|
1
|
Saldarriaga Cartagena AM, Rivera EM, Sánchez-López EF, Formigo PM, Legarralde A, Ganuza A, Alonso AM, Clemente M, Angel SO. Toxoplasma cyst wall CST9 elicits an acute-associated humoral response in humans and mice and protects against chronic infection in immunized mice. Microb Pathog 2025; 205:107638. [PMID: 40287105 DOI: 10.1016/j.micpath.2025.107638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 04/04/2025] [Accepted: 04/24/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND Toxoplasma gondii is an obligate intracellular parasite that causes human and animal toxoplasmosis. It is considered an essential zoonotic foodborne infection. Up to now, there is not an adequate determination of acute toxoplasmosis in a single assay or a low-cost, safe vaccine against animal or human toxoplasmosis. METHODS We selected three parasite proteins belonging to dense granules and present in the secretome: TGME49_200360 (hypothetical protein), GRA17, and CST9. These recombinant proteins were analyzed using serum from mice experimentally infected with Me49 cysts and using a panel of human sera grouped as acute, chronic, or seronegative by IgG-ELISA. Besides, C57BL mice were immunized with rCST9 combined with alum or PBS + alum and challenged with tachyzoite of RH (100) and Me49 (1000 and 10,000) strains. Survival, serology, and brain cysts were analyzed. RESULTS Of the three proteins, only rCST9 showed reactivity with experimentally infected mice, restricted to day 15 post-infection but not on day 21 and beyond. Analysis of human serum samples showed that 36.66 % of acute sera and 4.61 % of chronic sera reacted with rCST9, while the other rAGs showed sensitivities below 5 % in all cases. The immunization of rCST9 combined with alum showed that it could not protect against the virulent strain RH but efficiently control the chronic infection in mice challenged with the avirulent strain Me49. CONCLUSIONS These data indicate that rCST9 presents an antigenic exposure restricted to the acute stage and can protect against chronic infection in the mouse model.
Collapse
Affiliation(s)
- Ana M Saldarriaga Cartagena
- Laboratorio de Parasitología Molecular, Instituto Tecnológico de Chascomús (INTECH), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)/Universidad Nacional General San Martin (UNSAM), Chascomús, Prov. Buenos Aires, Argentina; Escuela de Bio y Nanotecnologías, CONICET/UNSAM, Chascomús, Prov. Buenos Aires, Argentina
| | - Elias M Rivera
- Laboratorio de Parasitología Molecular, Instituto Tecnológico de Chascomús (INTECH), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)/Universidad Nacional General San Martin (UNSAM), Chascomús, Prov. Buenos Aires, Argentina; Escuela de Bio y Nanotecnologías, CONICET/UNSAM, Chascomús, Prov. Buenos Aires, Argentina
| | - Edwin F Sánchez-López
- Escuela de Bio y Nanotecnologías, CONICET/UNSAM, Chascomús, Prov. Buenos Aires, Argentina; Laboratorio de Molecular Farming y Vacunas, INTECH, EByN, CONICET-UNSAM, Chascomús, Buenos Aires, Argentina
| | - Paula M Formigo
- Laboratorio de Parasitología Molecular, Instituto Tecnológico de Chascomús (INTECH), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)/Universidad Nacional General San Martin (UNSAM), Chascomús, Prov. Buenos Aires, Argentina; Escuela de Bio y Nanotecnologías, CONICET/UNSAM, Chascomús, Prov. Buenos Aires, Argentina
| | - Ariel Legarralde
- Laboratorio de Molecular Farming y Vacunas, INTECH, EByN, CONICET-UNSAM, Chascomús, Buenos Aires, Argentina
| | - Agustina Ganuza
- Laboratorio de Parasitología Molecular, Instituto Tecnológico de Chascomús (INTECH), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)/Universidad Nacional General San Martin (UNSAM), Chascomús, Prov. Buenos Aires, Argentina; Escuela de Bio y Nanotecnologías, CONICET/UNSAM, Chascomús, Prov. Buenos Aires, Argentina
| | - Andrés M Alonso
- Laboratorio de Parasitología Molecular, Instituto Tecnológico de Chascomús (INTECH), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)/Universidad Nacional General San Martin (UNSAM), Chascomús, Prov. Buenos Aires, Argentina; Escuela de Bio y Nanotecnologías, CONICET/UNSAM, Chascomús, Prov. Buenos Aires, Argentina
| | - Marina Clemente
- Escuela de Bio y Nanotecnologías, CONICET/UNSAM, Chascomús, Prov. Buenos Aires, Argentina; Laboratorio de Molecular Farming y Vacunas, INTECH, EByN, CONICET-UNSAM, Chascomús, Buenos Aires, Argentina.
