fucoidan is a sulfated polysaccharide, derived from various marine brown seaweeds, that has immunomodulatory effects. In this study, we analyzed the effects of five different fucoidans, which were extracted from Ascophyllum nodosum, Undaria pinnatifida, Macrocystis pyrifera, Fucus vesiculosus, and Ecklonia cava, on natural killer (NK) cell activation in mice. Among these, E. cava fucoidan (ECF) promoted an increase in the number of NK cells in the spleen and had the strongest effect on the activation of NK cells. Additionally, we observed that DC stimulation was required for NK cell activation and that ECF had the most potent effect on splenic dendritic cells (DC). Finally, ECF treatment effectively prevented infiltration of CT-26 carcinoma cells in the lungs of BALB/c mice in an NK cell dependent manner. Collectively, these results suggest that ECF could be a suitable candidate for enhancing NK cell-mediated anti-cancer immunity.
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Affiliation(s)
- Wei Zhang
- Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 201508, China
| | - Eun-Koung An
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Republic of Korea; Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Hae-Bin Park
- Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 201508, China; Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Republic of Korea; Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Juyoung Hwang
- Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 201508, China; Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Republic of Korea; Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Yadav Dhananjay
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - So-Jung Kim
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Hee-Yun Eom
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Tatsuya Oda
- Division of Biochemistry, Faculty of Fisheries, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, Nagasaki 852-8521, Japan
| | - Minseok Kwak
- Department of Chemistry, Pukyong National University, Busan 48513, South Korea
| | - Peter Chang-Whan Lee
- Department of Biomedical Sciences, University of Ulsan College of Medicine, ASAN Medical Center, Seoul 05505, South Korea.
| | - Jun-O Jin
- Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 201508, China; Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Republic of Korea; Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea.
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Meijerink N, van den Biggelaar RHGA, van Haarlem DA, Stegeman JA, Rutten VPMG, Jansen CA. A detailed analysis of innate and adaptive immune responsiveness upon infection with Salmonella enterica serotype Enteritidis in young broiler chickens. Vet Res 2021; 52:109. [PMID: 34404469 PMCID: PMC8369617 DOI: 10.1186/s13567-021-00978-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 07/15/2021] [Indexed: 12/31/2022] Open
Abstract
Salmonella enterica serotype Enteritidis (SE) is a zoonotic pathogen which causes foodborne diseases in humans as well as severe disease symptoms in young chickens. More insight in innate and adaptive immune responses of chickens to SE infection is needed to understand elimination of SE. Seven-day-old broiler chickens were experimentally challenged with SE and numbers and responsiveness of innate and adaptive immune cells as well as antibody titers were assessed. SE was observed in the ileum and spleen of SE-infected chickens at 7 days post-infection (dpi). At 1 dpi numbers of intraepithelial cytotoxic CD8+ T cells were significantly increased alongside numerically increased intraepithelial IL-2Rα+ and 20E5+ natural killer (NK) cells at 1 and 3 dpi. At both time points, activation of intraepithelial and splenic NK cells was significantly enhanced. At 7 dpi in the spleen, presence of macrophages and expression of activation markers on dendritic cells were significantly increased. At 21 dpi, SE-induced proliferation of splenic CD4+ and CD8+ T cells was observed and SE-specific antibodies were detected in sera of all SE-infected chickens. In conclusion, SE results in enhanced numbers and activation of innate cells and we hypothesized that in concert with subsequent specific T cell and antibody responses, reduction of SE is achieved. A better understanding of innate and adaptive immune responses important in the elimination of SE will aid in developing immune-modulation strategies, which may increase resistance to SE in young broiler chickens.
