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Han Q, Zhao H, Chen M, Xue W, Li J, Sun L, Shang Y. Retinol binding protein 4 restricts PCV2 replication via selective autophagy degradation of viral ORF1 protein. Commun Biol 2024; 7:1438. [PMID: 39500783 PMCID: PMC11538477 DOI: 10.1038/s42003-024-07052-1] [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: 03/18/2024] [Accepted: 10/11/2024] [Indexed: 11/08/2024] Open
Abstract
Autophagy is a highly conserved degradative process that has been linked to various functions, including defending host cells against pathogens. Although the involvement of autophagy in porcine circovirus 2 (PCV2) infection has become apparent, it remains unclear whether selective autophagy plays a critical role in PCV2 restriction. Here we show that retinol-binding protein 4 (RBP4), an adipokine for retinol carrier, initiates the autophagic degradation of PCV2 ORF1 protein. PCV2 infection increases RBP4 protein levels through MAPK-eIF4E axis in living cells. Ectopic expression of RBP4 or recombinant RBP4 treatment promotes the degradation of ORF1 protein. Mechanistically, RBP4 activates TRAF6 to induce K63-linked ubiquitination of ORF1, leading to SQSTM1/p62-mediated selective autophagy for degradation. Consequently, RBP4 deficiency increases viral loads and exacerbates the pathogenicity of PCV2 in vivo. Collectively, these results identify RBP4 as a key host restriction factor of PCV2 and reveal a previously undescribed antiviral mechanism against PCV2 in infected cells.
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Affiliation(s)
- Qingbing Han
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, Shandong, China
- Shandong Provincial Key Laboratory of Zoonoses, Shandong Agricultural University, Taian, Shandong, China
| | - Hejiao Zhao
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, Shandong, China
- Shandong Provincial Key Laboratory of Zoonoses, Shandong Agricultural University, Taian, Shandong, China
| | - Meng Chen
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, Shandong, China
- Shandong Provincial Key Laboratory of Zoonoses, Shandong Agricultural University, Taian, Shandong, China
| | - Wenshuo Xue
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, Shandong, China
- Shandong Provincial Key Laboratory of Zoonoses, Shandong Agricultural University, Taian, Shandong, China
| | - Jun Li
- Division of Swine Diseases, Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Lei Sun
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Yingli Shang
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, Shandong, China.
- Shandong Provincial Key Laboratory of Zoonoses, Shandong Agricultural University, Taian, Shandong, China.
- Institute of Immunology, Shandong Agricultural University, Taian, Shandong, China.
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2
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Zhuang C, Zhang R, Bai J, Zhang X, Zhao J. Lycopene promoted M2 macrophage polarization via inhibition of NOTCH1-PI3K-mTOR-NF-κB-JMJD3-IRF4 pathway in response to Escherichia coli infection in J744A.1 cells. Arch Microbiol 2024; 206:249. [PMID: 38713385 DOI: 10.1007/s00203-024-03971-z] [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: 02/25/2024] [Accepted: 04/21/2024] [Indexed: 05/08/2024]
Abstract
Escherichia coli (E. coli) can induce severe clinical bovine mastitis, which is to blame for large losses experienced by dairy farms. Macrophage polarization into various states is in response to pathogen infections. Lycopene, a naturally occurring hydrocarbon carotenoid, relieved inflammation by controlling M1/M2 status of macrophages. Thus, we wanted to explore the effect of lycopene on polarization states of macrophages in E. coli-induced mastitis. Macrophages were cultivated with lycopene for 24, before E. coli inoculation for 6 h. Lycopene (0.5 μmol/L) significantly enhanced cell viabilities and significantly reduced lactic dehydrogenase (LDH) levels in macrophages, whereas 2 and 3 μmol/L lycopene significantly enhanced LDH activities. Lycopene treatment significantly reduced the increase in LDH release, iNOS, CD86, TNF-α, IL-1β and phosphatase and tensin homolog (PTEN) expressions in E. coli group. 0.5 μmol/L lycopene significantly increased E. coli-induced downregulation of CD206, arginase I (ARG1), indoleamine 2,3-dioxygenase (IDO), chitinase 3-like 3 (YM1), PI3K, AKT, p-AKT, mammalian target of rapamycin (mTOR), p-mTOR, jumonji domain-containing protein-3 (JMJD3) and interferon regulatory factor 4 (IRF4) levels. Moreover, Ginkgolic acid C17:1 (a specific PTEN inhibitor), 740YPDGFR (a specific PI3K activator), SC79 (a specific AKT activator) or CHPG sodium salt (a specific NF-κB activator) significantly decreased CD206, AGR1, IDO and YM1 expressions in lycopene and E. coli-treated macrophages. Therefore, lycopene increased M2 macrophages via inhibiting NOTCH1-PI3K-mTOR-NF-κB-JMJD3-IRF4 pathway in response to E. coli infection in macrophages. These results contribute to revealing the pathogenesis of E. coli-caused bovine mastitis, providing the new angle of the prevention and management of mastitis.
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Affiliation(s)
- Cuicui Zhuang
- College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, Shanxi, 030801, People's Republic of China.
| | - Ruoqing Zhang
- School of Chemistry and Material Science, Shanxi Normal University, Taiyuan, Shanxi, 030031, People's Republic of China
| | - Jiangang Bai
- College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, Shanxi, 030801, People's Republic of China
| | - Xinying Zhang
- College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, Shanxi, 030801, People's Republic of China
| | - Jinhui Zhao
- College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, Shanxi, 030801, People's Republic of China
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Dankaona W, Nooroong P, Poolsawat N, Piewbang C, Techangamsuwan S, Anuracpreeda P. Recombinant expression and characterization of Canine circovirus capsid protein for diagnosis. Front Vet Sci 2024; 11:1363524. [PMID: 38659451 PMCID: PMC11040689 DOI: 10.3389/fvets.2024.1363524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 03/22/2024] [Indexed: 04/26/2024] Open
Abstract
Canine circovirus (CanineCV) is a contagious virus that causes severe gastroenteritis, diarrhea, respiratory disease, and vasculitis, often resulting in fatality among infected dogs. In this study, a recombinant Capsid protein (rCap) of CanineCV was expressed in the Escherichia coli (E. coli) Rosetta (DE3) pLysS host cell, followed by affinity purification, and then analyzed by SDS-PAGE, revealing a molecular weight of approximately 31 kDa. The antigenicity of the CanineCV rCap protein was confirmed through recognition by a rabbit anti-CanineCV rCap protein polyclonal antibody (PoAb). Additionally, the reactivity and specificity of this PoAb were assessed using indirect enzyme-linked immunosorbent assay (ELISA) and Western blot analysis before applying in an immunohistochemistry (IHC), namely, immunoperoxidase detection. The immunoperoxidase assay using rabbit anti-CanineCV rCap protein PoAb demonstrated that the CanineCV Cap protein was predominantly located in immune cells, especially lymphocytes and macrophages, within the spleen, lung, tracheobronchial lymph nodes, small intestine, and kidney. Similarly, the Cap protein was also found in pneumocytes in the lung and renal tubular epithelial cells in the kidney. These findings reflected the biological activity and cell tropism of the virus. Therefore, the recombinant Cap protein and its PoAb could be used for the development of a valuable diagnostic tool for CanineCV detection.
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Affiliation(s)
- Wichan Dankaona
- Department of Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
- Animal Virome and Diagnostic Development Research Unit, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
- Parasitology Research Laboratory (PRL), Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
| | - Pornpiroon Nooroong
- Parasitology Research Laboratory (PRL), Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
| | - Napassorn Poolsawat
- Parasitology Research Laboratory (PRL), Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
| | - Chutchai Piewbang
- Department of Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
- Animal Virome and Diagnostic Development Research Unit, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| | - Somporn Techangamsuwan
- Department of Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
- Animal Virome and Diagnostic Development Research Unit, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| | - Panat Anuracpreeda
- Parasitology Research Laboratory (PRL), Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
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Wang X, Hao G, Zhou M, Chen M, Ling H, Shang Y. Secondary metabolites of Bacillus subtilis L2 show antiviral activity against pseudorabies virus. Front Microbiol 2023; 14:1277782. [PMID: 37965547 PMCID: PMC10642297 DOI: 10.3389/fmicb.2023.1277782] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 10/13/2023] [Indexed: 11/16/2023] Open
Abstract
Bacillus subtilis (B. subtilis) is a commercially important probiotic known to produce secondary metabolites with antibacterial, antifungal and anti-inflammatory activities. However, the potential ability of B. subtilis to combat viruses, especially DNA viruses, has not been extensively investigated. In this study, we identified two distinct B. subtilis strains and examined the efficiency of their secondary metabolites against pseudorabies virus (PRV), a swine herpesvirus resulting in economic losses worldwide. We found that treatment with the secondary metabolites of B. subtilis L2, but not the metabolites of B. subtilis V11, significantly inhibited PRV replication in multiple cells. Notably, the antiviral activity of the metabolites of B. subtilis L2 was thermal stable, resistant to protease digestion. Moreover, these metabolites effectively impeded PRV binding, entry and replication. Importantly, oral administration of the metabolites of B. subtilis L2 protected mice from lethal PRV infection, rescuing weight loss and reducing the viral load in vivo. In summary, our results reveal that the metabolites of B. subtilis L2 exhibit anti-PRV activity both in vitro and in vivo, providing a potential candidate for novel antiviral drugs.
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Affiliation(s)
- Xiaoli Wang
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, China
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, China
| | - Guijuan Hao
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, China
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, China
| | - Meng Zhou
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, China
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, China
| | - Meng Chen
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, China
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, China
| | | | - Yingli Shang
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, China
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, China
- Institute of Immunology, Shandong Agricultural University, Taian, China
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5
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KDM6B promotes gastric carcinogenesis and metastasis via upregulation of CXCR4 expression. Cell Death Dis 2022; 13:1068. [PMID: 36564369 PMCID: PMC9789124 DOI: 10.1038/s41419-022-05458-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 11/17/2022] [Accepted: 11/18/2022] [Indexed: 12/24/2022]
Abstract
KDM6B (Lysine-specific demethylase 6B) is a histone lysine demethyltransferase that plays a key role in many types of cancers. However, its potential role in gastric cancer (GC) remains unclear. Here, we focused on the clinical significance and potential role of KDM6B in GC. We found that the KDM6B expression is upregulated in GC tissues and that its high expression in patients is related to poor prognosis. KDM6B ectopic expression promotes GC cells' proliferation and metastasis, while its inhibition has opposite effects in vitro and in vivo. Mechanistically, KDM6B promotes GC cells proliferation and metastasis through its enzymatic activity through the induction of H3K27me3 demethylation near the CXCR4 (C-X-C chemokine receptor type 4) promoter region, resulting in the upregulation of CXCR4 expression. Furthermore, H. pylori was found to induce KDM6B expression. In conclusion, our results suggest that KDM6B is aberrantly expressed in GC and plays a key role in gastric carcinogenesis and metastasis through CXCR4 upregulation. Our work also suggests that KDM6B may be a potential oncogenic factor and a therapeutic target for GC.
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Liu ZH, Deng ZF, Lu Y, Fang WH, He F. A modular and self-adjuvanted multivalent vaccine platform based on porcine circovirus virus-like nanoparticles. J Nanobiotechnology 2022; 20:493. [PMID: 36424615 PMCID: PMC9685936 DOI: 10.1186/s12951-022-01710-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 11/15/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Virus-like particles (VLPs) are supramolecular structures composed of multiple protein subunits and resemble natural virus particles in structure and size, making them highly immunogenic materials for the development of next-generation subunit vaccines. The orderly and repetitive display of antigenic epitopes on particle surface allows efficient recognition and cross-link by B cell receptors (BCRs), thereby inducing higher levels of neutralizing antibodies and cellular immune responses than regular subunit vaccines. Here, we present a novel multiple antigen delivery system using SpyCatcher/Spytag strategy and self-assembled VLPs formed by porcine circovirus type 2 (PCV2) Cap, a widely used swine vaccine in solo. RESULTS Cap-SC, recombinant Cap with a truncated SpyCatcher polypeptide at its C-terminal, self-assembled into 26-nm VLPs. Based on isopeptide bonds formed between SpyCatcher and SpyTag, classical swine fever virus (CSFV) E2, the antigen of interest, was linked to SpyTag and readily surface-displayed on SpyCatcher decorated Cap-SC via in vitro covalent conjugation. E2-conjugated Cap VLPs (Cap-E2 NPs) could be preferentially captured by antigen presenting cells (APCs) and effectively stimulate APC maturation and cytokine production. In vivo studies confirmed that Cap-E2 NPs elicited an enhanced E2 specific IgG response, which was significantly higher than soluble E2, or the admixture of Cap VLPs and E2. Moreover, E2 displayed on the surface did not mask the immunodominant epitopes of Cap-SC VLPs, and Cap-E2 NPs induced Cap-specific antibody levels and neutralizing antibody levels comparable to native Cap VLPs. CONCLUSION These results demonstrate that this modularly assembled Cap-E2 NPs retains the immune potential of Cap VLP backbone, while the surface-displayed antigen significantly elevated E2-induced immune potency. This immune strategy provides distinctly improved efficacy than conventional vaccine combination. It can be further applied to the development of dual or multiple nanoparticle vaccines to prevent co-infection of PCV2 and other swine pathogens.
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Affiliation(s)
- Ze-Hui Liu
- grid.13402.340000 0004 1759 700XInstitute of Preventive Veterinary Medicine, Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, 866 Yuhangtang road, 310058 Hangzhou, China
| | - Zhuo-Fan Deng
- grid.13402.340000 0004 1759 700XInstitute of Preventive Veterinary Medicine, Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, 866 Yuhangtang road, 310058 Hangzhou, China
| | - Ying Lu
- grid.13402.340000 0004 1759 700XInstitute of Preventive Veterinary Medicine, Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, 866 Yuhangtang road, 310058 Hangzhou, China
| | - Wei-Huan Fang
- grid.13402.340000 0004 1759 700XInstitute of Preventive Veterinary Medicine, Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, 866 Yuhangtang road, 310058 Hangzhou, China ,grid.13402.340000 0004 1759 700XLaboratory of Animal Virology of Ministry of Agriculture, Zhejiang University, 310058 Hangzhou, China
| | - Fang He
- grid.13402.340000 0004 1759 700XInstitute of Preventive Veterinary Medicine, Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, 866 Yuhangtang road, 310058 Hangzhou, China ,grid.13402.340000 0004 1759 700XLaboratory of Animal Virology of Ministry of Agriculture, Zhejiang University, 310058 Hangzhou, China
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Zhao N, Wang F, Kong Z, Shang Y. Pseudorabies Virus Tegument Protein UL13 Suppresses RLR-Mediated Antiviral Innate Immunity through Regulating Receptor Transcription. Viruses 2022; 14:1465. [PMID: 35891444 PMCID: PMC9317333 DOI: 10.3390/v14071465] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/30/2022] [Accepted: 06/30/2022] [Indexed: 11/17/2022] Open
Abstract
Pseudorabies virus (PRV) has evolved various strategies to escape host antiviral immune responses. However, it remains unclear whether and how PRV-encoded proteins modulate the RIG-I-like receptor (RLR)-mediated signals for immune evasion. Here, we show that the PRV tegument protein UL13 functions as an antagonist of RLR-mediated antiviral responses via suppression of the transcription of RIG-I and MDA5, but not LGP2. UL13 overexpression significantly inhibits both the mRNA and protein levels of RIG-I and MDA5, along with RIG-I- or MDA5-mediated antiviral immune responses, whereas overexpression of RIG-I or MDA5 counteracts such UL13-induced suppression. Mechanistically, UL13 suppresses the expression of RIG-I and MDA5 by inhibiting activation of the transcription factor NF-κB. Consequently, overexpression of p65 promotes the activation of RIG-I and MDA5 promoters. Moreover, deletion of the p65-binding sites in the promoters of RIG-I or MDA5 abolishes the suppression role of UL13. As a result, mutant PRV lacking UL13 elicits stronger host antiviral immune responses than PRV-WT. Hence, our results provide a novel functional role of UL13-induced suppression of host antiviral immunity through modulating receptors' transcription.
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Affiliation(s)
- Ningning Zhao
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian 271018, China; (N.Z.); (F.W.); (Z.K.)
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian 271018, China
- Institute of Immunology, Shandong Agricultural University, Taian 271018, China
| | - Fan Wang
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian 271018, China; (N.Z.); (F.W.); (Z.K.)
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian 271018, China
| | - Zhengjie Kong
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian 271018, China; (N.Z.); (F.W.); (Z.K.)
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian 271018, China
| | - Yingli Shang
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian 271018, China; (N.Z.); (F.W.); (Z.K.)
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian 271018, China
- Institute of Immunology, Shandong Agricultural University, Taian 271018, China
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Yarani R, Shojaeian A, Palasca O, Doncheva NT, Jensen LJ, Gorodkin J, Pociot F. Differentially Expressed miRNAs in Ulcerative Colitis and Crohn’s Disease. Front Immunol 2022; 13:865777. [PMID: 35734163 PMCID: PMC9208551 DOI: 10.3389/fimmu.2022.865777] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 04/13/2022] [Indexed: 12/14/2022] Open
Abstract
Differential microRNA (miRNA or miR) regulation is linked to the development and progress of many diseases, including inflammatory bowel disease (IBD). It is well-established that miRNAs are involved in the differentiation, maturation, and functional control of immune cells. miRNAs modulate inflammatory cascades and affect the extracellular matrix, tight junctions, cellular hemostasis, and microbiota. This review summarizes current knowledge of differentially expressed miRNAs in mucosal tissues and peripheral blood of patients with ulcerative colitis and Crohn’s disease. We combined comprehensive literature curation with computational meta-analysis of publicly available high-throughput datasets to obtain a consensus set of miRNAs consistently differentially expressed in mucosal tissues. We further describe the role of the most relevant differentially expressed miRNAs in IBD, extract their potential targets involved in IBD, and highlight their diagnostic and therapeutic potential for future investigations.
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Affiliation(s)
- Reza Yarani
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, United States
- *Correspondence: Reza Yarani, ; Flemming Pociot,
| | - Ali Shojaeian
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Oana Palasca
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
- Center for Non-Coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nadezhda T. Doncheva
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
- Center for Non-Coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lars Juhl Jensen
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
- Center for Non-Coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark
| | - Jan Gorodkin
- Center for Non-Coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Flemming Pociot
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Center for Non-Coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark
- Copenhagen Diabetes Research Center, Department of Pediatrics, Herlev University Hospital, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- *Correspondence: Reza Yarani, ; Flemming Pociot,
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Kong Z, Yin H, Wang F, Liu Z, Luan X, Sun L, Liu W, Shang Y. Pseudorabies virus tegument protein UL13 recruits RNF5 to inhibit STING-mediated antiviral immunity. PLoS Pathog 2022; 18:e1010544. [PMID: 35584187 PMCID: PMC9154183 DOI: 10.1371/journal.ppat.1010544] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 05/31/2022] [Accepted: 04/22/2022] [Indexed: 12/21/2022] Open
Abstract
Pseudorabies virus (PRV) has evolved various immune evasion mechanisms that target host antiviral immune responses. However, it is unclear whether and how PRV encoded proteins modulate the cGAS-STING axis for immune evasion. Here, we show that PRV tegument protein UL13 inhibits STING-mediated antiviral signaling via regulation of STING stability. Mechanistically, UL13 interacts with the CDN domain of STING and recruits the E3 ligase RING-finger protein 5 (RNF5) to promote K27-/K29-linked ubiquitination and degradation of STING. Consequently, deficiency of RNF5 enhances host antiviral immune responses triggered by PRV infection. In addition, mutant PRV lacking UL13 impaired in antagonism of STING-mediated production of type I IFNs and shows attenuated pathogenicity in mice. Our findings suggest that PRV UL13 functions as an antagonist of IFN signaling via a novel mechanism by targeting STING to persistently evade host antiviral responses. Induction of type I interferons mediated by cGAS-STING axis is critical for host against DNA virus infection whereas herpesviruses employ multiple strategies to antagonize this signaling pathway for immune evasion. Herein, our findings provide strong evidence that PRV tegument protein UL13 functions as a suppressor of STING-mediated antiviral response via recruitment of E3 ligase RNF5 to induce K27-/K29-linked ubiquitination and degradation of STING. Therefore, our study reveals a novel evasion strategy of PRV against host defense and suggests UL13 could be a promising target for development of gene-deleted vaccine for pseudorabies.
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Affiliation(s)
- Zhengjie Kong
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, Shandong, China
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong, China
| | - Hongyan Yin
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, Shandong, China
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong, China
| | - Fan Wang
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, Shandong, China
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong, China
| | - Zhen Liu
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, Shandong, China
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong, China
| | - Xiaohan Luan
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Lei Sun
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Wenjun Liu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yingli Shang
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, Shandong, China
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong, China
- Institute of Immunology, Shandong Agricultural University, Taian, Shandong, China
- * E-mail:
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10
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Yu S, Ge H, Li S, Qiu HJ. Modulation of Macrophage Polarization by Viruses: Turning Off/On Host Antiviral Responses. Front Microbiol 2022; 13:839585. [PMID: 35222345 PMCID: PMC8874017 DOI: 10.3389/fmicb.2022.839585] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 01/12/2022] [Indexed: 11/17/2022] Open
Abstract
Macrophages are professional antigen-presenting cells and serve as the first line of defense against invading pathogens. Macrophages are polarized toward the proinflammatory classical (M1) or anti-inflammatory alternative (M2) phenotype upon viral infections. M1-polarized macrophages exert critical roles in antiviral responses via different mechanisms. Within the long competitive history between viruses and hosts, viruses have evolved various immune evasion strategies, inhibiting macrophage acquisition of an antiviral phenotype, impairing the antiviral responses of activated macrophages, and/or exploiting macrophage phenotypes for efficient replication. This review focuses on the sophisticated regulation of macrophage polarization utilized by viruses and is expected to provide systematic insights into the regulatory mechanisms of macrophage polarization by viruses and further facilitate the design of therapeutic targets for antivirals.
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Cheuk YC, Zhang P, Xu S, Wang J, Chen T, Mao Y, Jiang Y, Luo Y, Guo J, Wang W, Rong R. Bioinformatics analysis of pathways of renal infiltrating macrophages in different renal disease models. Transl Androl Urol 2022; 10:4333-4343. [PMID: 35070815 PMCID: PMC8749068 DOI: 10.21037/tau-21-761] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 12/03/2021] [Indexed: 12/11/2022] Open
Abstract
Background Recent studies have suggested that macrophages are significantly involved in different renal diseases. However, the role of these renal infiltrating macrophages has not been entirely uncovered. To further clarify the underlying mechanism and identify therapeutic targets, a bioinformatic analysis based on transcriptome profiles was performed. Methods Three transcription profiling datasets, GSE27045, GSE51466 and GSE75808, were obtained from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were assessed by Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and gene set enrichment analysis (GSEA). Results The classic signaling pathways and metabolic pathways of macrophages infiltrating the kidney in different pathophysiological processes, including lupus nephritis (LN), renal crystal formation and renal ischemia-reperfusion injury (IRI), were analysed. Furthermore, the common classical pathways significantly altered in the three renal disorders were the oxidative phosphorylation, VEGF signaling and JAK/STAT signaling pathways, while the renin-angiotensin system was uniquely altered in LN, the glycolysis and gluconeogenesis pathways were uniquely altered in models of renal crystal formation, and the calcium signaling pathway was specific to renal IRI. Conclusions Via bioinformatics analysis, this study revealed the transcriptional features of macrophages in murine LN, renal crystal formation and IRI models, which may serve as promising targets for mechanistic research and the clinical treatment of multiple renal diseases.
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Affiliation(s)
- Yin Celeste Cheuk
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Pingbao Zhang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Shihao Xu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Jiyan Wang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Tian Chen
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Yongxin Mao
- Department of Urology, Huadong Hospital, Fudan University, Shanghai, China
| | - Yamei Jiang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Yongsheng Luo
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Jingjing Guo
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Weixi Wang
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ruiming Rong
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
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