| | - Sergio O Angel
- Laboratorio de Parasitología Molecular, Instituto Tecnológico de Chascomús (INTECH), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)/Universidad Nacional General San Martin (UNSAM), Chascomús, Prov. Buenos Aires, Argentina; Escuela de Bio y Nanotecnologías, CONICET/UNSAM, Chascomús, Prov. Buenos Aires, Argentina.
| |
Collapse
|
|
2
|
Hernandez-Castro LE, Cook EAJ, Matika O, Mengele IJ, Motto SK, Bwatota SF, Zirra-Shallangwa B, Pong-Wong R, Prendergast J, Mrode R, Toye PG, Komwihangilo DM, Lyatuu E, Karani BE, Nangekhe G, Mwai AO, Shirima GM, Bronsvoort BMDC. Genetic estimates and genome-wide association studies of antibody response in Tanzanian dairy cattle. Front Genet 2025; 16:1497355. [PMID: 40342962 PMCID: PMC12060032 DOI: 10.3389/fgene.2025.1497355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 03/03/2025] [Indexed: 05/11/2025] Open
Abstract
Identifying the genetic determinants of host defence against infectious pathogens is central to enhancing disease resilience and therapeutic efficacy in livestock. Here, we investigated immune response heritability to important infectious diseases affecting smallholder dairy cattle using variance component analysis. We also conducted genome-wide association studies (GWAS) to identify genetic variants that may help understand the underlying biology of these health traits. By assessing 668,911 single-nucleotide polymorphisms (SNPs) genotyped in 2,045 crossbred cattle sampled from six regions of Tanzania, we identified high levels of interregional admixture and European introgression, which may increase infectious disease susceptibility relative to indigenous breeds. Heritability estimates were low to moderate, ranging from 0.03 (SE ± 0.06) to 0.44 (SE ± 0.07), depending on the health trait. GWAS results revealed several loci associated with seropositivity to the viral diseases Rift Valley fever and bovine viral diarrhoea, the protozoan parasites Neospora caninum and Toxoplasma gondii, and the bacterial pathogens Brucella sp, Leptospira hardjo, and Coxiella burnetii. The identified quantitative trait loci mapped to genes involved in immune defence, tumour suppression, neurological processes, and cell exocytosis. We propose that our results provide a basis for future understanding of the cellular pathways contributing to general and taxon-specific infection responses, and for advancing selective breeding and therapeutic target design.