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Affiliation(s)
- Nathalie Meijerink
- Department Biomolecular Health Sciences, Division Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Robin H G A van den Biggelaar
- Department Biomolecular Health Sciences, Division Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Daphne A van Haarlem
- Department Biomolecular Health Sciences, Division Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - J Arjan Stegeman
- Department Population Health Sciences, Division Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Victor P M G Rutten
- Department Biomolecular Health Sciences, Division Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.,Department of Veterinary Tropical Diseases, Faculty of Veterinary Science, University of Pretoria, Pretoria, South Africa
| | - Christine A Jansen
- Department Biomolecular Health Sciences, Division Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands. .,Department of Animal Sciences, Cell Biology and Immunology Group, Wageningen University and Research, Wageningen, The Netherlands.
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Fortes-Andrade T, Almeida JS, Sousa LM, Santos-Rosa M, Freitas-Tavares P, Casanova JM, Rodrigues-Santos P. The Role of Natural Killer Cells in Soft Tissue Sarcoma: Prospects for Immunotherapy. Cancers (Basel) 2021; 13:cancers13153865. [PMID: 34359767 PMCID: PMC8345358 DOI: 10.3390/cancers13153865] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/26/2021] [Accepted: 07/28/2021] [Indexed: 12/19/2022] Open
Abstract
Simple Summary Soft-tissue sarcomas (STS) represent about 80% of sarcomas, and are a heterogeneous group of rare and malignant tumors. Morphological evaluation has been the standard model for the diagnosis of sarcomas, and even in samples with similar characteristics, they present genetic differences, which further increases the diversity of sarcomas. This variety is one of the main challenges for the classification and understanding of STS patterns, as well as for the respective treatments, which further decreases patient survival (<5 years). Natural Killer (NK) cells have a fundamental role in the control and immune surveillance of cancer development, progression and metastases. Notwithstanding the scarcity of studies to characterize NK cells in STS, it is noteworthy that the progression of these malignancies is associated with altered NK cells. These findings support the additional need to explore NK cell-based immunotherapy in STS; some clinical trials, although very tentatively, are already underway. Abstract Soft-tissue sarcomas (STS) represent about 80% of sarcomas, and are a heterogeneous group of rare and malignant tumors. STS arise from mesenchymal tissues and can grow into structures such as adipose tissue, muscles, nervous tissue and blood vessels. Morphological evaluation has been the standard model for the diagnosis of sarcomas, and even in samples with similar characteristics, they present a diversity in cytogenetic and genetic sequence alterations, which further increases the diversity of sarcomas. This variety is one of the main challenges for the classification and understanding of STS patterns, as well as for their respective treatments, which further decreases patient survival (<5 years). Despite some studies, little is known about the immunological profile of STS. As for the immunological profile of STS in relation to NK cells, there is also a shortage of studies. Observations made in solid tumors show that the infiltration of NK cells in tumors is associated with a good prognosis of the disease. Notwithstanding the scarcity of studies to characterize NK cells, their receptors, and ligands in STS, it is noteworthy that the progression of these malignancies is associated with altered NK phenotypes. Despite the scarcity of information on the function of NK cells, their phenotypes and their regulatory pathways in STS, the findings of this study support the additional need to explore NK cell-based immunotherapy in STS further. Some clinical trials, very tentatively, are already underway. STS clinical trials are still the basis for adoptive NK-cell and cytokine-based therapy.
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Affiliation(s)
- Tânia Fortes-Andrade
- Center for Neuroscience and Cell Biology (CNC), Laboratory of Immunology and Oncology, University of Coimbra, 3004-504 Coimbra, Portugal; (T.F.-A.); (J.S.A.); (L.M.S.)
| | - Jani Sofia Almeida
- Center for Neuroscience and Cell Biology (CNC), Laboratory of Immunology and Oncology, University of Coimbra, 3004-504 Coimbra, Portugal; (T.F.-A.); (J.S.A.); (L.M.S.)
- Faculty of Medicine, Immunology Institute, University of Coimbra, 3004-504 Coimbra, Portugal;
- Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal;
- Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
| | - Luana Madalena Sousa
- Center for Neuroscience and Cell Biology (CNC), Laboratory of Immunology and Oncology, University of Coimbra, 3004-504 Coimbra, Portugal; (T.F.-A.); (J.S.A.); (L.M.S.)
| | - Manuel Santos-Rosa
- Faculty of Medicine, Immunology Institute, University of Coimbra, 3004-504 Coimbra, Portugal;
- Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal;
- Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
| | - Paulo Freitas-Tavares
- Coimbra Hospital and University Center (CHUC), Tumor Unit of the Locomotor Apparatus (UTAL), University Clinic of Orthopedics, Orthopedics Service, 3000-075 Coimbra, Portugal;
| | - José Manuel Casanova
- Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal;
- Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Coimbra Hospital and University Center (CHUC), Tumor Unit of the Locomotor Apparatus (UTAL), University Clinic of Orthopedics, Orthopedics Service, 3000-075 Coimbra, Portugal;
| | - Paulo Rodrigues-Santos
- Center for Neuroscience and Cell Biology (CNC), Laboratory of Immunology and Oncology, University of Coimbra, 3004-504 Coimbra, Portugal; (T.F.-A.); (J.S.A.); (L.M.S.)
- Faculty of Medicine, Immunology Institute, University of Coimbra, 3004-504 Coimbra, Portugal;
- Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal;
- Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Correspondence: ; Tel.: +351-239-85-77-77 (ext. 24-28-44)
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Nishikawa M, Kinoshita M, Morimoto Y, Ishikiriyama T, Nakashima M, Nakashima H, Ono T, Seki S, Moriya T, Yamamoto J, Kishi Y. Lipopolysaccharide preconditioning reduces liver metastasis of Colon26 cells by enhancing antitumor activity of natural killer cells and natural killer T cells in murine liver. J Gastroenterol Hepatol 2021; 36:1889-1898. [PMID: 33326135 DOI: 10.1111/jgh.15375] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/27/2020] [Accepted: 12/08/2020] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND AIM Lipopolysaccharide (LPS) preconditioning drastically augments bactericidal activity but reduces the host inflammatory response. Therefore, it may be beneficial to prevent postoperative infectious complications and mitigate host damage by surgical stress. Considering its clinical application, how LPS preconditioning influences the antitumor effect in the liver is an important issue. We then investigated the effect of LPS preconditioning on antitumor activity against Colon26 tumor cells in mice. METHODS Lipopolysaccharide preconditioning was induced in mice by the intraperitoneal injection of 5 μg/kg LPS for three consecutive days. Intraportal inoculation of Colon26 cells, which express luminescent protein called Nano-lantern, was performed to evaluate the effect of LPS preconditioning on tumor liver metastasis. The antitumor activities of cytotoxic liver lymphocytes, especially natural killer (NK) cells and natural killer T (NKT) cells, against Colon26 cells were also examined in LPS preconditioned mice. RESULTS Lipopolysaccharide preconditioning remarkably prevented liver metastasis of Colon26 cells, as observed by IVIS imaging system, and prolonged survival after tumor inoculation. LPS preconditioning increased the proportions and number of liver NK cells and NKT cells and augmented their intracellular perforin and granzyme B expression, while reducing their intracellular expression of IFN-γ. An in vitro antitumor cytotoxicity assay revealed that LPS preconditioning significantly augmented antitumor cytotoxicities of the liver NK cells and NKT cells, especially NKT cells, against Colon26 cells. CONCLUSIONS Lipopolysaccharide preconditioning potently augmented antitumor cytotoxicity of liver NK cells and NKT cells, thereby improving mouse survival after intraportal inoculation of Colon26 tumor cells. It may be useful for perioperative care in oncological patients.
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Affiliation(s)
- Makoto Nishikawa
- Department of Surgery, National Defense Medical College, Tokorozawa, Japan
| | - Manabu Kinoshita
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan
| | - Yuji Morimoto
- Department of Physiology, National Defense Medical College, Tokorozawa, Japan
| | - Takuya Ishikiriyama
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan
| | - Masahiro Nakashima
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan
| | - Hiroyuki Nakashima
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan
| | - Takeshi Ono
- Global Infectious Diseases and Tropical Medicine, National Defense Medical College, Tokorozawa, Japan
| | - Shuhji Seki
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan
| | - Tomoyuki Moriya
- Department of Breast Surgery, Saitama Medical Center Library, Kawagoe, Japan
| | - Junji Yamamoto
- Department of Gastrointestinal Surgery, Ibaraki Prefectural Central Hospital, Kasama, Japan
| | - Yoji Kishi
- Department of Surgery, National Defense Medical College, Tokorozawa, Japan
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Transient blockade of TBK1/IKKε allows efficient transduction of primary human natural killer cells with vesicular stomatitis virus G-pseudotyped lentiviral vectors. Cytotherapy 2021; 23:787-792. [PMID: 34119434 DOI: 10.1016/j.jcyt.2021.04.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 04/27/2021] [Accepted: 04/27/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AIMS Vesicular stomatitis virus G (VSV-G)-pseudotyped lentiviral vectors (LVs) are widely used to reliably generate genetically modified, clinical-grade T-cell products. However, the results of genetically modifying natural killer (NK) cells with VSV-G LVs have been variable. The authors explored whether inhibition of the IKK-related protein kinases TBK1 and IKKε, key signaling molecules of the endosomal TLR4 pathway, which is activated by VSV-G, would enable the reliable transduction of NK cells by VSV-G LVs. METHODS The authors activated NK cells from peripheral blood mononuclear cells using standard procedures and transduced them with VSV-G LVs encoding a marker gene (yellow fluorescent protein [YFP]) or functional genes (chimeric antigen receptors [CARs], co-stimulatory molecules) in the presence of three TBK1/IKKε inhibitors (MRT67307, BX-795, amlexanox). NK cell transduction was evaluated by flow cytometry and/or western blot and the functionality of expressed CARs was evaluated in vitro. RESULTS Blocking TBK1/IKKε during transduction of NK cells enabled their efficient transduction by VSV-G LVs as judged by YFPexpression of 40-50%, with half maximal effective concentrations of 1.1 µM (MRT67307), 5 µM (BX-795) and 24.8 µM (amlexanox). Focusing on MRT67307, the authors successfully generated NK cells expressing CD19-CARs or HER2-CARs with an inducible co-stimulatory molecule. CAR NK cells exhibited increased cytolytic activity and ability to produce cytokines in comparison to untreated controls, confirming CAR functionality. CONCLUSIONS The authors demonstrate that inhibition of TBK1/IKKε enables the reliable generation of genetically modified NK cells using VSV-G LVs. The authors' protocol can be readily adapted to generate clinical-grade NK cells and thus has the potential to facilitate the clinical evaluation of genetically modified NK cell-based therapeutics in the future.
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Kim DO, Byun JE, Kim WS, Kim MJ, Choi JH, Kim H, Choi E, Kim TD, Yoon SR, Noh JY, Park YJ, Lee J, Cho HJ, Lee HG, Min SH, Choi I, Jung H. TXNIP Regulates Natural Killer Cell-Mediated Innate Immunity by Inhibiting IFN-γ Production during Bacterial Infection. Int J Mol Sci 2020; 21:ijms21249499. [PMID: 33327533 PMCID: PMC7765025 DOI: 10.3390/ijms21249499] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/07/2020] [Accepted: 12/08/2020] [Indexed: 12/13/2022] Open
Abstract
The function of natural killer (NK) cell-derived interferon-γ (IFN-γ) expands to remove pathogens by increasing the ability of innate immune cells. Here, we identified the critical role of thioredoxin-interacting protein (TXNIP) in the production of IFN-γ in NK cells during bacterial infection. TXNIP inhibited the production of IFN-γ and the activation of transforming growth factor β-activated kinase 1 (TAK1) activity in primary mouse and human NK cells. TXNIP directly interacted with TAK1 and inhibited TAK1 activity by interfering with the complex formation between TAK1 and TAK1 binding protein 1 (TAB1). Txnip−/− (KO) NK cells enhanced the activation of macrophages by inducing IFN-γ production during Pam3CSK4 stimulation or Staphylococcus aureus (S. aureus) infection and contributed to expedite the bacterial clearance. Our findings suggest that NK cell-derived IFN-γ is critical for host defense and that TXNIP plays an important role as an inhibitor of NK cell-mediated macrophage activation by inhibiting the production of IFN-γ during bacterial infection.
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Affiliation(s)
- Dong Oh Kim
- Department of Innovative Toxicology Research, Korea Institute of Toxicology, Yuseong-gu, Daejeon 34114, Korea;
| | - Jae-Eun Byun
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
- Department of Biochemistry, School of Life Sciences, Chungbuk National University, Cheongju 28644, Korea
| | - Won Sam Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
| | - Mi Jeong Kim
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Korea;
| | - Jung Ha Choi
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
| | - Hanna Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
| | - Eunji Choi
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
| | - Tae-Don Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
- Department of Functional Genomics, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Korea
| | - Suk Ran Yoon
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
- Department of Functional Genomics, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Korea
| | - Ji-Yoon Noh
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
| | - Young-Jun Park
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (Y.-J.P.); (J.L.)
| | - Jungwoon Lee
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (Y.-J.P.); (J.L.)
| | - Hee Jun Cho
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
| | - Hee Gu Lee
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
- Department of Biomolecular Science, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Korea
| | - Sang-Hyun Min
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), 80 Chumbokro Dong-gu, Daegu 41061, Korea;
| | - Inpyo Choi
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
- Department of Functional Genomics, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Korea
- Correspondence: (I.C.); (H.J.)
| | - Haiyoung Jung
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
- Department of Functional Genomics, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Korea
- Correspondence: (I.C.); (H.J.)
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P-MAPA, a Fungi-Derived Immunomodulatory Compound, Induces a Proinflammatory Response in a Human Whole Blood Model. Mediators Inflamm 2020; 2020:8831389. [PMID: 33299378 PMCID: PMC7707968 DOI: 10.1155/2020/8831389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 10/29/2020] [Accepted: 11/06/2020] [Indexed: 11/18/2022] Open
Abstract
P-MAPA is a complex compound, derived from Aspergillus oryzae cultures, that has shown immunomodulatory properties in infection and cancer animal models. Despite promising results in these models, the mechanisms of cellular activation by P-MAPA, suggested to be Toll-like receptor- (TLR-) dependent, and its effect on human immune cells, remain unclear. Using an ex vivo model of human whole blood, the effects of P-MAPA on complement system activation, production of cytokines, and the expression of complement receptors (CD11b, C5aR, and C3aR), TLR2, TLR4, and the coreceptor CD14 were analyzed in neutrophils and monocytes. P-MAPA induced complement activation in human blood, detected by increased levels of C3a, C5a, and SC5b-9 in plasma. As a consequence, CD11b expression increased and C5aR decreased upon activation, while C3aR expression remained unchanged in leukocytes. TLR2 and TLR4 expressions were not modulated by P-MAPA treatment on neutrophils, but TLR4 expression was reduced in monocytes, while CD14 expression increased in both cell types. P-MAPA also induced the production of TNF-α, IL-8, and IL-12 and oxidative burst, measured by peroxynitrite levels, in human leukocytes. Complement inhibition with compstatin showed that P-MAPA-induced complement activation drives modulation of C5aR, but not of CD11b, suggesting that P-MAPA acts through both complement-dependent and complement-independent mechanisms. Compstatin also significantly reduced the peroxynitrite generation. Altogether, our results show that P-MAPA induced proinflammatory response in human leukocytes, which is partially mediated by complement activation. Our data contribute to elucidate the complement-dependent and complement-independent mechanisms of P-MAPA, which ultimately result in immune cell activation and in its immunomodulatory properties in infection and cancer animal models.
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TLR agonists enhance responsiveness of inflammatory innate immune cells in HLA-B*57-positive HIV patients. J Mol Med (Berl) 2020; 99:147-158. [PMID: 33278000 PMCID: PMC7782382 DOI: 10.1007/s00109-020-01996-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 10/15/2020] [Accepted: 10/19/2020] [Indexed: 12/13/2022]
Abstract
Abstract HLA-B*57 affects the course of HIV infection. Under antiretroviral therapy, its effects cannot be explained by outstandingly efficient T cell responses alone but may also involve cells of innate immunity. Studying in vitro stimulation with Pam3CSK4, E. coli LPS-B5 and CpG-ODN-2216, we observed greater induction of IL-6/IL-1beta double-positive CD14+CD16++ monocytes as well as IFN-gamma-positive cytotoxic CD56highCD16neg NK cells in HLA-B*57- versus HLA-B*44-positive HIV patients, while TNF-alpha induction remained unchanged. Differences were not seen in the other monocyte and NK cell subsets or in HLA-matched healthy controls. Our findings show that, in virally suppressed HIV infection, HLA-B*57 is associated with enhanced responsiveness of inflammatory innate immune cells to TLR ligands, possibly contributing to increased vulnerability in sepsis. Key messages • HLA-B*57 is a host factor affecting clinical outcomes of HIV infection. • HLA-B*57 modifies inflammatory subsets of NK cells and monocytes in HIV infection. • In HLA-B*57-positive HIV patients TLR agonists induce enhanced IL-6/IL-1beta in monocytes. • NK cells from HLA-B*57 HIV patients release more IFN-gamma upon TLR costimulation. • HLA-B*57 is linked to enhanced inflammatory responsiveness to TLR ligands. Supplementary Information The online version contains supplementary material available at 10.1007/s00109-020-01996-7.
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Culos A, Tsai AS, Stanley N, Becker M, Ghaemi MS, McIlwain DR, Fallahzadeh R, Tanada A, Nassar H, Espinosa C, Xenochristou M, Ganio E, Peterson L, Han X, Stelzer IA, Ando K, Gaudilliere D, Phongpreecha T, Marić I, Chang AL, Shaw GM, Stevenson DK, Bendall S, Davis KL, Fantl W, Nolan GP, Hastie T, Tibshirani R, Angst MS, Gaudilliere B, Aghaeepour N. Integration of mechanistic immunological knowledge into a machine learning pipeline improves predictions. NAT MACH INTELL 2020; 2:619-628. [PMID: 33294774 PMCID: PMC7720904 DOI: 10.1038/s42256-020-00232-8] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 08/26/2020] [Indexed: 12/17/2022]
Abstract
The dense network of interconnected cellular signalling responses that are quantifiable in peripheral immune cells provides a wealth of actionable immunological insights. Although high-throughput single-cell profiling techniques, including polychromatic flow and mass cytometry, have matured to a point that enables detailed immune profiling of patients in numerous clinical settings, the limited cohort size and high dimensionality of data increase the possibility of false-positive discoveries and model overfitting. We introduce a generalizable machine learning platform, the immunological Elastic-Net (iEN), which incorporates immunological knowledge directly into the predictive models. Importantly, the algorithm maintains the exploratory nature of the high-dimensional dataset, allowing for the inclusion of immune features with strong predictive capabilities even if not consistent with prior knowledge. In three independent studies our method demonstrates improved predictions for clinically relevant outcomes from mass cytometry data generated from whole blood, as well as a large simulated dataset. The iEN is available under an open-source licence.
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Affiliation(s)
- Anthony Culos
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
- These authors contributed equally: Anthony Culos, Amy S. Tsai
| | - Amy S Tsai
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
- These authors contributed equally: Anthony Culos, Amy S. Tsai
| | - Natalie Stanley
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
| | - Martin Becker
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
| | - Mohammad S Ghaemi
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
- Digital Technologies Research Centre, National Research Council Canada, Toronto, Ontario, Canada
| | - David R McIlwain
- Department of Microbiology and Immunology, Baxter Laboratory in Stem Cell Biology, Stanford University School of Medicine, Stanford, CA, USA
| | - Ramin Fallahzadeh
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
| | - Athena Tanada
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
| | - Huda Nassar
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
| | - Camilo Espinosa
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
| | - Maria Xenochristou
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
| | - Edward Ganio
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Laura Peterson
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Xiaoyuan Han
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Ina A Stelzer
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Kazuo Ando
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Dyani Gaudilliere
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Thanaphong Phongpreecha
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Ivana Marić
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Alan L Chang
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
| | - Gary M Shaw
- Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - David K Stevenson
- Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Sean Bendall
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Kara L Davis
- Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Wendy Fantl
- Department of Microbiology and Immunology, Baxter Laboratory in Stem Cell Biology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Urology, Stanford University School of Medicine, Stanford, CA, USA
| | - Garry P Nolan
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Trevor Hastie
- Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
- Department of Statistics, Stanford University, Stanford, CA, USA
| | - Robert Tibshirani
- Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
- Department of Statistics, Stanford University, Stanford, CA, USA
| | - Martin S Angst
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
- These authors jointly supervised this work: Martin S. Angst, Brice Gaudilliere, Nima Aghaeepour
| | - Brice Gaudilliere
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, USA
- These authors jointly supervised this work: Martin S. Angst, Brice Gaudilliere, Nima Aghaeepour
| | - Nima Aghaeepour
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
- Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, USA
- These authors jointly supervised this work: Martin S. Angst, Brice Gaudilliere, Nima Aghaeepour
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50
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Deeba E, Lambrianides A, Pantzaris M, Krashias G, Christodoulou C. The expression profile of virus-recognizing toll-like receptors in natural killer cells of Cypriot multiple sclerosis patients. BMC Res Notes 2020; 13:460. [PMID: 32993761 PMCID: PMC7526110 DOI: 10.1186/s13104-020-05300-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 09/22/2020] [Indexed: 11/14/2022] Open
Abstract
Objective The exact aetiology of multiple sclerosis (MS) remains elusive, although several environmental and genetic risk factors have been implicated to varying degrees. Among the environmental risk factors, viral infections have been suggested as strong candidates contributing to MS pathology/progression. Viral recognition and control are largely tasked to the NK cells via TLR recognition and various cytotoxic and immunoregulatory functions. Additionally, the complex roles of different TLRs in MS pathology are highlighted in multiple, often contradictory, studies. The present work aims to analyse the TLR expression profile of NK cells isolated from MS patients. Highly purified CD56+CD3− NK cells isolated from peripheral blood of MS patients (n = 19) and healthy controls (n = 20) were analysed via flow cytometry for their expression of viral antigen-recognizing TLRs (TLR2, TLR3, TLR7, and TLR9). Results No difference was noted in TLR expression between MS patients and healthy controls. These results aim to supplement previous findings which study expressional or functional differences in TLRs present in various subsets of the immune system in MS, thus aiding in a better understanding of MS as a complex multifaceted disease.
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Affiliation(s)
- Elie Deeba
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 6 International Airport Avenue, 2370, Nicosia, Cyprus
| | - Anastasia Lambrianides
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 6 International Airport Avenue, 2370, Nicosia, Cyprus.,Neurology Clinic C, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Marios Pantzaris
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 6 International Airport Avenue, 2370, Nicosia, Cyprus.,Neurology Clinic C, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - George Krashias
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 6 International Airport Avenue, 2370, Nicosia, Cyprus. .,Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, P.O.Box 23462, 1683, Nicosia, Cyprus.
| | - Christina Christodoulou
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 6 International Airport Avenue, 2370, Nicosia, Cyprus.,Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, P.O.Box 23462, 1683, Nicosia, Cyprus
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