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Wan X, Zhang H, Tian J, Liu L, An Z, Zhao X, Zhang L, Yang X, Ge C, Song X. The cGAS-STING/PERK-eIF2α: Individual or Potentially Collaborative Signaling Transduction in Cardiovascular Diseases. Int J Biol Sci 2024; 20:5868-5887. [PMID: 39664570 PMCID: PMC11628330 DOI: 10.7150/ijbs.101247] [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: 07/31/2024] [Accepted: 10/19/2024] [Indexed: 12/13/2024] Open
Abstract
Over the past several decades, a canonical pathway called the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) mediating type I interferon (IFN) release via TANK-binding kinase 1(TBK1) / IFN regulatory factor 3 (IRF3) pathway has been widely investigated and characterized. Unexpectedly, recent studies show that the cGAS-STING noncanonically activates the protein kinase RNA-like ER kinase (PERK)-eukaryotic initiation factor 2α (eIF2α), an essential branch of unfolded protein response (UPR), even before the activation of the TBK1/IRF3 signaling. Additionally, we found that the PERK could regulate the STING signaling besides being modulated by upstream cGAS-STING. However, earlier evidence solely focused on the unidirectional regulation of STING and PERK, lacking their functional crosstalk. Hence, we postulate that there is a complex relationship between the cGAS-STING and PERK-eIF2α pathways and that, through convergent downstream signaling, they may collaboratively contribute to the pathophysiology of cardiovascular diseases (CVDs) via the cGAS-STING/PERK-eIF2α signaling axis. This study provides a novel pathway for the development of CVDs and paves the foundation for potential therapeutic targets for CVDs.
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Affiliation(s)
- Xueqi Wan
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing 100029, P.R. China
| | - Huan Zhang
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing 100029, P.R. China
| | - Jinfan Tian
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing 100029, P.R. China
| | - Libo Liu
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing 100029, P.R. China
| | - Ziyu An
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing 100029, P.R. China
| | - Xin Zhao
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing 100029, P.R. China
| | - Lijun Zhang
- Department of Radiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing 100029, P.R. China
| | - Xueyao Yang
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing 100029, P.R. China
| | - Changjiang Ge
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing 100029, P.R. China
| | - Xiantao Song
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing 100029, P.R. China
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Lu Y, Zhao M, Chen L, Wang Y, Liu T, Liu H. cGAS: action in the nucleus. Front Immunol 2024; 15:1380517. [PMID: 38515746 PMCID: PMC10954897 DOI: 10.3389/fimmu.2024.1380517] [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: 02/01/2024] [Accepted: 02/23/2024] [Indexed: 03/23/2024] Open
Abstract
As a canonical cytoplasmic DNA sensor, cyclic GMP-AMP synthase (cGAS) plays a key role in innate immunity. In recent years, a growing number of studies have shown that cGAS can also be located in the nucleus and plays new functions such as regulating DNA damage repair, nuclear membrane repair, chromosome fusion, DNA replication, angiogenesis and other non-canonical functions. Meanwhile, the mechanisms underlying the nucleo-cytoplasmic transport and the regulation of cGAS activation have been revealed in recent years. Based on the current understanding of the structure, subcellular localization and canonical functions of cGAS, this review focuses on summarizing the mechanisms underlying nucleo-cytoplasmic transport, activity regulation and non-canonical functions of cGAS in the nucleus. We aim to provide insights into exploring the new functions of cGAS in the nucleus and advance its clinical translation.
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Affiliation(s)
- Yikai Lu
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Mengmeng Zhao
- Research Center of Translational Medicine, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Li Chen
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yan Wang
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Tianhao Liu
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Haipeng Liu
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
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3
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Hendy DA, Pena ES, Ontiveros‐Padilla L, Dixon TA, Middleton DD, Williamson GL, Lukesh NR, Simpson SR, Stiepel RT, Islam MJ, Carlock MA, Ross TM, Bachelder EM, Ainslie KM. Immunogenicity of an adjuvanted broadly active influenza vaccine in immunocompromised and diverse populations. Bioeng Transl Med 2024; 9:e10634. [PMID: 38435811 PMCID: PMC10905549 DOI: 10.1002/btm2.10634] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 11/13/2023] [Accepted: 11/24/2023] [Indexed: 03/05/2024] Open
Abstract
Influenza virus outbreaks are a major burden worldwide each year. Current vaccination strategies are inadequate due to antigenic drift/shift of the virus and the elicitation of low immune responses. The use of computationally optimized broadly reactive antigen (COBRA) hemagglutinin (HA) immunogens subvert the constantly mutating viruses; however, they are poorly immunogenic on their own. To increase the immunogenicity of subunit vaccines such as this, adjuvants can be delivered with the vaccine. For example, agonists of the stimulator of interferon genes (STING) have proven efficacy as vaccine adjuvants. However, their use in high-risk populations most vulnerable to influenza virus infection has not been closely examined. Here, we utilize a vaccine platform consisting of acetalated dextran microparticles loaded with COBRA HA and the STING agonist cyclic GMP-AMP. We examine the immunogenicity of this platform in mouse models of obesity, aging, and chemotherapy-induced immunosuppression. Further, we examine vaccine efficacy in collaborative cross mice, a genetically diverse population that mimics human genetic heterogeneity. Overall, this vaccine platform had variable efficacy in these populations supporting work to better tailor adjuvants to specific populations.
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Affiliation(s)
- Dylan A. Hendy
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Erik S. Pena
- Joint Department of Biomedical EngineeringUniversity of North Carolina at Chapel Hill and North Carolina State UniversityChapel HillNorth CarolinaUSA
| | - Luis Ontiveros‐Padilla
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Timothy A. Dixon
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Denzel D. Middleton
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Grace L. Williamson
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Nicole Rose Lukesh
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Sean R. Simpson
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Rebeca T. Stiepel
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Md Jahirul Islam
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | | | - Ted M. Ross
- Florida Research and Innovation CenterPort St. LucieFloridaUSA
- Center for Vaccines and ImmunologyUniversity of GeorgiaAthensGeorgiaUSA
- Department of Infectious DiseasesUniversity of GeorgiaAthensGeorgiaUSA
| | - Eric M. Bachelder
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Kristy M. Ainslie
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Joint Department of Biomedical EngineeringUniversity of North Carolina at Chapel Hill and North Carolina State UniversityChapel HillNorth CarolinaUSA
- Department of Microbiology and Immunology, UNC School of MedicineUniversity of North CarolinaChapel HillNorth CarolinaUSA
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4
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Pan M, Hu T, Lyu J, Yin Y, Sun J, Wang Q, Xu L, Hu H, Wang C. CSNK1A1/CK1α suppresses autoimmunity by restraining the CGAS-STING1 signaling. Autophagy 2024; 20:311-328. [PMID: 37723657 PMCID: PMC10813568 DOI: 10.1080/15548627.2023.2256135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 08/22/2023] [Accepted: 08/31/2023] [Indexed: 09/20/2023] Open
Abstract
STING1 (stimulator of interferon response cGAMP interactor 1) is the quintessential protein in the CGAS-STING1 signaling pathway, crucial for the induction of type I IFN (interferon) production and eliciting innate immunity. Nevertheless, the overactivation or sustained activation of STING1 has been closely associated with the onset of autoimmune disorders. Notably, the majority of these disorders manifest as an upregulated expression of type I interferons and IFN-stimulated genes (ISGs). Hence, strict regulation of STING1 activity is paramount to preserve immune homeostasis. Here, we reported that CSNK1A1/CK1α, a serine/threonine protein kinase, was essential to prevent the overactivation of STING1-mediated type I IFN signaling through autophagic degradation of STING1. Mechanistically, CSNK1A1 interacted with STING1 upon the CGAS-STING1 pathway activation and promoted STING1 autophagic degradation by enhancing the phosphorylation of SQSTM1/p62 at serine 351 (serine 349 in human), which was critical for SQSTM1-mediated STING1 autophagic degradation. Consistently, SSTC3, a selective CSNK1A1 agonist, significantly attenuated the response of the CGAS-STING1 signaling by promoting STING1 autophagic degradation. Importantly, pharmacological activation of CSNK1A1 using SSTC3 markedly repressed the systemic autoinflammatory responses in the trex1-/- mouse autoimmune disease model and effectively suppressed the production of IFNs and ISGs in the PBMCs of SLE patients. Taken together, our study reveals a novel regulatory role of CSNK1A1 in the autophagic degradation of STING1 to maintain immune homeostasis. Manipulating CSNK1A1 through SSTC3 might be a potential therapeutic strategy for alleviating STING1-mediated aberrant type I IFNs in autoimmune diseases.Abbreviations: BMDMs: bone marrow-derived macrophages; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; HTDNA: herring testes DNA; IFIT1: interferon induced protein with tetratricopeptide repeats 1; IFNA4: interferon alpha 4; IFNB: interferon beta; IRF3: interferon regulatory factor 3; ISD: interferon stimulatory DNA; ISGs: IFN-stimulated genes; MEFs: mouse embryonic fibroblasts; PBMCs: peripheral blood mononuclear cells; RSAD2: radical S-adenosyl methionine domain containing 2; SLE: systemic lupus erythematosus; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1.
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Affiliation(s)
- Mingyu Pan
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China
- Department of Biomedical Science, City University of Hong Kong, Hong Kong, Hong Kong, China
| | - Tongyu Hu
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Jiao Lyu
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Yue Yin
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Jing Sun
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Quanyi Wang
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Lingxiao Xu
- Department of Rheumatology, The affiliated Suqian First People’s Hospital of Nanjing Medical University, Suqian, Jiangsu, China
- Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Haiyang Hu
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Chen Wang
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China
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Elean M, Raya Tonetti F, Fukuyama K, Arellano-Arriagada L, Namai F, Suda Y, Gobbato N, Nishiyama K, Villena J, Kitazawa H. Immunobiotic Ligilactobacillus salivarius FFIG58 Confers Long-Term Protection against Streptococcus pneumoniae. Int J Mol Sci 2023; 24:15773. [PMID: 37958756 PMCID: PMC10648150 DOI: 10.3390/ijms242115773] [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: 10/02/2023] [Revised: 10/27/2023] [Accepted: 10/29/2023] [Indexed: 11/15/2023] Open
Abstract
Previously, we isolated potentially probiotic Ligilactobacillus salivarius strains from the intestines of wakame-fed pigs. The strains were characterized based on their ability to modulate the innate immune responses triggered by the activation of Toll-like receptor (TLR)-3 or TLR4 signaling pathways in intestinal mucosa. In this work, we aimed to evaluate whether nasally administered L. salivarius strains are capable of modulating the innate immune response in the respiratory tract and conferring long-term protection against the respiratory pathogen Streptococcus pneumoniae. Infant mice (3-weeks-old) were nasally primed with L. salivarius strains and then stimulated with the TLR3 agonist poly(I:C). Five or thirty days after the last poly(I:C) administration mice were infected with pneumococci. Among the strains evaluated, L. salivarius FFIG58 had a remarkable ability to enhance the protection against the secondary pneumococcal infection by modulating the respiratory immune response. L. salivarius FFIG58 improved the ability of alveolar macrophages to produce interleukin (IL)-6, interferon (IFN)-γ, IFN-β, tumor necrosis factor (TNF)-α, IL-27, chemokine C-C motif ligand 2 (CCL2), chemokine C-X-C motif ligand 2 (CXCL2), and CXCL10 in response to pneumococcal challenge. Furthermore, results showed that the nasal priming of infant mice with the FFIG58 strain protected the animals against secondary infection until 30 days after stimulation with poly(I:C), raising the possibility of using nasally administered immunobiotics to stimulate trained immunity in the respiratory tract.
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Affiliation(s)
- Mariano Elean
- Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), Tucuman 4000, Argentina; (M.E.); (F.R.T.); (L.A.-A.)
| | - Fernanda Raya Tonetti
- Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), Tucuman 4000, Argentina; (M.E.); (F.R.T.); (L.A.-A.)
| | - Kohtaro Fukuyama
- Food and Feed Immunology Group, Laboratory of Animal Food Function, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan; (K.F.); (F.N.); (K.N.)
- Livestock Immunology Unit, International Education and Research Center for Food and Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan
| | - Luciano Arellano-Arriagada
- Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), Tucuman 4000, Argentina; (M.E.); (F.R.T.); (L.A.-A.)
- Food and Feed Immunology Group, Laboratory of Animal Food Function, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan; (K.F.); (F.N.); (K.N.)
| | - Fu Namai
- Food and Feed Immunology Group, Laboratory of Animal Food Function, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan; (K.F.); (F.N.); (K.N.)
- Livestock Immunology Unit, International Education and Research Center for Food and Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan
| | - Yoshihito Suda
- Department of Food, Agriculture and Environment, Miyagi University, Sendai 980-8572, Japan;
| | - Nadia Gobbato
- Laboratory of Immunology, Microbiology Institute, Faculty of Biochemistry, Chemistry and Pharmacy, National University of Tucuman, Tucuman 4000, Argentina;
| | - Keita Nishiyama
- Food and Feed Immunology Group, Laboratory of Animal Food Function, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan; (K.F.); (F.N.); (K.N.)
- Livestock Immunology Unit, International Education and Research Center for Food and Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan
| | - Julio Villena
- Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), Tucuman 4000, Argentina; (M.E.); (F.R.T.); (L.A.-A.)
- Food and Feed Immunology Group, Laboratory of Animal Food Function, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan; (K.F.); (F.N.); (K.N.)
| | - Haruki Kitazawa
- Food and Feed Immunology Group, Laboratory of Animal Food Function, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan; (K.F.); (F.N.); (K.N.)
- Livestock Immunology Unit, International Education and Research Center for Food and Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan
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Pan M, Yin Y, Hu T, Wang X, Jia T, Sun J, Wang Q, Meng W, Zhu J, Dai C, Hu H, Wang C. UXT attenuates the CGAS-STING1 signaling by targeting STING1 for autophagic degradation. Autophagy 2023; 19:440-456. [PMID: 35543189 PMCID: PMC9851252 DOI: 10.1080/15548627.2022.2076192] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
STING1 (stimulator of interferon response cGAMP interactor 1), the pivotal adaptor protein of CGAS (cyclic GMP-AMP synthase)-STING1 signaling, is critical for type I IFN production of innate immunity. However, excessive or prolonged activation of STING1 is associated with autoinflammatory and autoimmune diseases. Thus, preventing STING1 from over-activation is important to maintain immune homeostasis. Here, we reported that UXT (ubiquitously expressed prefoldin like chaperone), a small chaperone-like protein, was essential to prevent the excessive activation of STING1-mediated type I IFN signaling through autophagic degradation of STING1 via SQSTM1 (sequestosome 1). Upon DNA mimics or cyclic GMP-AMP (cGAMP) stimulation, UXT specifically interacted with STING1 and promoted STING1 degradation through selective macroautophagy/autophagy. Moreover, UXT was required for more efficient autophagic degradation of STING1 by facilitating the interaction of SQSTM1 and STING1. The in vivo role of UXT in attenuating the CGAS-STING1 signaling was further confirmed in the mouse model of DNA-virus infection and the TMPD (2,6,10,14-tetramethylpentadecane)-induced murine lupus model. Intriguingly, the expression of UXT was consistently impaired and exhibited a remarkable inverse correlation with type I IFN signature in the leukocytes and PBMCs (peripheral blood mononuclear cells) of several large SLE (systemic lupus erythematosus) cohorts. Importantly, the replenishment of UXT effectively suppressed the production of IFNs and ISGs in the PBMCs of SLE patients. Taken together, our study reveals a novel regulatory role of UXT in autophagic degradation of STING1 to maintain immune homeostasis. UXT might be a potential therapeutic target for alleviating aberrant type I IFNs in autoimmune diseasesAbbreviations: 3-MA: 3-methyladenine; BMDMs: bone marrow-derived macrophages; cGAMP: cyclic GMP-AMP; CGAS: cyclic gmp-amp synthase; cKO: conditional knockout; CXCL10: C-X-C motif chemokine ligand 10; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HSV-1: herpes simplex virus type 1; HTDNA: herring testes DNA; IFIT1: interferon induced protein with tetratricopeptide repeats 1; IFNA4: interferon alpha 4; IFNB: interferon beta; IRF3: interferon regulatory factor 3; ISD: interferon stimulatory DNA; ISGs: IFN-stimulated genes; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MEFs: mouse embryonic fibroblasts; RNA-seq: RNA sequencing; PBMCs: peripheral blood mononuclear cells; RSAD2: radical S-adenosyl methionine domain containing 2; SLE: systemic lupus erythematosus; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TMPD: 2,6,10,14-tetramethylpentadecane; UXT: ubiquitously expressed prefoldin like chaperone.
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Affiliation(s)
- Mingyu Pan
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangning District, China
| | - Yue Yin
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangning District, China
| | - Tongyu Hu
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangning District, China
| | - Xinxia Wang
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangning District, China
| | - Tian Jia
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangning District, China
| | - Jing Sun
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangning District, China
| | - Quanyi Wang
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangning District, China
| | - Wei Meng
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangning District, China
| | - Juanjuan Zhu
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangning District, China
| | - Chunsun Dai
- Center for Kidney Diseases, The 2nd Affiliated Hospital of Nanjing Medical University, Nanjing, China,CONTACT Chunsun Dai Center for Kidney Diseases, The 2nd Affiliated Hospital of Nanjing Medical University, 262 North Zhongshan Road, Nanjing, China
| | - Haiyang Hu
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangning District, China,Haiyang Hu State Key Laboratory of Natural Medicines, School of Life Science and Technology China Pharmaceutical University, 639 Longmian AvenueNanjingChina
| | - Chen Wang
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangning District, China,Chen Wang State Key Laboratory of Natural Medicines, School of Life Science and Technology China Pharmaceutical University, 639 Longmian AvenueNanjingChina
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7
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Kumar M, James MM, Kumawat M, Nabi B, Sharma P, Pal N, Shubham S, Tiwari RR, Sarma DK, Nagpal R. Aging and Microbiome in the Modulation of Vaccine Efficacy. Biomedicines 2022; 10:biomedicines10071545. [PMID: 35884849 PMCID: PMC9313064 DOI: 10.3390/biomedicines10071545] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 06/22/2022] [Accepted: 06/27/2022] [Indexed: 12/29/2022] Open
Abstract
From infancy through to old age, the microbiome plays an important role in modulating the host-immune system. As we age, our immune system and our gut microbiota change significantly in composition and function, which is linked to an increased vulnerability to infectious diseases and a decrease in vaccine responses. Our microbiome remains largely stable throughout adulthood; however, aging causes a major shift in the composition and function of the gut microbiome, as well as a decrease in diversity. Considering the critical role of the gut microbiome in the host-immune system, it is important to address, prevent, and ameliorate age-related dysbiosis, which could be an effective strategy for preventing/restoring functional deficits in immune responses as we grow older. Several factors, such as the host’s genetics and nutritional state, along with the gut microbiome, can influence vaccine efficacy or reaction. Emerging evidence suggests that the microbiome could be a significant determinant of vaccine immunity. Physiological mechanisms such as senescence, or the steady loss of cellular functions, which affect the aging process and vaccination responses, have yet to be comprehended. Recent studies on several COVID-19 vaccines worldwide have provided a considerable amount of data to support the hypothesis that aging plays a crucial role in modulating COVID-19 vaccination efficacy across different populations.
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Affiliation(s)
- Manoj Kumar
- National Institute for Research in Environmental Health, Bhopal 462030, India; (M.K.); (M.M.J.); (M.K.); (P.S.); (N.P.); (S.S.); (R.R.T.)
| | - Meenu Mariya James
- National Institute for Research in Environmental Health, Bhopal 462030, India; (M.K.); (M.M.J.); (M.K.); (P.S.); (N.P.); (S.S.); (R.R.T.)
| | - Manoj Kumawat
- National Institute for Research in Environmental Health, Bhopal 462030, India; (M.K.); (M.M.J.); (M.K.); (P.S.); (N.P.); (S.S.); (R.R.T.)
| | - Bilkees Nabi
- Department of Biochemistry and Biochemical Engineering, Sam Higginbottom University of Agriculture, Technology and Sciences, Allahabad 211007, India;
| | - Poonam Sharma
- National Institute for Research in Environmental Health, Bhopal 462030, India; (M.K.); (M.M.J.); (M.K.); (P.S.); (N.P.); (S.S.); (R.R.T.)
| | - Namrata Pal
- National Institute for Research in Environmental Health, Bhopal 462030, India; (M.K.); (M.M.J.); (M.K.); (P.S.); (N.P.); (S.S.); (R.R.T.)
| | - Swasti Shubham
- National Institute for Research in Environmental Health, Bhopal 462030, India; (M.K.); (M.M.J.); (M.K.); (P.S.); (N.P.); (S.S.); (R.R.T.)
| | - Rajnarayan R. Tiwari
- National Institute for Research in Environmental Health, Bhopal 462030, India; (M.K.); (M.M.J.); (M.K.); (P.S.); (N.P.); (S.S.); (R.R.T.)
| | - Devojit Kumar Sarma
- National Institute for Research in Environmental Health, Bhopal 462030, India; (M.K.); (M.M.J.); (M.K.); (P.S.); (N.P.); (S.S.); (R.R.T.)
- Correspondence: (D.K.S.); (R.N.)
| | - Ravinder Nagpal
- Department of Nutrition and Integrative Physiology, Florida State University, Tallahassee, FL 32302, USA
- Correspondence: (D.K.S.); (R.N.)
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8
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Sundaresh B, Xu S, Noonan B, Mansour MK, Leong JM, van Opijnen T. Host-informed therapies for the treatment of pneumococcal pneumonia. Trends Mol Med 2021; 27:971-989. [PMID: 34376327 DOI: 10.1016/j.molmed.2021.07.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/06/2021] [Accepted: 07/12/2021] [Indexed: 12/11/2022]
Abstract
Over the past two decades, traditional antimicrobial strategies have lost efficacy due to a rapid rise in antibiotic resistance and limited success in developing new antibiotics. Rather than relying on therapeutics solely targeting the bacterial pathogen, therapies are emerging that simultaneously focus on host responses. Here, we describe the most promising 'host-informed therapies' (HITs) in two categories: those that aid patients with fully functional immune systems, and those that aid patients with perturbed immune processes. Using Streptococcus pneumoniae, the leading cause of bacterial pneumonia, as a case study, we show HITs as an attractive option for supplementing infection management. However, to broaden their applicability and design new strategies, targeted research and clinical trials will be essential.
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Affiliation(s)
| | - Shuying Xu
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, USA; Graduate Program in Immunology, Tufts Graduate School of Biomedical Sciences, Boston, MA, USA
| | - Brian Noonan
- Stuart B. Levy Center for Integrated Management of Antimicrobial Resistance, Tufts Medical Center, Boston, MA, USA
| | - Michael K Mansour
- Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - John M Leong
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, USA; Stuart B. Levy Center for Integrated Management of Antimicrobial Resistance, Tufts Medical Center, Boston, MA, USA.
| | - Tim van Opijnen
- Department of Biology, Boston College, Chestnut Hill, MA, USA; Stuart B. Levy Center for Integrated Management of Antimicrobial Resistance, Tufts Medical Center, Boston, MA, USA.
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9
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Zhang R, Kang R, Tang D. The STING1 network regulates autophagy and cell death. Signal Transduct Target Ther 2021; 6:208. [PMID: 34078874 PMCID: PMC8172903 DOI: 10.1038/s41392-021-00613-4] [Citation(s) in RCA: 148] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 04/01/2021] [Accepted: 04/08/2021] [Indexed: 01/18/2023] Open
Abstract
Cell death and immune response are at the core of life. In past decades, the endoplasmic reticulum (ER) protein STING1 (also known as STING or TMEM173) was found to play a fundamental role in the production of type I interferons (IFNs) and pro-inflammatory cytokines in response to DNA derived from invading microbial pathogens or damaged hosts by activating multiple transcription factors. In addition to this well-known function in infection, inflammation, and immunity, emerging evidence suggests that the STING1-dependent signaling network is implicated in health and disease by regulating autophagic degradation or various cell death modalities (e.g., apoptosis, necroptosis, pyroptosis, ferroptosis, mitotic cell death, and immunogenic cell death [ICD]). Here, we outline the latest advances in our understanding of the regulating mechanisms and signaling pathways of STING1 in autophagy and cell death, which may shed light on new targets for therapeutic interventions.
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Affiliation(s)
- Ruoxi Zhang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
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10
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Neulinger-Muñoz M, Schaack D, Grekova SP, Bauer AS, Giese T, Salg GA, Espinet E, Leuchs B, Heller A, Nüesch JPF, Schenk M, Volkmar M, Giese NA. Human Retrotransposons and the Global Shutdown of Homeostatic Innate Immunity by Oncolytic Parvovirus H-1PV in Pancreatic Cancer. Viruses 2021; 13:v13061019. [PMID: 34071585 PMCID: PMC8228339 DOI: 10.3390/v13061019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/14/2021] [Accepted: 05/25/2021] [Indexed: 12/20/2022] Open
Abstract
Although the oncolytic parvovirus H-1PV has entered clinical trials, predicting therapeutic success remains challenging. We investigated whether the antiviral state in tumor cells determines the parvoviral oncolytic efficacy. The interferon/interferon-stimulated genes (IFN/ISG)-circuit and its major configurator, human endogenous retroviruses (HERVs), were evaluated using qRT-PCR, ELISA, Western blot, and RNA-Seq techniques. In pancreatic cancer cell lines, H-1PV caused a late global shutdown of innate immunity, whereby the concomitant inhibition of HERVs and IFN/ISGs was co-regulatory rather than causative. The growth-inhibitory IC50 doses correlated with the power of suppression but not with absolute ISG levels. Moreover, H-1PV was not sensitive to exogenous IFN despite upregulated antiviral ISGs. Such resistance questioned the biological necessity of the oncotropic ISG-shutdown, which instead might represent a surrogate marker for personalized oncolytic efficacy. The disabled antiviral homeostasis may modify the activity of other viruses, as demonstrated by the reemergence of endogenous AluY-retrotransposons. This way of suppression may compromise the interferogenicity of drugs having gemcitabine-like mechanisms of action. This shortcoming in immunogenic cell death induction is however amendable by immune cells which release IFN in response to H-1PV.
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Affiliation(s)
- Matthias Neulinger-Muñoz
- Department of Surgery, European Pancreas Center, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.N.-M.); (S.P.G.); (G.A.S.); (A.H.); (M.S.)
| | - Dominik Schaack
- Department of Anesthesiology, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Svetlana P. Grekova
- Department of Surgery, European Pancreas Center, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.N.-M.); (S.P.G.); (G.A.S.); (A.H.); (M.S.)
| | - Andrea S. Bauer
- German Cancer Research Center (DKFZ), Division of Functional Genome Analysis, 69120 Heidelberg, Germany;
| | - Thomas Giese
- Institute of Immunology and German Center for Infection Research (DZIF), Partner Site Heidelberg, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Gabriel A. Salg
- Department of Surgery, European Pancreas Center, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.N.-M.); (S.P.G.); (G.A.S.); (A.H.); (M.S.)
| | - Elisa Espinet
- German Cancer Research Center (DKFZ), Division of Stem Cells and Cancer, 69120 Heidelberg, Germany;
- HI-STEM—Heidelberg Institute for Stem Cell Technology and Experimental Medicine GmbH, 69120 Heidelberg, Germany
| | - Barbara Leuchs
- German Cancer Research Center (DKFZ), Division of Tumor Virology, 69120 Heidelberg, Germany;
| | - Anette Heller
- Department of Surgery, European Pancreas Center, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.N.-M.); (S.P.G.); (G.A.S.); (A.H.); (M.S.)
| | - Jürg P. F. Nüesch
- German Cancer Research Center (DKFZ), Division of Virus-Associated Carcinogenesis F170, 69120 Heidelberg, Germany;
| | - Miriam Schenk
- Department of Surgery, European Pancreas Center, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.N.-M.); (S.P.G.); (G.A.S.); (A.H.); (M.S.)
| | - Michael Volkmar
- German Cancer Research Center (DKFZ), Division of Molecular Oncology of Gastrointestinal Tumors, 69120 Heidelberg, Germany;
| | - Nathalia A. Giese
- Department of Surgery, European Pancreas Center, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.N.-M.); (S.P.G.); (G.A.S.); (A.H.); (M.S.)
- Correspondence:
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11
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Weight CM, Jochems SP, Adler H, Ferreira DM, Brown JS, Heyderman RS. Insights Into the Effects of Mucosal Epithelial and Innate Immune Dysfunction in Older People on Host Interactions With Streptococcus pneumoniae. Front Cell Infect Microbiol 2021; 11:651474. [PMID: 34113578 PMCID: PMC8185287 DOI: 10.3389/fcimb.2021.651474] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 05/10/2021] [Indexed: 12/21/2022] Open
Abstract
In humans, nasopharyngeal carriage of Streptococcus pneumoniae is common and although primarily asymptomatic, is a pre-requisite for pneumonia and invasive pneumococcal disease (IPD). Together, these kill over 500,000 people over the age of 70 years worldwide every year. Pneumococcal conjugate vaccines have been largely successful in reducing IPD in young children and have had considerable indirect impact in protection of older people in industrialized country settings (herd immunity). However, serotype replacement continues to threaten vulnerable populations, particularly older people in whom direct vaccine efficacy is reduced. The early control of pneumococcal colonization at the mucosal surface is mediated through a complex array of epithelial and innate immune cell interactions. Older people often display a state of chronic inflammation, which is associated with an increased mortality risk and has been termed 'Inflammageing'. In this review, we discuss the contribution of an altered microbiome, the impact of inflammageing on human epithelial and innate immunity to S. pneumoniae, and how the resulting dysregulation may affect the outcome of pneumococcal infection in older individuals. We describe the impact of the pneumococcal vaccine and highlight potential research approaches which may improve our understanding of respiratory mucosal immunity during pneumococcal colonization in older individuals.
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Affiliation(s)
- Caroline M. Weight
- Research Department of Infection, Division of Infection and Immunity, University College London, London, United Kingdom
| | - Simon P. Jochems
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
| | - Hugh Adler
- Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
- Tropical and Infectious Diseases Unit, Liverpool University Hospitals National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom
| | - Daniela M. Ferreira
- Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
| | - Jeremy S. Brown
- Respiratory Medicine, University College London, London, United Kingdom
| | - Robert S. Heyderman
- Research Department of Infection, Division of Infection and Immunity, University College London, London, United Kingdom
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12
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Mraheil MA, Toque HA, La Pietra L, Hamacher J, Phanthok T, Verin A, Gonzales J, Su Y, Fulton D, Eaton DC, Chakraborty T, Lucas R. Dual Role of Hydrogen Peroxide as an Oxidant in Pneumococcal Pneumonia. Antioxid Redox Signal 2021; 34:962-978. [PMID: 32283950 PMCID: PMC8035917 DOI: 10.1089/ars.2019.7964] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Significance:Streptococcus pneumoniae (Spn), a facultative anaerobic Gram-positive human pathogen with increasing rates of penicillin and macrolide resistance, is a major cause of lower respiratory tract infections worldwide. Pneumococci are a primary agent of severe pneumonia in children younger than 5 years and of community-acquired pneumonia in adults. A major defense mechanism toward Spn is the generation of reactive oxygen species, including hydrogen peroxide (H2O2), during the oxidative burst of neutrophils and macrophages. Paradoxically, Spn produces high endogenous levels of H2O2 as a strategy to promote colonization. Recent Advances: Pneumococci, which express neither catalase nor common regulators of peroxide stress resistance, have developed unique mechanisms to protect themselves from H2O2. Spn generates high levels of H2O2 as a strategy to promote colonization. Production of H2O2 moreover constitutes an important virulence phenotype and its cellular activities overlap and complement those of other virulence factors, such as pneumolysin, in modulating host immune responses and promoting organ injury. Critical Issues: This review examines the dual role of H2O2 in pneumococcal pneumonia, from the viewpoint of both the pathogen (defense mechanisms, lytic activity toward competing pathogens, and virulence) and the resulting host-response (inflammasome activation, endoplasmic reticulum stress, and damage to the alveolar-capillary barrier in the lungs). Future Directions: An understanding of the complexity of H2O2-mediated host-pathogen interactions is necessary to develop novel strategies that target these processes to enhance lung function during severe pneumonia.
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Affiliation(s)
- Mobarak Abu Mraheil
- Institute for Medical Microbiology, Justus-Liebig University, Giessen, Germany
| | - Haroldo A Toque
- Vascular Biology Center and Medical College of Georgia at Augusta University, Augusta, Georgia, USA.,Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
| | - Luigi La Pietra
- Institute for Medical Microbiology, Justus-Liebig University, Giessen, Germany
| | - Juerg Hamacher
- Internal Medicine and Pneumology, Lindenhofspital, Bern, Switzerland.,Lungen- und Atmungsstiftung Bern, Bern, Switzerland.,Internal Medicine V-Pneumology, Allergology, Respiratory and Environmental Medicine, Faculty of Medicine, Saarland University, Saarbrücken, Germany
| | - Tenzing Phanthok
- Department of Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
| | - Alexander Verin
- Vascular Biology Center and Medical College of Georgia at Augusta University, Augusta, Georgia, USA.,Department of Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
| | - Joyce Gonzales
- Department of Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
| | - Yunchao Su
- Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
| | - David Fulton
- Vascular Biology Center and Medical College of Georgia at Augusta University, Augusta, Georgia, USA.,Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
| | - Douglas C Eaton
- Department of Medicine, Emory School of Medicine, Atlanta, Georgia, USA
| | - Trinad Chakraborty
- Institute for Medical Microbiology, Justus-Liebig University, Giessen, Germany
| | - Rudolf Lucas
- Vascular Biology Center and Medical College of Georgia at Augusta University, Augusta, Georgia, USA.,Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.,Department of Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
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13
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Rashid F, Dzakah EE, Wang H, Tang S. The ORF8 protein of SARS-CoV-2 induced endoplasmic reticulum stress and mediated immune evasion by antagonizing production of interferon beta. Virus Res 2021; 296:198350. [PMID: 33626380 PMCID: PMC7897408 DOI: 10.1016/j.virusres.2021.198350] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 02/16/2021] [Accepted: 02/17/2021] [Indexed: 12/20/2022]
Abstract
The open reading frame 8 (orf8) is an accessory protein of SARS-CoV-2. It has 121 amino acids with two genotypes, orf8L and orf8S. In this study, we overexpressed the orf8L and orf8S of SARS-CoV-2 as well as the orf8b of SARS-CoV to investigate their roles in the regulation of endoplasmic reticulum (ER) stress and the inhibition of interferon beta (IFNß) production. We found that the two genotypes of SARS-CoV-2 orf8 are capable of inducing ER stress without significant difference by triggering the activating transcription factor 6 (ATF6) and inositol-requiring enzymes 1 (IRE1) branches of the ER stress pathway. However, the third branch of ER stress pathway, i.e. the protein kinase-like ER kinase (PERK), was unaffected by the overexpression of SARS-CoV-2 orf8L or orf8S. Moreover, both orf8L and orf8S of SARS-CoV-2 are capable of down regulating the production of IFNß and interferon-stimulated genes (ISG), ISG15 and ISG56 induced by polyinosinic-polycytidylic acid (poly (I:C)). Moreover, we also found decreased nuclear translocation of Interferon regulatory factor 3 (IRF3), after overexpressing orf8L and orf8S induced by poly (I:C). Our data demonstrated that SARS-CoV-2 orf8 protein could induce ER stress by activating the ATF6 and IRE1 pathways, but not the PERK pathway, and functions as an interferon antagonist to inhibit the production of IFNß. However, these functions appeared not to be affected by the genotypes of SARS-CoV-2 orf8L and orf8S.
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Affiliation(s)
- Farooq Rashid
- Dermatology Hospital, Southern Medical University, Guangzhou, China.
| | - Emmanuel Enoch Dzakah
- Dermatology Hospital, Southern Medical University, Guangzhou, China; Department of Molecular Biology and Biotechnology, School of Biological Sciences, College of Agriculture and Natural Sciences, University of Cape Coast, Cape Coast, Ghana.
| | - Haiying Wang
- Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.
| | - Shixing Tang
- Dermatology Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.
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14
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The impact of immuno-aging on SARS-CoV-2 vaccine development. GeroScience 2021; 43:31-51. [PMID: 33569701 PMCID: PMC7875765 DOI: 10.1007/s11357-021-00323-3] [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] [Received: 07/28/2020] [Accepted: 01/07/2021] [Indexed: 12/14/2022] Open
Abstract
The SARS-CoV-2 pandemic has almost 56 million confirmed cases resulting in over 1.3 million deaths as of November 2020. This infection has proved more deadly to older adults (those >65 years of age) and those with immunocompromising conditions. The worldwide population aged 65 years and older is increasing, and the total number of aged individuals will outnumber those younger than 65 years by the year 2050. Aging is associated with a decline in immune function and chronic activation of inflammation that contributes to enhanced viral susceptibility and reduced responses to vaccination. Here we briefly review the pathogenicity of the virus, epidemiology and clinical response, and the underlying mechanisms of human aging in improving vaccination. We review current methods to improve vaccination in the older adults using novel vaccine platforms and adjuvant systems. We conclude by summarizing the existing clinical trials for a SARS-CoV-2 vaccine and discussing how to address the unique challenges for vaccine development presented with an aging immune system.
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15
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Jiang W, Wang Y, Wargo JA, Lang FF, Kim BYS. Considerations for designing preclinical cancer immune nanomedicine studies. NATURE NANOTECHNOLOGY 2021; 16:6-15. [PMID: 33349682 PMCID: PMC8103921 DOI: 10.1038/s41565-020-00817-9] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 11/04/2020] [Indexed: 05/02/2023]
Abstract
Immunotherapy is known to be clinically beneficial for cancer patients and in many cases represents the new standard of care. Because of this success, the interest in integrating nanomedicine with cancer immunotherapy to further improve clinical response and toxicity profiles has grown. However, unlike conventional systemic therapies, which are directly cytotoxic to tumour cells, cancer immunotherapy relies on the host's immune system to generate tumouricidal effects. As such, proper design of cancer immune nanomedicine requires scrutiny of tumours' intrinsic and extrinsic factors that may impact host antitumour immunity. Here, we highlight key parameters that differentiate cancer immunotherapy from conventional cytotoxic agents, and we discuss their implications for designing preclinical cancer immune nanomedicine studies. We emphasize that these factors, including intratumoural genomic heterogeneity, commensal diversity, sexual dimorphism and biological ageing, which were largely ignored in traditional cancer nanomedicine experiments, should be carefully considered and incorporated into cancer immune nanomedicine investigations given their critical involvement in shaping the body's antitumour immune responses.
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Affiliation(s)
- Wen Jiang
- Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Yifan Wang
- Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Jennifer A Wargo
- Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Frederick F Lang
- Department of Neurosurgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Betty Y S Kim
- Department of Neurosurgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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16
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Kimkong I, Kunanopparat A. Autophagy related protein 9A increase in hepatitis B virus-associated hepatocellular carcinoma and the role in apoptosis. World J Hepatol 2020; 12:1367-1371. [PMID: 33442462 PMCID: PMC7772733 DOI: 10.4254/wjh.v12.i12.1367] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/29/2020] [Accepted: 10/19/2020] [Indexed: 02/06/2023] Open
Abstract
The majority of hepatocellular carcinoma (HCC) cases are associated with the hepatitis B virus (HBV) infection. Autophagy related protein 9A (ATG9A) is a transmembrane protein required for autophagosome formation. In order to investigate the role of ATG9A in HBV-associated HCC, ATG9A protein expression was determined in tumor liver tissues and compared with adjacent nontumor tissues from HCC patients with or without HBV infection. In HBV-associated HCC tissues, ATG9A protein level was increased in tumor liver tissues, but not in cases of non-HBV HCC. Our findings suggested that ATG9A might be involved in HBV and cancer cell survival. Therefore, we aimed to analyze the function of ATG9A in HBV replication using RNA interference to evaluate the HBV DNA level using real-time PCR. In the present study, there were no significant differences between shATG9A-transfected HepG2.2.15 cells and the mock control. However, we found that silencing ATG9A affected apoptosis in HepG2.2.15 and HepG2 cell lines. Our results indicated that ATG9A might be partly involved in the survival of HCC. Thus, the inhibition of ATG9A together with other targets might be a potential drug target for HCC treatment.
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Affiliation(s)
- Ingorn Kimkong
- Department of Microbiology, Faculty of Science, Kasetsart University, Center for Advanced Studies in Tropical Natural Resources, National Research University – Kasetsart University, Bangkok 10900, Thailand
| | - Areerat Kunanopparat
- Department of Microbiology, Center of Excellence in Immunology and Immune Mediated Diseases, Chulalongkorn University, Bangkok 10330, Thailand
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17
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Macrophage LC3-associated phagocytosis is an immune defense against Streptococcus pneumoniae that diminishes with host aging. Proc Natl Acad Sci U S A 2020; 117:33561-33569. [PMID: 33376222 PMCID: PMC7776987 DOI: 10.1073/pnas.2015368117] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Streptococcus pneumoniae is a leading cause of pneumonia and invasive disease, particularly, in the elderly. S. pneumoniae lung infection of aged mice is associated with high bacterial burdens and detrimental inflammatory responses. Macrophages can clear microorganisms and modulate inflammation through two distinct lysosomal trafficking pathways that involve 1A/1B-light chain 3 (LC3)-marked organelles, canonical autophagy, and LC3-associated phagocytosis (LAP). The S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers an autophagic response in nonphagocytic cells, but the role of LAP in macrophage defense against S. pneumoniae or in age-related susceptibility to infection is unexplored. We found that infection of murine bone-marrow-derived macrophages (BMDMs) by PLY-producing S. pneumoniae triggered Atg5- and Atg7-dependent recruitment of LC3 to S. pneumoniae-containing vesicles. The association of LC3 with S. pneumoniae-containing phagosomes required components specific for LAP, such as Rubicon and the NADPH oxidase, but not factors, such as Ulk1, FIP200, or Atg14, required specifically for canonical autophagy. In addition, S. pneumoniae was sequestered within single-membrane compartments indicative of LAP. Importantly, compared to BMDMs from young (2-mo-old) mice, BMDMs from aged (20- to 22-mo-old) mice infected with S. pneumoniae were not only deficient in LAP and bacterial killing, but also produced higher levels of proinflammatory cytokines. Inhibition of LAP enhanced S. pneumoniae survival and cytokine responses in BMDMs from young but not aged mice. Thus, LAP is an important innate immune defense employed by BMDMs to control S. pneumoniae infection and concomitant inflammation, one that diminishes with age and may contribute to age-related susceptibility to this important pathogen.
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18
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Cho SJ, Moon JS, Nikahira K, Yun HS, Harris R, Hong KS, Huang H, Choi AMK, Stout-Delgado H. GLUT1-dependent glycolysis regulates exacerbation of fibrosis via AIM2 inflammasome activation. Thorax 2020; 75:227-236. [PMID: 31822523 PMCID: PMC7063401 DOI: 10.1136/thoraxjnl-2019-213571] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 10/24/2019] [Accepted: 11/16/2019] [Indexed: 11/28/2022]
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a rapidly progressive, fatal lung disease that affects older adults. One of the detrimental natural histories of IPF is acute exacerbation of IPF (AE-IPF), of which bacterial infection is reported to play an important role. However, the mechanism by which bacterial infection modulates the fibrotic response remains unclear. OBJECTIVES Altered glucose metabolism has been implicated in the pathogenesis of fibrotic lung diseases. We have previously demonstrated that glucose transporter 1 (GLUT1)-dependent glycolysis regulates fibrogenesis in a murine fibrosis model. To expand on these findings, we hypothesised that GLUT1-dependent glycolysis regulates acute exacerbation of lung fibrogenesis during bacterial infection via AIM2 inflammasome activation. RESULTS In our current study, using a murine model of Streptococcus pneumoniae (S. pneumoniae) infection, we investigated the potential role of GLUT1 on mediating fibrotic responses to an acute exacerbation during bleomycin-induced fibrosis. The results of our current study illustrate that GLUT1 deficiency ameliorates S. pneumoniae-mediated exacerbation of lung fibrosis (wild type (WT)/phosphate buffered saline (PBS), n=3; WT/S. pneumoniae, n=3; WT/Bleomycin, n=5 ; WT/Bleomycin+S. pneumoniae, n=7; LysM-Cre-Glut1fl/f /PBS, n=3; LysM-Cre-Glut1fl/fl /S. pneumoniae, n=3; LysM-Cre-Glut1fl/fl /Bleomycin, n=6; LysM-Cre-Glut1fl/fl /Bleomycin+S. pneumoniae, n=9, p=0.041). Further, the AIM2 inflammasome, a multiprotein complex essential for sensing cytosolic bacterial DNA as a danger signal, is an important regulator of this GLUT1-mediated fibrosis and genetic deficiency of AIM2 reduced bleomycin-induced fibrosis after S. pneumoniae infection (WT/PBS, n=6; WT/Bleomycin+S. pneumoniae, n=15; Aim2-/-/PBS, n=6, Aim2-/-/Bleomycin+S. pneumoniae, n=11, p=0.034). GLUT1 deficiency reduced expression and function of the AIM2 inflammasome, and AIM2-deficient mice showed substantial reduction of lung fibrosis after S. pneumoniae infection. CONCLUSION Our results demonstrate that GLUT1-dependent glycolysis promotes exacerbation of lung fibrogenesis during S. pneumoniae infection via AIM2 inflammasome activation.
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Affiliation(s)
- Soo Jung Cho
- Medicine, Weill Cornell Medical College, New York City, New York, USA
| | - Jong-Seok Moon
- Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-bio Science (SIMS), Soon Chun Hyang University, Asan, Chungcheongnam-do, Korea
| | - Kiichi Nikahira
- Medicine, Weill Cornell Medical College, New York City, New York, USA
| | - Ha Seon Yun
- Medicine, Weill Cornell Medical College, New York City, New York, USA
| | - Rebecca Harris
- Medicine, Weill Cornell Medical College, New York City, New York, USA
| | - Kyung Sook Hong
- Medicine, Weill Cornell Medical College, New York City, New York, USA
| | - Huarong Huang
- Medicine, Weill Cornell Medical College, New York City, New York, USA
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19
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Wen Y, Li Z. The STING pathway in response to chlamydial infection. Microb Pathog 2019; 140:103950. [PMID: 31899324 DOI: 10.1016/j.micpath.2019.103950] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 12/10/2019] [Accepted: 12/23/2019] [Indexed: 02/08/2023]
Abstract
The past decades have witnessed significant progress in discovery and characterize cytosolic DNA sensing and signaling, especially the understanding of the stimulator of interferon genes (STING). This pathway to foreign nucleic acids enables the initiation of robust anti-pathogenic responses to protect the host, and provides a new understanding for therapeutic intervention in a growing infectious disease, including chlamydial infection. Chlamydiae are obligate intracellular pathogenic bacterium causing widespread human diseases such as sexually transmitted infections and respiratory tract infections. Previous studies have shown that IFN production and autophagy are well recognized as being two critical processes induced by STING, and these two processes were also activated during chlamydial infection. In this review, we summarize the important characteristics of the STING activation pathway and recent snapshots about the role of STING in chlamydial infection. Studying the role of STING in chlamydial infection could provide valuable information to further understand the pathogenesis and treatment of chlamydial infection.
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Affiliation(s)
- Yating Wen
- Institute of Pathogenic Biology, Hengyang Medical College, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, PR China
| | - Zhongyu Li
- Institute of Pathogenic Biology, Hengyang Medical College, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, PR China.
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20
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Vassilieva EV, Taylor DW, Compans RW. Combination of STING Pathway Agonist With Saponin Is an Effective Adjuvant in Immunosenescent Mice. Front Immunol 2019; 10:3006. [PMID: 31921219 PMCID: PMC6935580 DOI: 10.3389/fimmu.2019.03006] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 12/09/2019] [Indexed: 12/19/2022] Open
Abstract
There is an urgent need to improve protective responses to influenza vaccination in the elderly population, which is at especially high risk for adverse outcomes from influenza infection. Currently available inactivated vaccines provide limited protection, even when a 4-fold higher dose of the vaccine is administered. Adjuvants are often added to vaccines to boost protective efficacy. Here we describe a novel combination of an activator of the STING pathway, 2′,3′-cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) with a saponin adjuvant, that we found to be highly effective in boosting protective immunity from vaccination in an aged mouse model. Using this combination with a subunit influenza vaccine, we observed that survival of vaccinated 20 month-old mice after lethal challenge increased from 0 to 20% with unadjuvanted vaccine to 80–100%, depending on the vaccination route. Compared to unadjuvanted vaccine, the levels of vaccine-specific IgG and IgG2a increased by almost two orders of magnitude as early as 2 weeks after a single immunization with the adjuvanted formulation. By analyzing phosphorylation of interferon regulatory factor 3 (IRF3) in cell culture, we provide evidence that the saponin component increases access of exogenous cGAMP to the intracellular STING pathway. Our findings suggest that combining a STING activator with a saponin-based adjuvant increases the effectiveness of influenza vaccine in aged hosts, without having to increase dose or perform additional vaccinations. This study reports a novel adjuvant combination that (a) is more effective than current methods of boosting vaccine efficacy, (b) can be used to enhance efficacy of licensed influenza vaccines, and (c) results in effective protection using a single vaccine dose.
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Affiliation(s)
- Elena V Vassilieva
- Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, United States
| | - Dahnide W Taylor
- Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, United States
| | - Richard W Compans
- Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, United States
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21
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Ahn J, Barber GN. STING signaling and host defense against microbial infection. Exp Mol Med 2019; 51:1-10. [PMID: 31827069 PMCID: PMC6906460 DOI: 10.1038/s12276-019-0333-0] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 08/06/2019] [Accepted: 08/07/2019] [Indexed: 12/19/2022] Open
Abstract
The first line of host defense against infectious agents involves activation of innate immune signaling pathways that recognize specific pathogen-associated molecular patterns (PAMPs). Key triggers of innate immune signaling are now known to include microbial-specific nucleic acid, which is rapidly detected in the cytosol of the cell. For example, RIG-I-like receptors (RLRs) have evolved to detect viral RNA species and to activate the production of host defense molecules and cytokines that stimulate adaptive immune responses. In addition, host defense countermeasures, including the production of type I interferons (IFNs), can also be triggered by microbial DNA from bacteria, viruses and perhaps parasites and are regulated by the cytosolic sensor, stimulator of interferon genes (STING). STING-dependent signaling is initiated by cyclic dinucleotides (CDNs) generated by intracellular bacteria following infection. CDNs can also be synthesized by a cellular synthase, cGAS, following interaction with invasive cytosolic self-DNA or microbial DNA species. The importance of STING signaling in host defense is evident since numerous pathogens have developed strategies to prevent STING function. Here, we review the relevance of STING-controlled innate immune signaling in host defense against pathogen invasion, including microbial endeavors to subvert this critical process.
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Affiliation(s)
- Jeonghyun Ahn
- Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Glen N Barber
- Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
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22
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Sprooten J, Garg AD. Type I interferons and endoplasmic reticulum stress in health and disease. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2019; 350:63-118. [PMID: 32138904 PMCID: PMC7104985 DOI: 10.1016/bs.ircmb.2019.10.004] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Type I interferons (IFNs) comprise of pro-inflammatory cytokines created, as well as sensed, by all nucleated cells with the main objective of blocking pathogens-driven infections. Owing to this broad range of influence, type I IFNs also exhibit critical functions in many sterile inflammatory diseases and immunopathologies, especially those associated with endoplasmic reticulum (ER) stress-driven signaling pathways. Indeed, over the years accumulating evidence has indicated that the presence of ER stress can influence the production, or sensing of, type I IFNs induced by perturbations like pattern recognition receptor (PRR) agonists, infections (bacterial, viral or parasitic) or autoimmunity. In this article we discuss the link between type I IFNs and ER stress in various diseased contexts. We describe how ER stress regulates type I IFNs production or sensing, or how type I IFNs may induce ER stress, in various circumstances like microbial infections, autoimmunity, diabetes, cancer and other ER stress-related contexts.
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Affiliation(s)
- Jenny Sprooten
- Department for Cellular and Molecular Medicine, Cell Death Research & Therapy (CDRT) Unit, KU Leuven, Leuven, Belgium
| | - Abhishek D Garg
- Department for Cellular and Molecular Medicine, Cell Death Research & Therapy (CDRT) Unit, KU Leuven, Leuven, Belgium.
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23
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Cui X, Zhang R, Cen S, Zhou J. STING modulators: Predictive significance in drug discovery. Eur J Med Chem 2019; 182:111591. [PMID: 31419779 PMCID: PMC7172983 DOI: 10.1016/j.ejmech.2019.111591] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 07/10/2019] [Accepted: 08/05/2019] [Indexed: 12/19/2022]
Abstract
Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) - stimulator of interferon genes (STING) signaling pathway plays the critical role in the immune response to DNA. Pharmacological modulation of the STING pathway has been well characterized both from structural and functional perspectives, which paves the way for the drug design of small modulators by medicinal chemists. Here, we outline recent progress in studies on the STING pathway, the structure and biological function of STING, the STING related disease, as well as the rationale and progress in the development of STING modulators. Our review demonstrates that STING is a promising drug target, and providing clues for the discovery of novel STING agonists and antagonists for the potential treatment of various disease including microbial infectious diseases, cancer, and autoimmune disease.
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Affiliation(s)
- Xiangling Cui
- Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua, 321004, PR China,Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China
| | - Rongyu Zhang
- Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua, 321004, PR China,Drug Development and Innovation Center, College of Chemistry and Life Sciences, Zhejiang Normal University, 688 Yingbin Road, Jinhua, 321004, PR China
| | - Shan Cen
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China
| | - Jinming Zhou
- Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua, 321004, PR China; Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China; Drug Development and Innovation Center, College of Chemistry and Life Sciences, Zhejiang Normal University, 688 Yingbin Road, Jinhua, 321004, PR China.
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24
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Hu X, Peng X, Lu C, Zhang X, Gan L, Gao Y, Yang S, Xu W, Wang J, Yin Y, Wang H. Type I
IFN
expression is stimulated by cytosolic Mt
DNA
released from pneumolysin‐damaged mitochondria via the
STING
signaling pathway in macrophages. FEBS J 2019; 286:4754-4768. [DOI: 10.1111/febs.15001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 03/08/2019] [Accepted: 07/13/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Xuexue Hu
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education Chongqing Medical University China
- School of Laboratory Medicine Chongqing Medical University China
| | - Xiaoqiong Peng
- Department of Ultrasound The First Affiliated Hospital of Chongqing Medical University China
| | - Chang Lu
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education Chongqing Medical University China
- School of Laboratory Medicine Chongqing Medical University China
| | - Xuemei Zhang
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education Chongqing Medical University China
- School of Laboratory Medicine Chongqing Medical University China
| | - Lingling Gan
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education Chongqing Medical University China
- School of Laboratory Medicine Chongqing Medical University China
| | - Yue Gao
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education Chongqing Medical University China
- School of Laboratory Medicine Chongqing Medical University China
| | - Shenghui Yang
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education Chongqing Medical University China
- School of Laboratory Medicine Chongqing Medical University China
| | - Wenchun Xu
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education Chongqing Medical University China
- School of Laboratory Medicine Chongqing Medical University China
| | - Jian Wang
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education Chongqing Medical University China
- School of Laboratory Medicine Chongqing Medical University China
| | - Yibing Yin
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education Chongqing Medical University China
- School of Laboratory Medicine Chongqing Medical University China
| | - Hong Wang
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education Chongqing Medical University China
- School of Laboratory Medicine Chongqing Medical University China
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25
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Mathavarajah S, Salsman J, Dellaire G. An emerging role for calcium signalling in innate and autoimmunity via the cGAS-STING axis. Cytokine Growth Factor Rev 2019; 50:43-51. [PMID: 30955997 DOI: 10.1016/j.cytogfr.2019.04.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 04/01/2019] [Indexed: 12/18/2022]
Abstract
Type I interferons are effector cytokines essential for the regulation of the innate immunity. A key effector of the type I interferon response that is dysregulated in autoimmunity and cancer is the cGAS-STING signalling axis. Recent work suggests that calcium and associated signalling proteins can regulate both cGAS-STING and autoimmunity. How calcium regulates STING activation is complex and involves both stimulatory and inhibitory mechanisms. One of these is calmodulin-mediated signalling that is necessary for STING activation. The alterations in calcium flux that occur during STING activation can also regulate autophagy, which in turn plays a role in innate immunity through the clearance of intracellular pathogens. Also connected to calcium signalling pathways is the cGAS inhibitor TREX1, a cytoplasmic exonuclease linked to several autoimmune diseases including systemic lupus erythematosus (SLE). In this review, we summarize these and other findings that indicate a regulatory role for calcium signalling in innate and autoimmunity through the cGAS-STING pathway.
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Affiliation(s)
| | - Jayme Salsman
- Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Graham Dellaire
- Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada; Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada.
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26
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Plataki M, Cho SJ, Harris RM, Huang HR, Yun HS, Schiffer KT, Stout-Delgado HW. Mitochondrial Dysfunction in Aged Macrophages and Lung during Primary Streptococcus pneumoniae Infection is Improved with Pirfenidone. Sci Rep 2019; 9:971. [PMID: 30700745 PMCID: PMC6353918 DOI: 10.1038/s41598-018-37438-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 12/04/2018] [Indexed: 02/07/2023] Open
Abstract
Pneumococcal infections remain a leading cause of death in older adults, with the most serious cases occurring in persons ≥65 years of age. There is an urgent need to investigate molecular pathways underlying these impairments and devise new therapeutics to modulate innate immunity. The goal of our current study is to understand the impact of chronological aging on mitochondrial function in response to Streptococcus pneumoniae, a causative agent of bacterial pneumonia. Using chronologically aged murine models, our findings demonstrate that decreased ATP production is associated with dysregulated mitochondrial complex expression, enhanced oxidative stress, diminished antioxidant responses, and decreased numbers of healthy mitochondria in aged adult macrophages and lung in response to S. pneumoniae. Pre-treatment of aged macrophages with pirfenidone, an anti-fibrotic drug with antioxidant and anti-inflammatory properties, improved mitochondrial function and decreased cellular oxidative stress responses. In vivo administration of pirfenidone decreased superoxide formation, increased healthy mitochondria number, improved ATP production, and decreased inflammatory cell recruitment and pulmonary oedema in aged mouse lung during infection. Taken together, our data shed light on the susceptibility of older persons to S. pneumoniae and provide a possible therapeutic to improve mitochondrial responses in this population.
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Affiliation(s)
- Maria Plataki
- Department of Medicine, Pulmonary and Critical Care, Weill Cornell Medicine, New York, NY, USA
| | - Soo Jung Cho
- Department of Medicine, Pulmonary and Critical Care, Weill Cornell Medicine, New York, NY, USA
| | - Rebecca M Harris
- Department of Medicine, Pulmonary and Critical Care, Weill Cornell Medicine, New York, NY, USA
| | - Hua-Rong Huang
- Department of Medicine, Pulmonary and Critical Care, Weill Cornell Medicine, New York, NY, USA
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ha Seon Yun
- Department of Medicine, Pulmonary and Critical Care, Weill Cornell Medicine, New York, NY, USA
| | - Kristen T Schiffer
- Department of Medicine, Pulmonary and Critical Care, Weill Cornell Medicine, New York, NY, USA
| | - Heather W Stout-Delgado
- Department of Medicine, Pulmonary and Critical Care, Weill Cornell Medicine, New York, NY, USA.
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27
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Age-related changes in the levels and kinetics of pulmonary cytokine and chemokine responses to Streptococcuspneumoniae in mouse pneumonia models. Cytokine 2018; 111:389-397. [PMID: 30463053 DOI: 10.1016/j.cyto.2018.09.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 09/17/2018] [Accepted: 09/18/2018] [Indexed: 11/20/2022]
Abstract
Streptococcuspneumoniae is a major human pathogen at the extremes of age. The elderly are particularly vulnerable to S.pneumoniae, the most common causative agent of bacterial pneumonia in this population. Despite the availability of vaccines and antibiotics, mortality rates associated with pneumococcal pneumonia in this age group remain high. In light of globally increasing life-expectancy, a better understanding of the patho-mechanisms of elderly pneumococcal pneumonia, including alterations in innate immune responses, is needed to develop improved therapies. In this study we aimed at investigating how increased susceptibility to pneumococcal infection relates to inflammation kinetics in the aged mouse pneumonia model by determining pulmonary cytokine and chemokine levels and comparing these parameters to those measured in young adult mice. Firstly, we detected overall higher pulmonary cytokine and chemokine levels in aged mice. However, upon induction of pneumococcal pneumonia in aged mice, delayed production of certain analytes, such as IFN-γ, MIG (CXCL9), IP-10 (CXCL10), MCP-1 (CCL2), TARC (CCL17) and MDC (CCL22) became apparent. In addition, aged mice were unable to control excess inflammatory responses: while young mice showed peak inflammatory responses at 20 h and subsequent resolution by 48 h post intranasal challenge, in aged mice increasing cytokine and chemokine levels were measured. These findings highlight the importance of considering multiple time points when delineating inflammatory responses to S.pneumoniae in an age-related context. Finally, correlation between pulmonary bacterial burden and cytokine or chemokine levels in young mice suggested that appropriately controlled inflammatory responses support the host to fight pneumococcal infection.
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28
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Cho SJ, Plataki M, Mitzel D, Lowry G, Rooney K, Stout-Delgado H. Decreased NLRP3 inflammasome expression in aged lung may contribute to increased susceptibility to secondary Streptococcus pneumoniae infection. Exp Gerontol 2018; 105:40-46. [PMID: 29203400 PMCID: PMC5869149 DOI: 10.1016/j.exger.2017.11.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Revised: 11/17/2017] [Accepted: 11/20/2017] [Indexed: 11/24/2022]
Abstract
Post-viral pneumococcal pneumonia is a leading morbidity and mortality in older patients (≥65years of age). The goal of our current study is to understand the impact of chronological aging on innate immune responses to a secondary, post viral infection with Streptococcus pneumoniae, a causative agent of bacterial pneumonia. Using aged murine models of infection, our findings demonstrate increased morbidity and mortality in aged mice within 48h post-secondary S. pneumoniae infection. Increased susceptibility of aged mice was associated with decreased TLR1, TLR6, and TLR9 mRNA expression and diminished IL1β mRNA expression. Examination of NLRP3 inflammasome expression illustrated decreased NLRP3 mRNA expression and decreased IL1β production in aged lung in response to secondary S. pneumoniae infection.
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Affiliation(s)
- Soo Jung Cho
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, NY, United States
| | - Maria Plataki
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, NY, United States
| | - Dana Mitzel
- Lovelace Respiratory Research Institute, Albuquerque, NM, United States
| | - Gena Lowry
- Lovelace Respiratory Research Institute, Albuquerque, NM, United States
| | - Kristen Rooney
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, NY, United States
| | - Heather Stout-Delgado
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, NY, United States.
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29
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Cho SJ, Rooney K, Choi AMK, Stout-Delgado HW. NLRP3 inflammasome activation in aged macrophages is diminished during Streptococcus pneumoniae infection. Am J Physiol Lung Cell Mol Physiol 2018; 314:L372-L387. [PMID: 29097427 PMCID: PMC5900358 DOI: 10.1152/ajplung.00393.2017] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 10/17/2017] [Accepted: 10/17/2017] [Indexed: 11/22/2022] Open
Abstract
Pneumococcal infections are the eigth leading cause of death in the United States, and it is estimated that older patients (≥65 yr of age) account for the most serious cases. The goal of our current study is to understand the impact of biological aging on innate immune responses to Streptococcus pneumoniae, a causative agent of bacterial pneumonia. With the use of in vitro and in vivo aged murine models, our findings demonstrate that age-enhanced unfolded protein responses (UPRs) contribute to diminished inflammasome assembly and activation during S. pneumoniae infection. Pretreatment of aged mice with endoplasmic reticulum chaperone and the stress-reducing agent tauroursodeoxycholic acid (TUDCA) decreased mortality in aged hosts that was associated with increased NLRP3 inflammasome activation, improved pathogen clearance, and decreased pneumonitis during infection. Taken together, our data provide new evidence as to why older persons are more susceptible to S. pneumoniae and provide a possible therapeutic target to decrease morbidity and mortality in this population.
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Affiliation(s)
- Soo Jung Cho
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine , New York, New York
| | - Kristen Rooney
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine , New York, New York
| | - Augustine M K Choi
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine , New York, New York
| | - Heather W Stout-Delgado
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine , New York, New York
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30
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Marinho FV, Benmerzoug S, Oliveira SC, Ryffel B, Quesniaux VFJ. The Emerging Roles of STING in Bacterial Infections. Trends Microbiol 2017. [PMID: 28625530 DOI: 10.1016/j.tim.2017.05.008] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The STING (Stimulator of Interferon Genes) protein connects microorganism cytosolic sensing with effector functions of the host cell by sensing directly cyclic dinucleotides (CDNs), originating from pathogens or from the host upon DNA recognition. Although STING activation favors effective immune responses against viral infections, its role during bacterial diseases is controversial, ranging from protective to detrimental effects for the host. In this review, we summarize important features of the STING activation pathway and recent highlights about the role of STING in bacterial infections by Chlamydia, Listeria, Francisella, Brucella, Shigella, Salmonella, Streptococcus, and Neisseria genera, with a special focus on mycobacteria.
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Affiliation(s)
- Fabio V Marinho
- CNRS, UMR7355, Orleans, France; Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Sulayman Benmerzoug
- CNRS, UMR7355, Orleans, France; Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Sergio C Oliveira
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Bernhard Ryffel
- CNRS, UMR7355, Orleans, France; Experimental and Molecular Immunology and Neurogenetics, University of Orleans, France
| | - V F J Quesniaux
- CNRS, UMR7355, Orleans, France; Experimental and Molecular Immunology and Neurogenetics, University of Orleans, France.
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31
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Intact Pneumococci Trigger Transcription of Interferon-Related Genes in Human Monocytes, while Fragmented, Autolyzed Bacteria Subvert This Response. Infect Immun 2017; 85:IAI.00960-16. [PMID: 28223347 DOI: 10.1128/iai.00960-16] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 02/08/2017] [Indexed: 12/11/2022] Open
Abstract
A peculiar trait of pneumococci (Streptococcus pneumoniae) is their propensity to undergo spontaneous lysis during stationary growth due to activation of the enzyme autolysin (LytA), which fragments the peptidoglycan cell wall. The fragments that are generated upon autolysis impair phagocytosis and reduce production of interleukin-12 (IL-12) and gamma interferon (IFN-γ) by human leukocytes in response to intact pneumococci, thereby impeding crucial host defenses. The objective was to identify additional monocyte genes whose transcription is induced by intact pneumococci and subverted by autolyzed bacteria. Monocytes were isolated from healthy blood donors and stimulated for 3 h with UV-inactivated S. pneumoniae (Rx1PLY- LytA+ strain), which is capable of autolyzing, its LytA- isogenic autolysin-deficient mutant, or a mixture of the two (containing twice the initial bacterial concentration). Gene expression was assessed by Illumina microarray, and selected findings were confirmed by reverse transcription-quantitative real-time PCR (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and flow cytometry. In all, we identified 121 genes that were upregulated to a significantly higher degree by intact than autolyzed pneumococci. These included IFNB1 and a large set of interferon-induced genes, such as IFIT3, RSAD2, CFCL1, and CXCL10 genes, as well as IL12B and CD40 genes. RT-qPCR revealed that transcription of these genes in response to intact pneumococci diminished when autolyzed pneumococci were admixed and that this pattern was independent of pneumolysin. Thus, transcription of interferon-related genes is triggered by intact pneumococci and subverted by fragments generated by spontaneous bacterial autolysis. We suggest that interferon-related pathways are important for elimination of pneumococci and that autolysis contributes to virulence by extinguishing these pathways.
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32
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Kim JA, Seong RK, Shin OS. Enhanced Viral Replication by Cellular Replicative Senescence. Immune Netw 2016; 16:286-295. [PMID: 27799874 PMCID: PMC5086453 DOI: 10.4110/in.2016.16.5.286] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2016] [Revised: 10/11/2016] [Accepted: 10/13/2016] [Indexed: 12/30/2022] Open
Abstract
Cellular replicative senescence is a major contributing factor to aging and to the development and progression of aging-associated diseases. In this study, we sought to determine viral replication efficiency of influenza virus (IFV) and Varicella Zoster Virus (VZV) infection in senescent cells. Primary human bronchial epithelial cells (HBE) or human dermal fibroblasts (HDF) were allowed to undergo numbers of passages to induce replicative senescence. Induction of replicative senescence in cells was validated by positive senescence-associated β-galactosidase staining. Increased susceptibility to both IFV and VZV infection was observed in senescent HBE and HDF cells, respectively, resulting in higher numbers of plaque formation, along with the upregulation of major viral antigen expression than that in the non-senescent cells. Interestingly, mRNA fold induction level of virus-induced type I interferon (IFN) was attenuated by senescence, whereas IFN-mediated antiviral effect remained robust and potent in virus-infected senescent cells. Additionally, we show that a longevity-promoting gene, sirtuin 1 (SIRT1), has antiviral role against influenza virus infection. In conclusion, our data indicate that enhanced viral replication by cellular senescence could be due to senescence-mediated reduction of virus-induced type I IFN expression.
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Affiliation(s)
- Ji-Ae Kim
- Brain Korea 21 Plus for Biomedical Science, College of Medicine, Korea University, Seoul 08308, Korea
| | - Rak-Kyun Seong
- Brain Korea 21 Plus for Biomedical Science, College of Medicine, Korea University, Seoul 08308, Korea
| | - Ok Sarah Shin
- Brain Korea 21 Plus for Biomedical Science, College of Medicine, Korea University, Seoul 08308, Korea
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Kim JA, Park SK, Kumar M, Lee CH, Shin OS. Insights into the role of immunosenescence during varicella zoster virus infection (shingles) in the aging cell model. Oncotarget 2016; 6:35324-43. [PMID: 26473290 PMCID: PMC4742108 DOI: 10.18632/oncotarget.6117] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Accepted: 09/25/2015] [Indexed: 12/11/2022] Open
Abstract
Varicella zoster virus (VZV) is the etiological agent of shingles, a painful skin rash that affects a significant proportion of the elderly population. In the present study, we used two aging cell models, Hutchinson-Gilford progeria syndrome (HGPS) fibroblasts and stress or replicative senescence-induced normal human dermal fibroblasts (NHDFs), to investigate age-associated susceptibility to VZV infection. VZV infectivity titers were significantly associated with donor age in HGPS fibroblasts and senescence induction in NHDFs. High throughput RNA-sequencing (RNA-seq) analysis was performed to assess global and dynamic changes in the host transcriptomes of VZV-infected aging cells. Analysis of differentially expressed genes (DEGs) indicated that VZV infection in aged HGPS fibroblasts resembled that in senescent NHDFs, particularly in terms of genes associated with pattern recognition receptors in virus sensing network, providing novel insights into the mechanisms of senescence-associated susceptibility to VZV infection. Additionally, we identified stimulator of interferon genes (STING) as a potential VZV sensing receptor. Knockdown of STING expression resulted in increased viral replication in primary fibroblasts, whereas STING overexpression led to suppression of VZV plaque formation. In conclusion, our findings highlight the important role of immunosenescence following VZV infection and provide significant insights into the mechanisms underlying cellular sensing of VZV infection and the induction of immune responses in aged skin cells.
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Affiliation(s)
- Ji-Ae Kim
- Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Seul-Ki Park
- Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Mukesh Kumar
- Department of Tropical Medicine, Medical Microbiology and Pharmacology, Pacific Center for Emerging Infectious Diseases Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, USA
| | - Chan-Hee Lee
- Department of Microbiology, Chungbuk National University, Cheongju, Republic of Korea
| | - Ok Sarah Shin
- Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, Republic of Korea.,Department of Microbiology, College of Medicine, Korea University, Seoul, Republic of Korea
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Tao J, Zhou X, Jiang Z. cGAS-cGAMP-STING: The three musketeers of cytosolic DNA sensing and signaling. IUBMB Life 2016; 68:858-870. [PMID: 27706894 DOI: 10.1002/iub.1566] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Accepted: 09/11/2016] [Indexed: 12/19/2022]
Abstract
Innate immunity is the first line of host defense against invading pathogens. The detection of aberrant nucleic acids which represent some conserved PAMPs triggers robust type I IFN-mediated innate immune responses. Host- or pathogen-derived cytosolic DNA binds and activates the DNA sensor cGAS, which synthesizes the second messenger 2'3'-cGAMP and triggers STING-dependent downstream signaling. Here, we highlight recent progress in cGAS-cGAMP-STING, the Three Musketeers of cytosolic DNA sensing and signaling, and their essential roles in infection, autoimmune diseases, and cancer. We also focus on the regulation of these critical signal components by variant host/pathogen proteins and update our understanding of this indispensable pathway to provide new insights for drug discovery. © 2016 IUBMB Life, 68(11):858-870, 2016.
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Affiliation(s)
- Jianli Tao
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.,Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Xiang Zhou
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.,Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Zhengfan Jiang
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China. .,Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China. .,Peking-Tsinghua Center for Life Sciences, Beijing, China.
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Abstract
Stimulator of interferon genes (STING) is activated by binding to cyclic dinucleotides (CDNs), which results in potent cytokine production. CDNs are produced by certain intracellular bacteria and are generated by the cyclic GMP–AMP synthase (cGAS) following binding to cytosolic DNA species, such as viral DNA. STING-inducible innate immune molecules are essential for protection of the host against pathogens and are important for the stimulation of adaptive immunity. Self-DNA, for example from the nucleus or mitochondria, can leak into the cytosolic compartment and stimulate STING activity to cause autoinflammatory disease. Certain mutations in the gene encoding STING can cause the protein to become permanently active and similarly induce autoinflammatory responses. STING can be activated in phagocytes by DNA released from engulfed tumour cells and drive the production of cytokines necessary for generating robust antitumour T cell responses. DNA-damaging agents can cause the release of nuclear DNA into the cytosol that stimulates STING-dependent cytokine production and phagocyte infiltration. This may be essential for eliminating damaged cells and generating antitumour T cell responses, but chronic stimulation may also promote inflammation-aggravated cancer. STING agonists exert potent antitumour activity and may be effective, novel adjuvants in vaccine formulations. In contrast, inhibitors of STING signalling may be beneficial for the treatment of autoinflammatory disease, such as systemic lupus erythematosus (SLE), Aicardi–Goutières syndrome (AGS) and STING-associated vasculopathy with onset in infancy (SAVI). Activation of STING (stimulator of interferon genes) by cytosolic aberrant DNA species or cyclic dinucleotides triggers transcription of numerous innate immune genes. In this Review, the author summarizes recent insights into the regulation of STING signalling and its role in autoinflammatory disease and cancer. The rapid detection of microbial agents is essential for the effective initiation of host defence mechanisms against infection. Understanding how cells detect cytosolic DNA to trigger innate immune gene transcription has important implications — not only for comprehending the immune response to pathogens but also for elucidating the causes of autoinflammatory disease involving the sensing of self-DNA and the generation of effective antitumour adaptive immunity. The discovery of the STING (stimulator of interferon genes)-controlled innate immune pathway, which mediates cytosolic DNA-induced signalling events, has recently provided important insights into these processes, opening the way for the development of novel immunization regimes, as well as therapies to treat autoinflammatory disease and cancer.
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Affiliation(s)
- Glen N Barber
- Department of Cell Biology and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida 33136, USA
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Functions of DNA damage machinery in the innate immune response to DNA virus infection. Curr Opin Virol 2015; 15:56-62. [PMID: 26318640 DOI: 10.1016/j.coviro.2015.08.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 08/01/2015] [Accepted: 08/05/2015] [Indexed: 12/22/2022]
Abstract
DNA is potently immunostimulatory, and self-DNA is packaged in the nucleus or mitochondria allowing it to remain silent to cell-intrinsic sensors. However, damaged or mislocalised self-DNA is sensed by our innate immune systems, resulting in the production of type I interferons (IFNI), chemokines and inflammatory cytokines. During DNA virus infection the detection of viral DNA genomes by pattern recognition receptors (PRRs) is essential for the initiation of IFNI responses and host defence against these pathogens. It is intriguing that a number of molecular mechanisms have been found to be common to both of these DNA-induced stress responses and this has potentially important consequences for both sides of the host/pathogen arms race.
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