Collapse
Affiliation(s)
- Luis E. Hernandez-Castro
- Centre for Tropical Livestock Genetics and Health (CTLGH), Roslin Institute, University of Edinburgh, Roslin, United Kingdom
- The Roslin Institute and The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Edinburgh, United Kingdom
| | - Elizabeth Anne Jessie Cook
- International Livestock Research Institute (ILRI), Nairobi, Kenya
- Centre for Tropical Livestock Genetics and Health (CTLGH), ILRI Kenya, Nairobi, Kenya
| | - Oswald Matika
- Centre for Tropical Livestock Genetics and Health (CTLGH), Roslin Institute, University of Edinburgh, Roslin, United Kingdom
- The Roslin Institute and The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Edinburgh, United Kingdom
| | - Isaac Joseph Mengele
- Department of Global Health and Bio-Medical Sciences, School of Life Science and Bioengineering, The Nelson Mandela African Institution of Science and Technology, Arusha, Tanzania
- Tanzania Veterinary Laboratory Agency, Central Veterinary Laboratory, Dar es Salaam, Tanzania
| | - Shabani Kiyabo Motto
- Department of Global Health and Bio-Medical Sciences, School of Life Science and Bioengineering, The Nelson Mandela African Institution of Science and Technology, Arusha, Tanzania
- Tanzania Veterinary Laboratory Agency, Central Veterinary Laboratory, Dar es Salaam, Tanzania
| | - Shedrack Festo Bwatota
- Department of Global Health and Bio-Medical Sciences, School of Life Science and Bioengineering, The Nelson Mandela African Institution of Science and Technology, Arusha, Tanzania
| | - Bibiana Zirra-Shallangwa
- The Roslin Institute and The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Edinburgh, United Kingdom
| | - Ricardo Pong-Wong
- The Roslin Institute and The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Edinburgh, United Kingdom
| | - James Prendergast
- Centre for Tropical Livestock Genetics and Health (CTLGH), Roslin Institute, University of Edinburgh, Roslin, United Kingdom
- The Roslin Institute and The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Edinburgh, United Kingdom
| | | | - Philip G. Toye
- International Livestock Research Institute (ILRI), Nairobi, Kenya
- Centre for Tropical Livestock Genetics and Health (CTLGH), ILRI Kenya, Nairobi, Kenya
| | | | - Eliamoni Lyatuu
- International Livestock Research Institute (ILRI), Dar es Salaam, Tanzania
| | - Benedict E. Karani
- International Livestock Research Institute (ILRI), Nairobi, Kenya
- Centre for Tropical Livestock Genetics and Health (CTLGH), ILRI Kenya, Nairobi, Kenya
| | - Getrude Nangekhe
- International Livestock Research Institute (ILRI), Nairobi, Kenya
- Centre for Tropical Livestock Genetics and Health (CTLGH), ILRI Kenya, Nairobi, Kenya
| | - Ally Okeyo Mwai
- International Livestock Research Institute (ILRI), Nairobi, Kenya
| | - Gabriel Mkilema Shirima
- Department of Global Health and Bio-Medical Sciences, School of Life Science and Bioengineering, The Nelson Mandela African Institution of Science and Technology, Arusha, Tanzania
| | - Barend Mark de Clare Bronsvoort
- Centre for Tropical Livestock Genetics and Health (CTLGH), Roslin Institute, University of Edinburgh, Roslin, United Kingdom
- The Roslin Institute and The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Edinburgh, United Kingdom
| |
Collapse
|
|
3
|
Wang W, Jin X, Shao Q, Liu T, Liu T, Zhao X, Xu L, Gao W, Hu L, Chen Z. The Chinese herbal prescription JZ-1 promotes extracellular vesicle production and protects against herpes simplex virus type 2 infection in vitro. Heliyon 2024; 10:e27019. [PMID: 38495169 PMCID: PMC10940933 DOI: 10.1016/j.heliyon.2024.e27019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 02/08/2024] [Accepted: 02/22/2024] [Indexed: 03/19/2024] Open
Abstract
Objective Genital herpes, primarily caused by HSV-2 infection, remains a widespread sexually transmitted ailment. Extracellular vesicles play a pivotal role in host-virus confrontation. Recent research underscores the influence of Chinese herbal prescriptions on extracellular vesicle production and composition. This study aims to probe the impact of JieZe-1 (JZ-1) on extracellular vesicle components, elucidating its mechanisms against HSV-2 infection via extracellular vesicles. Methods The JZ-1's anti-HSV-2 effects were assessed using CCK-8 assay. Extracellular vesicles were precisely isolated utilizing ultracentrifugation and subsequently characterized through TEM, NTA, and Western Blot analyses. The anti-HSV-2 activity of extracellular vesicles was gauged using CCK-8, Western Blot, and immunofluorescence. Additionally, high-throughput sequencing was employed to detect miRNAs from extracellular vesicles, unraveling the potential antiviral mechanisms of JZ-1. Results Antiviral efficacy of JZ-1 was shown in VK2/E6E7, HeLa, and Vero cells. The samples extracted from cell supernatant by ultracentrifugation were identified as extracellular vesicles. In VK2/E6E7 cells, extracellular vesicles from JZ-1 group enhanced cell survival rates and diminished the expression of intracellular viral protein gD, contrasting with the inert effect of control group vesicles. Extracellular vesicles from JZ-1 treated Vero cells demonstrated a weaker yet discernible anti-HSV-2 effect. Conversely, extracellular vesicles of HeLa cells exhibited no anti-HSV-2 effect from either group. High-throughput sequencing of VK2/E6E7 cell extracellular vesicles unveiled significant upregulation of miRNA-101, miRNA-29a, miRNA-29b, miRNA-29c, and miRNA-637 in JZ-1 group vesicles. KEGG pathway analysis suggested that these miRNAs may inhibit PI3K/AKT/mTOR signaling pathway and induce autophagy of host cells to protect against HSV-2. Western blot confirmed the induction of autophagy and inhibition of AKT/mTOR in VK2/E6E7 cells with JZ-1 group extracellular vesicles treatment. Conclusion JZ-1 had an anti-HSV-2 efficacy. After JZ-1 stimulation, VK2/E6E7 cells secreted extracellular vesicles which protect host cells from HSV-2 infection. High-throughput sequencing showed that these extracellular vesicles contained a large number of miRNAs targeting PI3K/AKT/mTOR pathway. JZ-1 group extracellular vesicles could inhibit the activation of AKT/mTOR pathway and induce the host cells autophagy.
Collapse
Affiliation(s)
- Wenjia Wang
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ximing Jin
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Qingqing Shao
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Tong Liu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Tianli Liu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xinwei Zhao
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Lijun Xu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wen Gao
- Health Management Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Liu Hu
- Health Management Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Zhuo Chen
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| |
Collapse
|
|
4
|
John M, Orathel SP, Varghese J, Pradeep M, Jacob QM, Thomas R, John SB, Ramamoorthy V, Saxena A, Rubens M. Familial Aggregation and ABO Blood Groups and COVID-19 Severity Among Hospitalized Patients. INFECTIOUS DISEASES IN CLINICAL PRACTICE 2024; 22. [DOI: 10.1097/ipc.0000000000001335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
Abstract
Background
Planning effective preventive and control measures requires understanding of the variability in the severity of infectious illnesses and factors determining susceptibility. The present study aimed to assess the association between familial susceptibility and ABO blood group with COVID-19 disease severity and adverse outcomes.
Methods
The present study was a retrospective investigation that was carried out at a tertiary care hospital with a bed capacity of 560 in the state of Kerala, India. A structured questionnaire was used to extract demographic and clinical characteristics from screened records. The study participants were stratified into 2 distinct groups based on the severity of their illness: mild to moderate and severe. Familial aggregation was operationally defined as the occurrence of COVID-19 diagnosis in any first-degree relative.
Results
A total of 362 hospitalized patients with confirmed COVID-19 infection were included in the analysis. Among them 62 (17.1%) were categorized as severe COVID-19 and 300 (82.9%) were categorized as mild to moderate COVID-19. Binary logistic regression analysis showed that the odds of sever COVID-19 disease was significantly higher among patients with familial aggregation (odds ratio, 2.47; 95% confidence interval, 2.12–2.85) and with non-O blood group (odds ratio, 2.21; 95% confidence interval, 2.01–2.56).
Conclusions
The findings of our study highlight the significance of familial aggregation and ABO blood group as crucial factors in determining the severity of COVID-19 disease. Comprehending the interrelationship between these variables and the genetic makeup of the host may hold significance in prognosticating the gravity of COVID-19 consequences.
Collapse
|
|
5
|
Debost JPG, Thorsteinsson E, Trabjerg B, Benros ME, Albiñana C, Vilhjalmsson BJ, Børglum A, Mors O, Werge T, Mortensen PB, Agerbo E, Petersen LV. Genetic and psychosocial influence on the association between early childhood infections and later psychiatric disorders. Acta Psychiatr Scand 2022; 146:406-419. [PMID: 35999619 PMCID: PMC9826256 DOI: 10.1111/acps.13491] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 08/12/2022] [Accepted: 08/13/2022] [Indexed: 01/29/2023]
Abstract
To evaluate the influence of extensive genetic and psychosocial confounding on the association between early childhood infection and five major psychiatric disorders METHODS: A case-cohort study including participants from the Danish iPSYCH2012 sample, a case-cohort sample where all cases born between May 1, 1981, and December 31, 2005, diagnosed with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar affective disorder (BIP), Major Depressive Disorder (MDD) or schizophrenia (SCZ), were identified and pooled with a representative sample (subcohort) of the Danish population. We used Cox proportional hazards regression customized to the case-cohort setup to calculate hazard ratios of outcome with 95% confidence intervals (CIs), following exposure to early childhood infection before the age of 5 years for ADHD and ASD, and before the age of 10 years for BIP, MDD, and SCZ. To evaluate psychosocial confounding we included sex, calendar period, sibling infections, urbanicity, parental socio-economic status, parental mental health information, and polygenic risk scores for all five disorders, as covariates. To estimate how liability for psychiatric disorders measured through the PRS influenced the risk of early childhood infection, we calculated odds ratios (ORs) with 95% CIs, using logistic regression RESULTS: Early childhood infection was associated with ADHD, ASD, MDD, and SCZ with number of childhood infections increasing the hazard. The HR was still significant in the model with full adjustments after 1 infection for ADHD (HR 1.29, 95% CI: 1.19-1.41), ASD (HR 1.28, 95% CI: 1.18-1.40), MDD (HR 1.23, 95% CI: 1.14-1.33), and SCZ (HR 1.21, 95% CI: 1.07-1.36), but not for BIP (HR1.17, 95% CI: 0.96-1.42). Probands exposed to sibling infections, but not own infection had an absolute risk of ADHD, BIP, MDD, and SCZ that closely approached the absolute risk for individuals exposed to own infections. We found evidence of gene-environment correlation with higher PRS of MDD and to some extent SCZ increasing the risk of infections and higher PRS of BIP associated with significantly decreased risk CONCLUSION: Early childhood infection is significantly associated with ADHD, ASD, MDD, and SCZ and not explained by genetic or psychosocial confounding. Although we found evidence of gene-environment correlation, it had minor impact on the results.
Collapse
Affiliation(s)
- Jean‐Christophe Philippe Goldtsche Debost
- Department of PsychosisAarhus University Hospital – PsychiatryAarhusDenmark,National Centre for Register‐based Research, Department of Economics and Business EconomicsAarhus UniversityAarhusDenmark,iPSYCH ‐ The Lundbeck Foundation Initiative for Integrative Psychiatric ResearchDenmark
| | - Erla Thorsteinsson
- National Centre for Register‐based Research, Department of Economics and Business EconomicsAarhus UniversityAarhusDenmark,iPSYCH ‐ The Lundbeck Foundation Initiative for Integrative Psychiatric ResearchDenmark
| | - Betina Trabjerg
- National Centre for Register‐based Research, Department of Economics and Business EconomicsAarhus UniversityAarhusDenmark,iPSYCH ‐ The Lundbeck Foundation Initiative for Integrative Psychiatric ResearchDenmark
| | - Michael Eriksen Benros
- Biological and Precision Psychiatry, Copenhagen Research Centre for Mental Health, Mental Health Centre CopenhagenCopenhagen UniversityCopenhagenDenmark,Department of Immunology and Microbiology, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Clara Albiñana
- National Centre for Register‐based Research, Department of Economics and Business EconomicsAarhus UniversityAarhusDenmark,iPSYCH ‐ The Lundbeck Foundation Initiative for Integrative Psychiatric ResearchDenmark
| | - Bjarni Johann Vilhjalmsson
- National Centre for Register‐based Research, Department of Economics and Business EconomicsAarhus UniversityAarhusDenmark,iPSYCH ‐ The Lundbeck Foundation Initiative for Integrative Psychiatric ResearchDenmark
| | - Anders Børglum
- iPSYCH ‐ The Lundbeck Foundation Initiative for Integrative Psychiatric ResearchDenmark,Department of Biomedicine and Centre for Integrative Sequencing, iSEQAarhus UniversityAarhusDenmark,Center for Genomics and Personalized MedicineCentral Region Denmark and Aarhus UniversityAarhusDenmark
| | - Ole Mors
- iPSYCH ‐ The Lundbeck Foundation Initiative for Integrative Psychiatric ResearchDenmark,Psychosis Research UnitAarhus University Hospital – PsychiatryAarhusDenmark
| | - Thomas Werge
- iPSYCH ‐ The Lundbeck Foundation Initiative for Integrative Psychiatric ResearchDenmark,Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health ServicesRoskildeDenmark,Department of Clinical MedicineUniversity of CopenhagenCopenhagenDenmark,Center for GeoGeneticsGLOBE Institute, University of CopenhagenCopenhagenDenmark
| | - Preben Bo Mortensen
- National Centre for Register‐based Research, Department of Economics and Business EconomicsAarhus UniversityAarhusDenmark,iPSYCH ‐ The Lundbeck Foundation Initiative for Integrative Psychiatric ResearchDenmark,CIRRAU – Centre for Integrated Register‐based ResearchAarhus UniversityAarhusDenmark
| | - Esben Agerbo
- National Centre for Register‐based Research, Department of Economics and Business EconomicsAarhus UniversityAarhusDenmark,iPSYCH ‐ The Lundbeck Foundation Initiative for Integrative Psychiatric ResearchDenmark,CIRRAU – Centre for Integrated Register‐based ResearchAarhus UniversityAarhusDenmark
| | - Liselotte Vogdrup Petersen
- National Centre for Register‐based Research, Department of Economics and Business EconomicsAarhus UniversityAarhusDenmark,iPSYCH ‐ The Lundbeck Foundation Initiative for Integrative Psychiatric ResearchDenmark
| |
Collapse
|
|
6
|
Venkataraman T, Valencia C, Mangino M, Morgenlander W, Clipman SJ, Liechti T, Valencia A, Christofidou P, Spector T, Roederer M, Duggal P, Larman HB. Analysis of antibody binding specificities in twin and SNP-genotyped cohorts reveals that antiviral antibody epitope selection is a heritable trait. Immunity 2022; 55:174-184.e5. [PMID: 35021055 PMCID: PMC8852220 DOI: 10.1016/j.immuni.2021.12.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 08/19/2021] [Accepted: 12/07/2021] [Indexed: 01/13/2023]
Abstract
Human immune responses to viral infections are highly variable, but the genetic factors that contribute to this variability are not well characterized. We used VirScan, a high-throughput epitope scanning technology, to analyze pan-viral antibody reactivity profiles of twins and SNP-genotyped individuals. Using these data, we determined the heritability and genomic loci associated with antibody epitope selection, response breadth, and control of Epstein-Barr virus (EBV) viral load. 107 EBV peptide reactivities were heritable and at least two Epstein-Barr nuclear antigen 2 (EBNA-2) reactivities were associated with variants in the MHC class II locus. We identified an EBV serosignature that predicted viral load in peripheral blood mononuclear cells and was associated with variants in the MHC class I locus. Our study illustrates the utility of epitope profiling to investigate the genetics of pathogen immunity, reports heritable features of the antibody response to viruses, and identifies specific HLA loci important for EBV epitope selection.
Collapse
Affiliation(s)
- Thiagarajan Venkataraman
- Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
| | - Cristian Valencia
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Massimo Mangino
- Department of Twin Research & Genetic Epidemiology, King’s College of London, London, UK,NIHR Biomedical Research Centre at Guy’s and St Thomas’ Foundation Trust, London SE1 9RT, UK
| | - William Morgenlander
- Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
| | - Steven J. Clipman
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Thomas Liechti
- ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD, USA
| | - Ana Valencia
- School of Medicine, Universidad Pontificia Bolivariana, Medellín, Colombia
| | - Paraskevi Christofidou
- Department of Twin Research & Genetic Epidemiology, King’s College of London, London, UK
| | - Tim Spector
- Department of Twin Research & Genetic Epidemiology, King’s College of London, London, UK
| | - Mario Roederer
- ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD, USA
| | - Priya Duggal
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA,Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - H. Benjamin Larman
- Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University, Baltimore, MD, USA,Lead contact,Correspondence: (H.B.L)
| |
Collapse
|
|
7
|
Duan Q, Liu T, Huang C, Shao Q, Ma Y, Wang W, Liu T, Sun J, Fang J, Huang G, Chen Z. The Chinese Herbal Prescription JieZe-1 Inhibits Membrane Fusion and the Toll-like Receptor Signaling Pathway in a Genital Herpes Mouse Model. Front Pharmacol 2021; 12:707695. [PMID: 34630083 PMCID: PMC8497740 DOI: 10.3389/fphar.2021.707695] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 09/09/2021] [Indexed: 12/16/2022] Open
Abstract
Chinese herbal prescription JieZe-1 is effective for genital herpes with no visible adverse effects clinically. It showed an excellent anti-HSV-2 effect in vitro. However, its mechanism of anti-HSV-2 effect in vivo remains unclear. This study was designed to evaluate the anti-HSV-2 effect of JieZe-1 and berberine in a genital herpes mouse model and explore the underlying mechanism. The fingerprint of JieZe-1 was determined by high-performance liquid chromatography. First, we optimized a mouse model of genital herpes. Next, the weight, symptom score, morphological changes, viral load, membrane fusion proteins, critical proteins of the Toll-like receptor signaling pathway, cytokines, and immune cells of vaginal tissue in mice at different time points were measured. Finally, we treated the genital herpes mouse model with JieZe-1 gel (2.5, 1.5, and 0.5 g/ml) and tested the above experimental indexes at 12 h and on the 9th day after modeling. JieZe-1 improved the symptoms, weight, and histopathological damage of genital herpes mice, promoted the keratin repair of tissues, and protected organelles to maintain the typical morphology of cells. It downregulated the expression of membrane fusion proteins, critical proteins of the Toll-like receptor signaling pathway, cytokines, and immune cells. The vaginal, vulvar, and spinal cord viral load and vaginal virus shedding were also significantly reduced. In summary, JieZe-1 shows significant anti-HSV-2 efficacy in vivo. The mechanism is related to the inhibition of membrane fusion, the Toll-like receptor signaling pathway, inflammatory cytokines, and cellular immunity. However, berberine, the main component of JieZe-1 monarch medicine, showed no efficacy at a concentration of 891.8 μM (0.3 mg/ml).
Collapse
Affiliation(s)
- Qianni Duan
- Department of TCM, Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tong Liu
- Department of TCM, Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cong Huang
- Department of TCM, Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qingqing Shao
- Department of TCM, Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yonggui Ma
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenjia Wang
- Department of TCM, Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tianli Liu
- Department of TCM, Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Sun
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianguo Fang
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guangying Huang
- Department of TCM, Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhuo Chen
- Department of TCM, Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
8
|
van Blokland IV, Lanting P, Ori APS, Vonk JM, Warmerdam RCA, Herkert JC, Boulogne F, Claringbould A, Lopera-Maya EA, Bartels M, Hottenga JJ, Ganna A, Karjalainen J, Hayward C, Fawns-Ritchie C, Campbell A, Porteous D, Cirulli ET, Schiabor Barrett KM, Riffle S, Bolze A, White S, Tanudjaja F, Wang X, Ramirez JM, Lim YW, Lu JT, Washington NL, de Geus EJC, Deelen P, Boezen HM, Franke LH. Using symptom-based case predictions to identify host genetic factors that contribute to COVID-19 susceptibility. PLoS One 2021; 16:e0255402. [PMID: 34379666 PMCID: PMC8357137 DOI: 10.1371/journal.pone.0255402] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 07/15/2021] [Indexed: 01/24/2023] Open
Abstract
Epidemiological and genetic studies on COVID-19 are currently hindered by inconsistent and limited testing policies to confirm SARS-CoV-2 infection. Recently, it was shown that it is possible to predict COVID-19 cases using cross-sectional self-reported disease-related symptoms. Here, we demonstrate that this COVID-19 prediction model has reasonable and consistent performance across multiple independent cohorts and that our attempt to improve upon this model did not result in improved predictions. Using the existing COVID-19 prediction model, we then conducted a GWAS on the predicted phenotype using a total of 1,865 predicted cases and 29,174 controls. While we did not find any common, large-effect variants that reached genome-wide significance, we do observe suggestive genetic associations at two SNPs (rs11844522, p = 1.9x10-7; rs5798227, p = 2.2x10-7). Explorative analyses furthermore suggest that genetic variants associated with other viral infectious diseases do not overlap with COVID-19 susceptibility and that severity of COVID-19 may have a different genetic architecture compared to COVID-19 susceptibility. This study represents a first effort that uses a symptom-based predicted phenotype as a proxy for COVID-19 in our pursuit of understanding the genetic susceptibility of the disease. We conclude that the inclusion of symptom-based predicted cases could be a useful strategy in a scenario of limited testing, either during the current COVID-19 pandemic or any future viral outbreak.
Collapse
Affiliation(s)
- Irene V. van Blokland
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Pauline Lanting
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Anil P. S. Ori
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Judith M. Vonk
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert C. A. Warmerdam
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Johanna C. Herkert
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Floranne Boulogne
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Annique Claringbould
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Structural Computational Biology unit, EMBL, Heidelberg, Germany
| | - Esteban A. Lopera-Maya
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Meike Bartels
- Department of Biological Psychology, FGB, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Amsterdam Public Health research institute, Amsterdam UMC, Amsterdam, The Netherlands
| | - Jouke-Jan Hottenga
- Department of Biological Psychology, FGB, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Andrea Ganna
- Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
| | - Juha Karjalainen
- Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
- Broad Institute of MIT and Harvard, Cambridge, MA, United States of America
- Analytic and Translational Genetics Unit (ATGU), Massachusetts General Hospital, Boston, MA, United States of America
| | | | | | - Caroline Hayward
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Chloe Fawns-Ritchie
- Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom
| | - Archie Campbell
- Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - David Porteous
- Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | | | | | - Stephen Riffle
- Helix OpCo LLC, San Mateo, California, United States of America
| | - Alexandre Bolze
- Helix OpCo LLC, San Mateo, California, United States of America
| | - Simon White
- Helix OpCo LLC, San Mateo, California, United States of America
| | | | - Xueqing Wang
- Helix OpCo LLC, San Mateo, California, United States of America
| | | | - Yan Wei Lim
- