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Murugaiah V, Varghese PM, Beirag N, DeCordova S, Sim RB, Kishore U. Complement Proteins as Soluble Pattern Recognition Receptors for Pathogenic Viruses. Viruses 2021; 13:v13050824. [PMID: 34063241 PMCID: PMC8147407 DOI: 10.3390/v13050824] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 04/28/2021] [Indexed: 12/11/2022] Open
Abstract
The complement system represents a crucial part of innate immunity. It contains a diverse range of soluble activators, membrane-bound receptors, and regulators. Its principal function is to eliminate pathogens via activation of three distinct pathways: classical, alternative, and lectin. In the case of viruses, the complement activation results in effector functions such as virion opsonisation by complement components, phagocytosis induction, virolysis by the membrane attack complex, and promotion of immune responses through anaphylatoxins and chemotactic factors. Recent studies have shown that the addition of individual complement components can neutralise viruses without requiring the activation of the complement cascade. While the complement-mediated effector functions can neutralise a diverse range of viruses, numerous viruses have evolved mechanisms to subvert complement recognition/activation by encoding several proteins that inhibit the complement system, contributing to viral survival and pathogenesis. This review focuses on these complement-dependent and -independent interactions of complement components (especially C1q, C4b-binding protein, properdin, factor H, Mannose-binding lectin, and Ficolins) with several viruses and their consequences.
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Affiliation(s)
- Valarmathy Murugaiah
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK; (V.M.); (P.M.V.); (N.B.); (S.D.)
| | - Praveen M. Varghese
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK; (V.M.); (P.M.V.); (N.B.); (S.D.)
| | - Nazar Beirag
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK; (V.M.); (P.M.V.); (N.B.); (S.D.)
| | - Syreeta DeCordova
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK; (V.M.); (P.M.V.); (N.B.); (S.D.)
| | - Robert B. Sim
- Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK;
| | - Uday Kishore
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK; (V.M.); (P.M.V.); (N.B.); (S.D.)
- Correspondence: or
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Boldt ABW, Oliveira-Toré CDF, Kretzschmar GC, Weinschutz Mendes H, Stinghen ST, Andrade FA, Bumiller-Bini V, Gonçalves LB, Braga ACDM, Stahlke EVRS, Velavan TP, Thiel S, de Messias-Reason IJT. Hepatitis B Virus Infection Among Leprosy Patients: A Case for Polymorphisms Compromising Activation of the Lectin Pathway and Complement Receptors. Front Immunol 2021; 11:574457. [PMID: 33643280 PMCID: PMC7904891 DOI: 10.3389/fimmu.2020.574457] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 12/24/2020] [Indexed: 01/05/2023] Open
Abstract
Thousands of leprosy patients not only suffer from physical deformities, but also either have or have had hepatitis B virus (HBV) coinfection. Polymorphisms of the complement system modulate susceptibility to leprosy, but genetic susceptibility to past or present HBV infection is unknown. We used sequencing and multiplex sequence-specific PCR to genotype 72 polymorphisms of seven genes (MBL2, FCN1, FCN2, FCN3, MASP1, MASP2, C3) encoding components of the lectin pathway, and two genes encoding complement receptors (CR1, VSIG4) in 190 patients, of which 74 were positive for HBsAg and/or anti-HBc (HBV+, 93.2% with a resolved infection) and 116 lepromatous patients, and 408 HBV-blood donors. In addition, we tested for levels of proteins of the lectin pathway. We found no difference between serum concentrations of mannan-binding lectin (MBL), MBL-associated serine proteins (MASP-1, MASP-2, MASP-3, MAp44), ficolin-3 (FCN-3), soluble complement receptor 1 (sCR1) and MBL mediated C4 activation, measured by ELISA or TRIFMA in up to 167 HBV+ and HBV- patients. Haplotypes lowering protein levels or encoding dysfunctional proteins increased susceptibility to HBV infection: MBL2*LYQC (OR = 3.4, p = 0.02), MASP1*AC_CC (OR = 4.0, p = 0.015) and MASP2*1C2-l (OR = 5.4, p = 0.03). Conversely, FCN1*3C2 haplotype, associated with higher gene expression, was protective (OR = 0.56, P = 0.033). Other haplotypes associated with HBV susceptibility were: MASP2*2B1-i (OR = 19.25, P = 0.003), CR1*3A (OR = 2.65, P = 0.011) and VSIG4*TGGRCG (OR = 12.55, P = 0.014). Some polymorphisms in ficolin genes associated with lower protein levels increased susceptibility to leprosy/HBV infection: FCN*1 (OR = 1.66, P = 0.029), FCN2*GGGCAC (OR = 6.73, P = 0.008), and FCN3*del_del_C (OR = 12.54, P = 0.037), and to lepromatous disease/HBV infection: FCN2*TA (OR = 2.5, P = 0.009), whereas FCN2*MAG was associated with increased FCN-2 expression and resistance against coinfection (OR = 0.29, P = 0.026). These associations were independent of demographic factors and did not increase susceptibility to leprosy per se, except MASP2*1C2-l. Associations for FCN2, FCN3, MASP1, MASP2, and VSIG4 variants were also independent of each other. In conclusion, polymorphisms compromising activation of the lectin pathway of complement increase susceptibility to HBV infection, with ficolin polymorphisms playing a major role in modulating the susceptibility among leprosy patients.
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Affiliation(s)
- Angelica Beate Winter Boldt
- Laboratory of Human Molecular Genetics, Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba, Brazil
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Camila de Freitas Oliveira-Toré
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Gabriela Canalli Kretzschmar
- Laboratory of Human Molecular Genetics, Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba, Brazil
| | - Hellen Weinschutz Mendes
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Sérvio Túlio Stinghen
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Fabiana Antunes Andrade
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Valéria Bumiller-Bini
- Laboratory of Human Molecular Genetics, Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba, Brazil
| | - Letícia Boslooper Gonçalves
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Anna Carolina de Moraes Braga
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | | | - Thirumalaisamy P. Velavan
- Institute of Tropical Medicine, Universitätsklinikum Tübingen, Tübingen, Germany
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Faculty of Medicine, Duy Tan University, Da Nang, Vietnam
| | - Steffen Thiel
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Iara José Taborda de Messias-Reason
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
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Medetalibeyoglu A, Bahat G, Senkal N, Kose M, Avci K, Sayin GY, Isoglu-Alkac U, Tukek T, Pehlivan S. Mannose binding lectin gene 2 (rs1800450) missense variant may contribute to development and severity of COVID-19 infection. INFECTION GENETICS AND EVOLUTION 2021; 89:104717. [PMID: 33515713 PMCID: PMC7838598 DOI: 10.1016/j.meegid.2021.104717] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 12/06/2020] [Accepted: 01/06/2021] [Indexed: 12/20/2022]
Abstract
Background/objectives COVID-19 followed a mortal course in some young patients without any underlying factors, however, it followed a very benign course in some very older individuals with multiple comorbidities. These observations question if some genetic factors may be related to the vulnerability and poor prognosis of the disease. In this study, we aimed to investigate whether MBL2 gene B variant at codon 54 (rs1800450) were related to the variabilities in clinical course of this infection. Methods 284 PCR-confirmed COVID-19 patients and 100 healthy controls were included in the study. COVID-19 patients were subdivided according to the clinical features and clinical characteristics were analyzed. DNAs of all patients and controls were examined for the codon 54 A/B (gly54asp: rs1800450) variation in exon 1 of the MBL2 gene. Results In univariate analysis, BB genotype of MBL2 gene was more common among COVID-19 cases compared with controls (10.9% vs 1.0%, respectively; OR = 12.1, 95%CI = 1.6–90.1, p = 0.001). Multivariate analyses, adjusted for age, sex and MBL genetic variants, revealed that when compared with the COVID-19 patients that had AA genotype (reference), the patients that had BB or AB genotypes suffered from a higher risk for severe disease (for BB genotype, odds ratio (OR) = 5.3, p < 0.001; for AB genotype, OR = 2.9, p = 0.001) and for ICU need (for BB genotype, OR = 19.6, p < 0.001; for AB genotype, OR = 6.9, p = 0.001). On the other hand, there was not any significant difference between the genotype variants in terms of mortality at 28 days or development of secondary bacterial infection. Conclusion The B variants of MBL2 gene at codon 54, which were associated with lower MBL2 levels, were related to a higher risk for a more severe clinical course of COVID-19 infection in some respects. Our findings may have potential future implications, e.g. for use of MBL protein as potential therapeutics or prioritize the individuals with B variants during vaccination strategies.
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Affiliation(s)
- Alpay Medetalibeyoglu
- Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Gulistan Bahat
- Department of Internal Medicine, Division of Geriatrics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
| | - Naci Senkal
- Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Murat Kose
- Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Kader Avci
- Department of Medical Biology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Gozde Yesil Sayin
- Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Ummuhan Isoglu-Alkac
- Department of Physiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Tufan Tukek
- Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Sacide Pehlivan
- Department of Medical Biology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
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Murugaiah V, Tsolaki AG, Kishore U. Collectins: Innate Immune Pattern Recognition Molecules. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1204:75-127. [PMID: 32152944 PMCID: PMC7120701 DOI: 10.1007/978-981-15-1580-4_4] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Collectins are collagen-containing C-type (calcium-dependent) lectins which are important pathogen pattern recognising innate immune molecules. Their primary structure is characterised by an N-terminal, triple-helical collagenous region made up of Gly-X-Y repeats, an a-helical coiled-coil trimerising neck region, and a C-terminal C-type lectin or carbohydrate recognition domain (CRD). Further oligomerisation of this primary structure can give rise to more complex and multimeric structures that can be seen under electron microscope. Collectins can be found in serum as well as in a range of tissues at the mucosal surfaces. Mannanbinding lectin can activate the complement system while other members of the collectin family are extremely versatile in recognising a diverse range of pathogens via their CRDs and bring about effector functions designed at the clearance of invading pathogens. These mechanisms include opsonisation, enhancement of phagocytosis, triggering superoxidative burst and nitric oxide production. Collectins can also potentiate the adaptive immune response via antigen presenting cells such as macrophages and dendritic cells through modulation of cytokines and chemokines, thus they can act as a link between innate and adaptive immunity. This chapter describes the structure-function relationships of collectins, their diverse functions, and their interaction with viruses, bacteria, fungi and parasites.
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Affiliation(s)
- Valarmathy Murugaiah
- College of Health and Life Sciences, Brunel University London, London, UB8 3PH, UK
| | - Anthony G Tsolaki
- College of Health and Life Sciences, Brunel University London, London, UB8 3PH, UK
| | - Uday Kishore
- College of Health and Life Sciences, Brunel University London, London, UB8 3PH, UK.
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Madhukaran SP, Alhamlan FS, Kale K, Vatish M, Madan T, Kishore U. Role of collectins and complement protein C1q in pregnancy and parturition. Immunobiology 2016; 221:1273-88. [PMID: 27349595 DOI: 10.1016/j.imbio.2016.06.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 05/27/2016] [Accepted: 06/09/2016] [Indexed: 12/18/2022]
Abstract
Collectins such as surfactant proteins SP-A, SP-D, and mannan-binding lectin (MBL), as well as complement protein C1q are evolutionarily conserved innate immune molecules. They are known to opsonize a range of microbial pathogens (bacteria, fungi, virus, and parasites) and trigger effector clearance mechanisms involving phagocytosis and/or complement activation. Collectins and C1q have also attracted attention in studies involving pregnancy as they are expressed in the female reproductive tissues during pregnancy; a unique state of immune suppression with increased susceptibility to infectious diseases. Recent studies are beginning to unravel their functional significance in implantation, placentation, pregnancy maintenance and parturition in normal and adverse pregnancies. Collectins and C1q, expressed in gestational tissues during pregnancy, might alter the status of mother's immune response to the allogenic fetus and the microenvironment, thereby serving as important regulators of fetus-mother interaction. Here, we discuss the functional roles that have been assigned to SP-A, SP-D, MBL and C1q in pregnancy and parturition.
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Affiliation(s)
- Shanmuga Priyaa Madhukaran
- Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge UB8 3PH, United Kingdom; Centre for Biotechnology and Bioinformatics, School of Life Sciences, Jawaharlal Nehru Institute for Advanced Studies, Secunderabad, Telangana, India
| | - Fatimah S Alhamlan
- Department of Infection and Immunity, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Kavita Kale
- Department of Innate Immunity, National Institute for Research in Reproductive Health (ICMR), Mumbai 400 012, India
| | - Manu Vatish
- Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Oxford, OX3 9DU, United Kingdom
| | - Taruna Madan
- Department of Innate Immunity, National Institute for Research in Reproductive Health (ICMR), Mumbai 400 012, India
| | - Uday Kishore
- Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge UB8 3PH, United Kingdom.
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Human lectins and their roles in viral infections. Molecules 2015; 20:2229-71. [PMID: 25642836 PMCID: PMC6272597 DOI: 10.3390/molecules20022229] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 01/21/2015] [Accepted: 01/23/2015] [Indexed: 12/20/2022] Open
Abstract
Innate recognition of virus proteins is an important component of the immune response to viral pathogens. A component of this immune recognition is the family of lectins; pattern recognition receptors (PRRs) that recognise viral pathogen-associated molecular patterns (PAMPs) including viral glycoproteins. In this review we discuss the contribution of soluble and membrane-associated PRRs to immunity against virus pathogens, and the potential role of these molecules in facilitating virus replication. These processes are illustrated with examples of viruses including human immunodeficiency virus (HIV), hepatitis C virus (HCV) and Ebola virus (EBOV). We focus on the structure, function and genetics of the well-characterised C-type lectin mannose-binding lectin, the ficolins, and the membrane-bound CD209 proteins expressed on dendritic cells. The potential for lectin-based antiviral therapies is also discussed.
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Zeng Z. Human genes involved in hepatitis B virus infection. World J Gastroenterol 2014; 20:7696-7706. [PMID: 24976707 PMCID: PMC4069298 DOI: 10.3748/wjg.v20.i24.7696] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/10/2014] [Accepted: 03/07/2014] [Indexed: 02/06/2023] Open
Abstract
Persistent hepatitis B virus (HBV) infection is a significant public health problem because it is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Roughly one-third of the world population has been infected with HBV and there are about 350 million (5%-6%) persistent carriers. HBV causes 80% of all liver cancer cases and is the second most important carcinogen, after smoking tobacco. There is an approximate 90% risk of becoming a persistent carrier following perinatal infection in infants born to e antigen positive carrier mothers and a 30% risk in pre-school children. Only 5%-10% of adults become persistent carriers following infection. Of individuals persistently infected with HBV, 10%-30% will develop liver cirrhosis and HCC. These highly variable outcomes in both clearance rates and disease outcomes in persistently infected individuals cannot be fully explained by differences in immunological, viral or environmental factors. Thus, differences in host genetic factors may affect the natural history of hepatitis B.
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Association between Mannose-binding lectin gene polymorphisms and hepatitis B virus infection: a meta-analysis. PLoS One 2013; 8:e75371. [PMID: 24116040 PMCID: PMC3792921 DOI: 10.1371/journal.pone.0075371] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2013] [Accepted: 08/11/2013] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE The results of studies on the relation between Mannose-binding lectin gene (mbl2) polymorphism and HBV infection were contradictory and inconclusive. In order to shed a light on these inconsistent findings and to clarify the role of mbl2 polymorphisms in susceptibility or progression of chronic hepatitis B (CHB), a meta-analysis was performed. METHODS PubMed and Embase were searched for available articles. A meta-analysis was performed to examine the association between mbl2 polymorphisms and chronicity or progression of hepatitis B infection. Odds ratio (OR) and its 95% confidence interval (CI) served as indexes. RESULTS A total of 17 eligible studies were involved, including 2151 healthy controls (HC), 1293 spontaneous recovered (SR) patients with acute infection, 2337 cases with chronic hepatitis B (CHB) and 554 cases with progressive hepatitis B. There was no evidence of significant association between mbl2 exon1 polymorphisms and CHB risk in any genetic model or pairwise comparisons when compared with HC group or SR group. In the stratified analysis of ethnic groups, also no obvious relation between mbl2 polymorphism and CHB risk was identified. There was still no significant association between the complete mbl2 genotypic profile (including both the exon1 and the promoter gene) polymorphisms and CHB risk, as compared with SR group. However, it was found that there was an association between the mbl2 AO/OO genotype and severe hepatitis B (SHB) or liver cirrhosis (LC) (LC vs. HC:OR=3.66, 95%CI, 2.38-5.63; SHB vs. HC, OR=3.88, 95%CI, 2.26-6.64), but there was no relationship between the mbl2 AO/OO genotype and hepatocellular carcinoma (HCC) (OR=1.26, 95%CI, 0.82-1.94). CONCLUSION The present meta-analysis indicated that mbl2 exon1 polymorphisms might not significantly associate with chronicity of HBV infection, but might be significantly related to the progressive HBV such as SHB and LC.
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Zhang TC, Liu W, Liu XQ, Pan FM, Gao YF, Yan F, Li X. Single nucleotide polymorphisms rs2120131, rs4935047, and rs7095891 in the MBL2 gene show no association with susceptibility to chronic hepatitis B in a Chinese Han population. J Med Virol 2013; 85:602-7. [PMID: 23417614 DOI: 10.1002/jmv.23514] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/05/2012] [Indexed: 11/12/2022]
Abstract
Thus far, many studies have evaluated the correlation between MBL2 gene polymorphisms and hepatitis B infection. Tag single nucleotide polymorphisms (SNPs) were used to investigate the relationship between MBL2 gene polymorphisms and susceptibility to chronic hepatitis B virus (HBV) infection by comparing 996 chronic HBV infection cases to 301 acute infection controls. There was no significant correlation between rs2120131, rs4935047, and rs7095891 and chronic HBV infection. This suggested that the new SNPs within MBL2 were not associated with susceptibility to chronic hepatitis B in a Chinese Han population.
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Affiliation(s)
- Tian-Chen Zhang
- Jiangxi Center for Disease Control and Prevention, 555 Beijing East Road, Nanchang, Jiangxi 330000, China
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Filho RM, Carmo RF, Catsman C, Souza C, Silva A, Moura P, Tenorio AL, Vasconcelos LRS, Cavalcanti MDSM, Pereira LMMB. High frequency of variant alleles of the mannose-binding lectin 2 (MBL2) gene are associated with patients infected by hepatitis B virus. Viral Immunol 2011; 23:449-53. [PMID: 20712490 DOI: 10.1089/vim.2009.0105] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Patients with hepatitis B virus (HBV) infection may develop severe chronic liver disease. Carriers of HBV have an increased risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Worldwide an estimated 350 million people are infected with HBV, and 15-40% will develop serious sequelae in their lifetime. In our study we investigated the association of single nucleotide polymorphisms (SNPs) in the first exon and promoter region of the mannose-binding lectin gene 2 (MBL2) situated on chromosome 10, with susceptibility to HBV infection. One-hundred and two patients infected with HBV were included in this study, and 232 uninfected individuals were used as healthy controls. Genotyping of the first exon (alleles A/O) was performed using a melting temperature assay. Genotyping of the promoter region (-550 H/L; -221 Y/X) was performed using the Taqman PCR technique. In the HBV-infected group we found a significantly increased frequency of haplotypes associated with low serum MBL. Our findings may indicate that MBL has a protective role against HBV infection in the studied population.
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Davila S, Froeling FEM, Tan A, Bonnard C, Boland GJ, Snippe H, Hibberd ML, Seielstad M. New genetic associations detected in a host response study to hepatitis B vaccine. Genes Immun 2010; 11:232-8. [PMID: 20237496 DOI: 10.1038/gene.2010.1] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The immune response to hepatitis B vaccination differs greatly among individuals, with 5-10% of healthy people failing to produce protective levels of antibodies. Several factors have been implicated in determining this response, chiefly individual genetic variation and age. Aiming to identify genes involved in the response to hepatitis B vaccination, a two-stage investigation of 6091 single-nucleotide polymorphisms (SNPs) in 914 immune genes was performed in an Indonesian cohort of 981 individuals showing normal levels of anti-HBs versus 665 individuals displaying undetectable levels of anti-HBs 18 months after initial dose of the vaccine. Of 275 SNPs identified in the first stage (476 normal/372 nonresponders) with P<0.05, significant associations were replicated for 25 polymorphisms in 15 genes (503 normal/295 nonresponders). We validated previous findings (HLA-DRA, rs5000563, P-value combined=5.57 x 10(-10); OR (95%CI)=0.61 (0.52-0.71)). In addition, we detected a new association outside of the human leukocyte antigen loci region that passed correction for multiple testing. This SNP is in the 3' downstream region of FOXP1, a transcription factor involved in B-cell development (P-value combined=9.2 x 10(-6); OR (95%CI)=1.38 (1.2-1.6)).These findings might help to understand the biological reasons behind vaccine failure and other aspects of variation in the immune responses of healthy individuals.
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Affiliation(s)
- S Davila
- Genome Institute of Singapore, Singapore
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Fletcher GJ, Gnanamony M, Samuel P, Ismail AM, Kannangai R, Daniel D, Eapen CE, Abraham P. Association of mannose-binding lectin polymorphisms and HBV outcome in a South Indian population. Int J Immunogenet 2010; 37:177-84. [PMID: 20193030 DOI: 10.1111/j.1744-313x.2010.00908.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Mannose binding lectin (MBL) is an important innate immune system pattern recognition molecule. The MBL gene polymorphisms are reported to play a crucial role in outcome of hepatitis B virus (HBV) infection. In this study, we ascertained the association of MBL genotypes with HBV outcome in a South Indian population. The MBL gene polymorphisms at codons 52, 54 and 57 of exon I, and promoter polymorphisms at -221 were typed by polymerase chain reaction-sequence specific primer in spontaneously recovered and in chronic HBV group. The allele frequency of codon 52 'C' was significantly higher in chronic HBV group than in the recovered group (98.5% vs. 93.6%; P = 0.003) and codon 52 'T' was significantly higher in recovered group than in the chronic group (6.4% vs. 1.5%; P = 0.003). In multivariate analysis, after adjusting for age, sex and state of origin, codon 52 'CC' and 'CT' genotypes were significantly associated with chronicity and recovery respectively [odds ratio (OR), 0.25; 95% confidence interval (CI), 0.08-0.80, P = 0.02] in co-dominant analyzing models. This was re-affirmed in analysis performed exclusively on Tamil Nadu subjects (OR, 0.23; 95% CI, 0.06-0.93, P = 0.039). The frequency of low/none haplotype (XY/O) was significantly higher in recovered group than in chronic group (15.6% vs 7.5%) and associated with spontaneous recovery (OR, 2.28; 95% CI, 1.04-4.99, P = 0.035). Our results provide preliminary evidence that inheritance of codon 52 genotypes and XY/O haplotype associated with low MBL level substantially determine the outcome of HBV infection in a sympatrically isolated South Indian population.
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Affiliation(s)
- G J Fletcher
- Department of Gastrointestinal Sciences, Christian Medical College, Vellore, Tamil Nadu, India
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Gong QM, Kong XF, Yang ZT, Xu J, Wang L, Li XH, Jin GD, Gao J, Zhang DH, Jiang JH, Lu ZM, Zhang XX. Association study of IFNAR2 and IL10RB genes with the susceptibility and interferon response in HBV infection. J Viral Hepat 2009; 16:674-680. [PMID: 19714778 DOI: 10.1111/j.1365-2893.2009.01130.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
A recent genome-wide association study discovered that two polymorphisms, interferon (IFN) alpha receptor 2 (IFNAR-2) F8S and interleukin 10 receptor (IL10RB) K47E, were associated with susceptibility to hepatitis B virus (HBV) infection in Africa. Here, we reevaluate the effects of the two polymorphisms on HBV susceptibility in the Chinese Han population, and extended the study to look at their association with IFN response in chronic hepatitis B (CHB). We included 341 patients with CHB and 341 unrelated controls presenting with asymptotic HBV self-limited infection, who were well matched in age and sex. In the CHB group, 101 patients had been treated with peg-IFN-alpha-2a for 48 weeks and followed up for 24 weeks to determine the clinical response, resulting 34 individuals with sustained virological response (SVR) and 67 individuals with nonsustained response (NR). Subgroups in the CHB group were divided according to the viral loads, HBeAg and maternal HBsAg status. The association with the susceptibility to HBV infection was only observed for IL10RB K47E when we compared the individuals with persistent HBV infection through nonmaternal transmission to the controls with asymptomatic self-limited HBV infection. Further, we found that the IFNAR2-8SS genotype was associated with HBeAg negative patients (OR = 0.316, 95% CI: 0.121-0.825, P = 0.019) and that the IFNAR2-8F allele was associated with the risk to high viral loads (OR = 1.667, 95% CI: 1.148-2.420, P = 0.007). In addition, the IFNAR2-8FF genotype predisposed to higher MxA gene induction and correlated with sustained IFN response (OR = 0.348, 95% CI: 0.129-0.935, P = 0.036). Haplotype analysis based on polymorphisms of three single-nucleotide polymorphisms, MxA - 88 G/T, IFNAR-2 F8S and IL10RB K47E showed that the haplotype distribution was significantly different between the SVR and NR groups (P = 0.040). This study suggests that IFNAR2 may play an important role in determining IFN response and clinical phenotypes of HBV infection in the Chinese Han population.
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Affiliation(s)
- Q-M Gong
- Department of Infectious Diseases, School of Medicine, Shanghai Jiaotong University, Ruijin Hospital, Shanghai, China
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Ruseva M, Kolev M, Dagnaes-Hansen F, Hansen SB, Takahashi K, Ezekowitz A, Thiel S, Jensenius JC, Gadjeva M. Mannan-binding lectin deficiency modulates the humoral immune response dependent on the genetic environment. Immunology 2009; 127:279-88. [PMID: 19476514 DOI: 10.1111/j.1365-2567.2008.03016.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Mannan-binding lectin (MBL) is a plasma protein implicated in innate immune defence against a broad range of microorganisms, including viruses. It is also thought that MBL plays a role in the recruitment of the specific clonal immune response. This was studied by injecting soluble hepatitis B surface antigen (HBsAg) intravenously into mice deficient in both MBL-A and MBL-C (MBL DKO mice). The MBL DKO animals on mixed genetic background (SV129EvSv x C57BL/6) produced higher antibody titres than the wild-type littermates. After primary challenge with the antigen the immunoglobulin M anti-HBsAg antibody titres were threefold higher in the MBL DKO mice than in the wild-type mice. Following the boost, the immunoglobulin G anti-HBsAg antibody titres were 10-fold higher in the MBL DKO mice, suggesting that MBL plays a role in a negative feedback regulation of adaptive immunity. However, the modulating effect of MBL was dependent on the genetic environment. The MBL DKO mice backcrossed on a C57BL/6 background showed the opposite response with the MBL DKO mice now producing fewer antibodies than the wild-type animals, whereas MBL deficiency in mice with the SV129EvSv background did not show any effect in antibody production. These findings indicate that the modifying effect of MBL on the humoral immune response is influenced by the genetic environment.
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Affiliation(s)
- Marieta Ruseva
- Department of Medical Microbiology and Immunology, University of Aarhus, Denmark
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15
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Koutsounaki E, Goulielmos GN, Koulentaki M, Choulaki C, Kouroumalis E, Galanakis E. Mannose-binding lectin MBL2 gene polymorphisms and outcome of hepatitis C virus-infected patients. J Clin Immunol 2008; 28:495-500. [PMID: 18592362 DOI: 10.1007/s10875-008-9201-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2008] [Accepted: 03/26/2008] [Indexed: 01/27/2023]
Abstract
INTRODUCTION Mannose-binding lectin (MBL) is involved in host's response to several infections including hepatitis B but little is known about MBL and hepatitis C virus (HCV) infection. The present study attempts to investigate whether MBL2 genotype and serum MBL levels affect the course of HCV infection. RESULTS AND DISCUSSIONS We investigated the variant alleles in MBL2 gene promoter and exon-1 regions in 80 Caucasian HCV-infected patients. Mutations in MBL2 were determined by polymerase chain reaction and restriction fragment length polymorphisms analysis. Serum MBL levels were measured by ELISA. Polymorphism homozygosity in exon-1 region was significantly related to lower serum MBL levels (p < 0.001), to liver inflammation (p = 0.034, OR = 11.7) and, in a lesser degree, to fibrosis. Polymorphisms in promoter sites -221nt and -550nt were not shown to be related with serum MBL levels or progress to liver inflammation and fibrosis. Serum MBL levels were adversely associated with progression to fibrosis (p = 0.037). Response to antiviral treatment was related to hepatitis C virus genotype (p < 0.001, OR = 10.9), but not to MBL2 genotype or serum MBL levels. CONCLUSION These findings suggest that polymorphisms in MBL2 gene exon-1 region are related to low serum MBL levels and progression of HCV infection to liver inflammation and fibrosis.
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Affiliation(s)
- Eirini Koutsounaki
- Laboratory of Internal Medicine, Faculty of Medicine, University of Crete, P.O. Box 2208, Heraklion 710 03, Greece.
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16
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Methylenetetrahydrofolate reductase 677 T allele protects against persistent HBV infection in West Africa. J Hepatol 2008; 48:532-9. [PMID: 18222012 DOI: 10.1016/j.jhep.2007.11.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2007] [Revised: 10/06/2007] [Accepted: 11/08/2007] [Indexed: 01/12/2023]
Abstract
BACKGROUND/AIMS Homocysteine metabolism is linked to DNA methylation, a mechanism potentially involved in the course of hepatitis B virus (HBV) infection. We evaluated the association of determinants of homocysteine metabolism with the outcome of HBV infection. METHODS Four hundred and fifty-five healthy adults from Togo and Benin were tested for HBV serologic markers, HLA DR alleles, folate, vitamin B12, methylenetetrahydrofolate reductase (MTHFR) 677 C-->T, 1298 A-->C and methionine synthase 2756 A-->G polymorphisms. RESULTS Seventy-eight percent of the study population was anti-HBc positive. Among them, 202 (56.9%) were anti-HBs positive and 58 (16.3%) were HBsAg positive. After stepwise logistic regression, the MTHFR 677 T allele was independently associated with persistence of detectable anti-HBs antibodies (OR: 2.47; 95% CI: 1.29-4.71; p=0.006). The mean HBV DNA level was significantly lower in HBsAg positive subjects carrying the 677 T allele than in those with the 677 CC genotype (1000+/-1406 vs. 2,400,000+/-214,000 copies/ml, p=0.005). Beninese origin and HLA-DRB1*09 allele were the other determinants independently associated with favorable outcome of HBV infection. CONCLUSIONS The methylenetetrahydrofolate reductase 677 T allele seems to protect against chronic HBV infection in young African adults.
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17
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Zeng Z, Guan L, An P, Sun S, O'Brien SJ, Winkler CA. A population-based study to investigate host genetic factors associated with hepatitis B infection and pathogenesis in the Chinese population. BMC Infect Dis 2008; 8:1. [PMID: 18171470 PMCID: PMC2238742 DOI: 10.1186/1471-2334-8-1] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2007] [Accepted: 01/02/2008] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a significant public health problem that may lead to chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Approximately 30% of the world's population has been infected with HBV and approximately 350 million (5-6%) are persistent carriers. More than 120 million Chinese are infected with HBV. The role of host genetic factors and their interactions with environmental factors leading to chronic HBV infection and its complications are not well understood. We believe that a better understanding of these factors and interactions will lead to more effective diagnostic and therapeutic options. METHODS/DESIGN This is a population-based, case-control study protocol to enroll 2200 Han Chinese from medical centers in northern and western China. Adult subjects in the following groups are being enrolled: healthy donors (n = 200), HBV infected persons achieving virus clearance (n = 400), asymptomatic HBV persistent carriers (n = 400), chronic hepatitis B cases (n = 400), decompensated liver cirrhosis with HBV infection cases (n = 400), and hepatocellular carcinoma with HBV infection cases (n = 400). In addition, for haplotype inference and quality control of sample handling and genotyping results, children of 1000 cases will be asked to provide a buccal sample for DNA extraction. With the exception of adult patients presenting with liver cirrhosis or HCC, all other cases and controls will be 40 years or older at enrollment. A questionnaire is being administered to capture dietary and environmental risk factors. Both candidate-gene and genome-wide association approaches will be used to assess the role of single genetic factors and higher order interactions with other genetic or environmental factors in HBV diseases. CONCLUSION This study is designed and powered to detect single gene effects as well as gene-gene and environmental-gene interactions. The identification of allelic polymorphisms in genes involved in the pathway leading to chronic viral infection, liver cirrhosis and, ultimately, hepatocellular carcinoma would provide insights to those factors leading to HBV replication, liver inflammation, fibrosis, and the carcinogenic process. An understanding of the contribution of host genetic factors and their interactions may inform public health policy, improve diagnostics and clinical management, and provide targets for drug development.
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Affiliation(s)
- Zheng Zeng
- Department of Infectious Diseases, Peking University First Hospital, Beijing, P.R.China
| | - Li Guan
- SAIC/Laboratory of Genomic Diversity, National Cancer Institute-Frederick, National Institutes of Health, Frederick, USA
| | - Ping An
- SAIC/Laboratory of Genomic Diversity, National Cancer Institute-Frederick, National Institutes of Health, Frederick, USA
| | - Shan Sun
- Conservation International (CI) China program, Beijing, P.R.China
| | - Stephen J O'Brien
- Laboratory of Genomic Diversity, National Cancer Institute-Frederick, National Institutes of Health, Frederick, USA
| | - Cheryl A Winkler
- SAIC/Laboratory of Genomic Diversity, National Cancer Institute-Frederick, National Institutes of Health, Frederick, USA
| | - the HBV study consortium
- HBV study consortium: Department of Infectious Diseases, Peking University First Hospital, Beijing, P.R.China (Zheng Zeng, Yanyan Yu, Xiaoyuan Xu, Haiying Lu); Institute of Liver Diseases Research, Beijing Military General Hospital, Beijing, P.R.China (Darong Hu); Beijing Ditan Hospital (Rongbing Wang, Yifan Chen); Department of Surgery, Beijing Institute of Tumor Prevention and Therapy, Beijing, P.R.China (Cunyi Hao); Department of Infectious Diseases, Shanxi Medical University, Taiyuan, P.R.China (Heping Zhou); Department of Infectious Diseases, Qinhuangdao No. 3 Hospital, Qinhuangdao, P.R.China (Zhonghou Han); Department of Surgery, Inner Mongolia Medical College, Hohhot, P.R.China (Lidao Bao, Xiping Zhang); Department of Infectious Diseases, Xuzhou No. 3 Hospital, Xuzhou, P.R.China (Dasi Guo); Department of Infectious Diseases, Xinjian Medical University, Urumoqi, P.R.China (Yaoxin Zhang); Department of Infectious Diseases, the Second Affiliate Hospital of China Medical University, Shenyang, P.R.China (Xiaoguang Dou); Institute of Liver Diseases Research, Peking University Second Hospital, Beijing, P.R.China (Lai Wei); Department of Surgery, Peking Union Medical College, Beijing, P.R.China (Jingan Rui, Qiang Qu)
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Takahashi K, Ezekowitz RAB. The role of the mannose-binding lectin in innate immunity. Clin Infect Dis 2007; 41 Suppl 7:S440-4. [PMID: 16237644 DOI: 10.1086/431987] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
The innate immune system, which includes mannose-binding lectin (MBL), recognizes a broad range of molecular patterns on a broad range of infectious agents and is able to distinguish them from self. MBL is a liver-derived serum protein and is secreted into the serum, where it can activate an immune response before the induction of antigen-specific immunity. Circumstantial evidence in human populations suggests that low serum levels of MBL predispose to infection. To analyze the role of MBL in vivo, we created MBL-null mice and challenged these mice with infection under various conditions. Our results suggest that MBL plays an important role as a first-line host defense against certain infectious agents. In addition, it is likely that MBL is a key regulator of inflammation beyond expected roles in the infection.
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Affiliation(s)
- Kazue Takahashi
- Department of Pediatrics, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA.
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19
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Brown KS, Ryder SD, Irving WL, Sim RB, Hickling TP. Mannan binding lectin and viral hepatitis. Immunol Lett 2006; 108:34-44. [PMID: 17157924 DOI: 10.1016/j.imlet.2006.10.006] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2006] [Revised: 10/29/2006] [Accepted: 10/29/2006] [Indexed: 01/04/2023]
Abstract
Mannan binding lectin (MBL) is a pattern recognition molecule of the innate immune system that binds to sugars on the surface of invading micro-organisms. Target binding, complement activation and other functions of MBL are dependent on the presence of multiple carbohydrate recognition domains. Several polymorphisms in the promoter and structural regions of MBL2 adversely affect the plasma concentration and oligomeric state of MBL. The possession of mutant alleles has been linked to disease outcome for a variety of bacterial and viral infections. Viral hepatitis is caused by unrelated viruses referred to as hepatitis virus A-E. The disease usually has both acute and chronic phases, the latter leading to cirrhosis and hepatocellular carcinoma. Hepatitis viruses B and C (HBV and HCV, respectively) are a significant cause of morbidity worldwide. HBV encodes envelope glycoproteins termed large, middle, and small that may exist in glycosylated or unglycosylated forms on the virion. An interaction between HBV glycoproteins and MBL has been demonstrated in vitro. Significant associations between MBL levels, determined by MBL2 haplotypes, and HBV persistence and disease progression have been described. HCV encodes two highly glycosylated envelope proteins, E1 and E2, which are potential targets for interaction with MBL. Mutant MBL2 haplotypes have been linked to disease progression and response to therapy in HCV infection. Here we summarise the effect of MBL2 polymorphisms on MBL function and how this may relate to disease outcome in HBV and HCV infection.
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Affiliation(s)
- Kristelle S Brown
- Institute of Infection, Immunity and Inflammation, School of Molecular Medical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
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20
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Abstract
Mannose-binding lectin (MBL) is a pattern-recognition molecule that binds to characteristic carbohydrate motifs present on the surface of many different pathogens. MBL binding stimulates the immune system via the lectin pathway of complement activation. In certain clinical situations, often characterized by pre-existing immune compromise, MBL deficiency increases the risk of infectious and other disease-specific complications. Many of the key pathogenic processes inherent to common gastroenterological diseases, such as infection, immunological damage, and carcinogenesis, have been linked to MBL. This editorial reviews the biology of MBL, outlines key disease associations to document the breadth of influence of MBL, and finally, highlights the relevance of MBL to both gastroenterological health and disease.
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Affiliation(s)
- Daniel-L Worthley
- Department of Gastroenterology and Hepatology, Flinders Medical Centre, Room 3D230, Bedford Park, SA, 5042, Australia.
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21
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Chong WP, To YF, Ip WK, Yuen MF, Poon TP, Wong WHS, Lai CL, Lau YL. Mannose-binding lectin in chronic hepatitis B virus infection. Hepatology 2005; 42:1037-45. [PMID: 16231358 DOI: 10.1002/hep.20891] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mannose binding lectin (MBL) is a pattern-recognition molecule of the innate immune system. The roles of MBL and its gene (mbl2) polymorphisms, -221X/Y and codon 54A/B, in hepatitis B virus (HBV) infection were investigated in this study. We recruited 320 nonprogressed hepatitis B surface antigen (HBsAg) carriers; 199 progressed HBsAg carriers with hepatocellular carcinoma or cirrhosis; 87 spontaneously recovered individuals who were HBsAg negative and anti-HBs and anti HBc positive; and 484 controls who were naïve to HBV. There was no significant difference between nonprogressed carriers, spontaneously recovered individuals, and controls in terms of serum MBL levels and mbl2 polymorphisms distributions. However, the low MBL genotypes had a dose-dependent correlation with the cirrhosis and hepatocellular carcinoma in progressed carriers with odds ratios of 1.36 and 3.21 for the low and extremely low MBL genotypes, respectively (P = .01). The low-expression promoter haplotype XA (OR = 1.97) and the mutant haplotype YB (OR = 1.90) were also associated with the cirrhosis and hepatocellular carcinoma (P = .002). As expected, the lower serum MBL levels in progressed carriers as compared with nonprogressed carriers were due to an overrepresentation of low and extremely low MBL genotypes. Moreover, MBL could bind HBsAg in a dose- and calcium-dependent and mannan-inhibitable manner in vitro, suggesting that binding occurs via the carbohydrate recognition domains. This binding also enhanced C4 deposition. In conclusion, these results suggest that low MBL genotypes associate with the occurrence of cirrhosis and hepatocellular carcinoma in progressed HBsAg carriers, and MBL can bind HBsAg.
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Affiliation(s)
- Wai Po Chong
- Department of Paediatrics and Adolescent Medicine, Hong Kong Jockey Club Clinical Research Centre, Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
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22
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Thio CL, Mosbruger T, Astemborski J, Greer S, Kirk GD, O'Brien SJ, Thomas DL. Mannose binding lectin genotypes influence recovery from hepatitis B virus infection. J Virol 2005; 79:9192-6. [PMID: 15994813 PMCID: PMC1168757 DOI: 10.1128/jvi.79.14.9192-9196.2005] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Mannose binding lectin (MBL) is a central component of the innate immune response and thus may be important for determining hepatitis B virus (HBV) persistence. Since single-nucleotide polymorphisms (SNPs) in the gene encoding MBL (mbl2) alter the level of functional MBL, we hypothesized that mbl2 genotypes are a determinant of HBV persistence or recovery from viral infection. We tested this hypothesis by using a nested case control design with 189 persons with HBV persistence matched to 338 individuals who had naturally recovered from HBV infection. We determined genotypes of two promoter and three exon 1 SNPs in mbl2 and grouped these genotypes according to the amount of functional MBL production. We found that the promoter SNP -221C, which leads to deficient MBL production, was more common in those subjects with viral persistence (odds ratio [OR], 1.38; 95% confidence interval [CI], 1.01 to 1.89; P = 0.04). Those subjects homozygous for the combination of promoter and exon 1 genotypes associated with the highest amount of functional MBL had significantly increased odds of recovery from infection (OR, 0.55; 95% CI, 0.37 to 0.84; P = 0.005). Conversely, those homozygous for the combination of promoter and exon 1 genotypes which produce the lowest amount of functional MBL were more likely to have viral persistence (OR, 1.76; 95% CI, 1.02 to 3.01; P = 0.04). These data are consistent with the hypothesis that functional MBL plays a central role in the pathogenesis of acute hepatitis B.
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Affiliation(s)
- Chloe L Thio
- Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
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23
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Cheong JY, Cho SW, Lim SK, Shin DH, Yoon SK, Lee JE, Hahm KB, Kim JH. Lack of association between hepatitis B virus infection and polymorphism of mannose-binding lectin gene in Korean population. J Korean Med Sci 2005; 20:65-9. [PMID: 15716605 PMCID: PMC2808578 DOI: 10.3346/jkms.2005.20.1.65] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Mannose-binding lectin (MBL) plays an important role in immune defense. This study was undertaken to investigate the association between hepatitis B virus infection and polymorphisms of MBL gene. We assessed the single nucleotide polymorphism at codon 54 in exon 1 of MBL in patients with hepatitis B virus infection and HBsAg negative controls in Korean population. A total of 498 enrolled subjects was classified into four groups. Group 1; Clearance, Group 2; Inactive healthy carrier, Group 3; Chronic hepatitis, Group 4; Liver cirrhosis. MBL gene polymorphisms at codon 54 led to three genotypes (G/G, G/A, A/A). When we divided subjects into clearance group (group 1) and persistence group (group 2-4), G/G genotype and A-allele carrier were observed in 55.6% and 44.4% in clearance group, 64.8% and 35.2% in persistence group (p=0.081), respectively. When hepatitis B virus persistent cases were divided into inactive healthy carrier (group 2) and disease progression group (group 3 and 4), MBL gene polymorphisms at codon 54 were not related to disease progression (p=0.166). MBL gene polymorphism at codon 54 was not associated with the clearance of hepatitis B virus infection nor progression of disease in chronic hepatitis B virus infection.
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Affiliation(s)
- Jae Youn Cheong
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Sung Won Cho
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Sun Kyo Lim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Do Hyun Shin
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Seung Kew Yoon
- Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea
| | | | - Ki Baik Hahm
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Jin Hong Kim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
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Eisen DP, Minchinton RM. Impact of Mannose-Binding Lectin on Susceptibility to Infectious Diseases. Clin Infect Dis 2003; 37:1496-505. [PMID: 14614673 DOI: 10.1086/379324] [Citation(s) in RCA: 321] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2003] [Accepted: 07/16/2003] [Indexed: 01/16/2023] Open
Abstract
When the adaptive immune response is either immature or compromised, the innate immune system constitutes the principle defense against infection. Mannose-binding lectin (MBL) is a C-type serum lectin that plays a central role in the innate immune response. MBL binds microbial surface carbohydrates and mediates opsonophagocytosis directly and by activation of the lectin complement pathway. A wide variety of clinical isolates of bacteria, fungi, viruses, and parasites are bound by MBL. Three polymorphisms in the structural gene MBL2) and 2 promoter gene polymorphisms are commonly found that result in production of low serum levels of MBL. Clinical studies have shown that MBL insufficiency is associated with bacterial infection in patients with neutropenia and meningococcal sepsis. Low MBL levels appear to predispose persons to HIV infection. Numerous other potential infectious disease associations have been described. Therapy to supplement low MBL levels is being explored using either plasma-derived or recombinant material.
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Affiliation(s)
- Damon P Eisen
- Infectious Diseases Unit, Royal Brisbane Hospital, Herston, Queensland, Australia.
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25
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Wang FS. Current status and prospects of studies on human genetic alleles associated with hepatitis B virus infection. World J Gastroenterol 2003; 9:641-4. [PMID: 12679901 PMCID: PMC4611419 DOI: 10.3748/wjg.v9.i4.641] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection can cause a broad spectrum diseases, including from asymptomatic HBV carriers or cryptic hepatitis, to acute hepatitis, chronic hepatitis, Liver cirrhosis and primary hepatocellular carcinoma. The variable pattern and clinical outcome of the infection were mainly determined by virological itself factors, host immunological factors and genetic factors as well as the experimental factors. Among the human genetic factors, major candidate or identified genes involved in the process of HBV infection fall into the following categories: (1) genes that mediate the processes of viral entry into hepatocytes, including genes involved in viral binding, fusion with cellular membrane and transportation in target cells; (2) genes that modulate or control the immune response to HBV infection; (3) genes that participate in the pathological alterations in liver tissue; (4) genes involved in the development of liver cirrhosis and hepatocellular carcinoma associated with chronic HBV infection, including genes related to mother-to-infant transmission of HBV infection; and (5) those that contribute to resistance to antiviral therapies. Most of the reports of human genes associated with HBV infection have currently focused on HLA associations. For example, some investigators reported the association of the HLA class II alleles such as DRB1*1302 or HLA-DR13 or DQA1*0501-DQB1*0301-DQB1*1102 haplotypes with acute and/or chronic hepatitis B virus infection, respectively. Several pro-inflammatory cytokines such as Th1 cytokines (including IL-2 and IFN-γ) and TNF-α have been identified to participate the process of viral clearance and host immune response to HBV. In contrast, the Th2 cytokine IL-10 serves as a potent inhibitor of Th1 effector cells in HBV diseases. The MBP polymorphisms in its encoding region were found to be involved in chronic infection. Thus, reports from various laboratories have shown some inconsistencies with regard to the effects of host genetic factors on HBV clearance and persistence. Since genetic interactions are complex, it is unlikely that a single allelic variant is responsible for HBV resistance or susceptibility. However, the collective influence of several single nucleotide polymorphisms (SNPs) or haplotype (s) may underlie the natural combinational or synergistic protection against HBV. The future study including the multi-cohort collaboration will be needed to clarify these preliminary associations and identify other potential candidate genes. The ongoing study of the distributions and functions of the implicated allele polymorphisms will not only provide insight into the pathogenesis of HBV infection, but may also provide a novel rationale for new methods of diagnosis and therapeutic strategies.
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Affiliation(s)
- Fu-Sheng Wang
- Division of Bioengineering, Beijing Institute of Infectious Diseases, 100 Xi Si-Huan-Zhong Road, Beijing 100039, China.
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Song LH, Binh VQ, Duy DN, Jüliger S, Bock TC, Luty AJF, Kremsner PG, Kun JFJ. Mannose-binding lectin gene polymorphisms and hepatitis B virus infection in Vietnamese patients. Mutat Res 2003; 522:119-125. [PMID: 12517417 DOI: 10.1016/s0027-5107(02)00284-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Mannose-binding lectin (MBL) is a constituent of the human innate immune system which may play an important role in combating a variety of infectious diseases. We investigated the distribution of MBL gene mutations in a Vietnamese population, using polymerase chain reaction and DNA sequence analysis, and sought associations with the outcome of hepatitis B virus (HBV) infection. For this purpose we used samples from a total of 123 patients with confirmed, well-defined HBV infections, representing a full spectrum of clinical presentation from acute to chronic to malignant states, as well as from 112 healthy controls. The only MBL gene mutation found in this population, that at codon 54 of exon 1, was present at an overall frequency of 0.12, with a trend towards a higher frequency in the HBV-infected group compared with controls (0.15 versus 0.08, P = 0.079). Within the HBV-infected group there was a non-significant trend towards higher viral loads in those with this mutation, accompanied by significantly higher serum transaminase levels in the same individuals. Segregation according to clinical presentation showed that the mutation was present at a significantly higher frequency in the group with acute hepatitis B (AHB) compared with the healthy control group (0.25 versus 0.08, P = 0.01), and was associated with higher serum transaminase levels. Our results indicate that a mutation of the MBL gene might influence the clinical outcome of HBV infection in Vietnamese patients.
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Affiliation(s)
- Le H Song
- Tran Hung Dao Hospital, No 1 Tran Hung Dao street, Hanoi, Viet Nam
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28
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Höhler T, Reuss E, Evers N, Dietrich E, Rittner C, Freitag CM, Vollmar J, Schneider PM, Fimmers R. Differential genetic determination of immune responsiveness to hepatitis B surface antigen and to hepatitis A virus: a vaccination study in twins. Lancet 2002; 360:991-5. [PMID: 12383669 DOI: 10.1016/s0140-6736(02)11083-x] [Citation(s) in RCA: 145] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND The course of viral hepatitis is thought to be affected by genetic host variability and, in particular, by genes of the major histocompatibility locus. Hepatitis A and B vaccination is a useful model to study the effect of host factors on the immune response to viral antigens. We aimed to assess the heritability of the HBsAg (anti-HBs) and anti-hepatitis A virus (anti-HAV) immune response and to estimate the effect of the HLA-DRB1 locus and other genetic loci unlinked to HLA. METHODS We did an open prospective study and vaccinated 202 twin pairs with a combined recombinant HBsAg/inactivated hepatitis A vaccine. We measured antibodies to HBsAg and HAV and determined HLA-DRB1* alleles. Heritability was calculated based on variance of antibody response within pairs. Model-fitting analyses were done to analyse genetic and environmental components of vaccine responses. FINDINGS Anti-HBs and anti-HAV showed heritabilities of 0.61 (95% CI 0.41 to 0.81) and 0.36 (-0.02 to 0.73), respectively. For the anti-HBs immune response, 60% of the phenotypic variance was explained by additive genetic and 40% by non-shared environmental effects. The heritability of the HBsAg vaccine response accounted for by the DRB1* locus was estimated to be 0.25, leaving the remaining heritability of 0.36 to other gene loci. INTERPRETATION Genetic factors have a strong effect on the immune response to HBsAg. Although genes encoded within the MHC are important for this immune response, more than half the heritability is determined outside this complex. Identification of these genes will help us to understand regulation of immune responses to viral proteins.
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Affiliation(s)
- Thomas Höhler
- Department of Internal Medicine, Johannes Gutenberg-University, Mainz, Germany.
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29
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Rector A, Lemey P, Laffut W, Keyaerts E, Struyf F, Wollants E, Vermeire S, Rutgeerts P, Van Ranst M. Mannan-binding lectin (MBL) gene polymorphisms in ulcerative colitis and Crohn's disease. Genes Immun 2001; 2:323-8. [PMID: 11607788 DOI: 10.1038/sj.gene.6363784] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2001] [Revised: 06/06/2001] [Accepted: 07/02/2001] [Indexed: 12/20/2022]
Abstract
The inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC), are complex multifactorial traits involving both environmental and genetic factors. Mannan-binding lectin (MBL) plays an important role in non-specific immunity and complement activation. Point mutations in codons 52, 54 and 57 of exon 1 of the MBL gene are associated with decreased MBL plasma concentrations and increased susceptibility to various infectious diseases. If these MBL mutations could lead to susceptibility to putative IBD-etiological microbial agents, or could temper the complement-mediated mucosal damage in IBD, MBL could function as the link between certain microbial, immunological and genetic factors in IBD. In this study, we investigated the presence of the codon 52, 54 and 57 mutations of the MBL gene in 431 unrelated IBD patients, 112 affected and 141 unaffected first-degree relatives, and 308 healthy control individuals. In the group of sporadic IBD patients (n = 340), the frequency of the investigated MBL variants was significantly lower in UC patients when compared with CD patients (P = 0.01) and with controls (P = 0.02). These results suggest that MBL mutations which decrease the formation of functional MBL could protect against the clinical development of sporadic UC, but not of CD. This could be explained by the differential T-helper response in both diseases.
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Affiliation(s)
- A Rector
- Laboratory of Clinical & Epidemiological Virology, Department of Microbiology & Immunology, Rega Institute for Medical Research, Leuven, Belgium
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30
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McNicholl JM, Downer MV, Udhayakumar V, Alper CA, Swerdlow DL. Host-pathogen interactions in emerging and re-emerging infectious diseases: a genomic perspective of tuberculosis, malaria, human immunodeficiency virus infection, hepatitis B, and cholera. Annu Rev Public Health 2001; 21:15-46. [PMID: 10884944 DOI: 10.1146/annurev.publhealth.21.1.15] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
On exposure to a pathogen, a host may resist infection, become subclinically infected, or progress through several stages from mild to severe infection. Chronic sequelae may or may not occur. Host factors, particularly host genes, influence many of these stages. We have used a model of the continuum of pathogenesis of infectious diseases to consider the effect of host genes on five pathogens of significant public health burden: Mycobacterium tuberculosis, Plasmodium species, human immunodeficiency virus, hepatitis B virus, and Vibrio cholerae. The relationships between these infections and polymorphisms in human leukocyte antigen, cytokines, other immune response, or pathogen receptor genes are reviewed. We discuss gene-gene interactions and their effects in complex settings, such as coinfections with several pathogens. Priorities for prevention and control of these pathogens include vaccines and antimicrobial drugs. Research on how host genes can influence vaccine responses and the efficacy of drugs or other interventions, as well as further research into the relationship of host genes to infectious disease outcomes, may lead to new strategies for prevention and control.
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Affiliation(s)
- J M McNicholl
- Division of AIDS, National Center for Infectious Diseases, Centers for Disease Control, Atlanta, Georgia 30333, USA.
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31
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Affiliation(s)
- C L Thio
- Division of Infectious Diseases, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
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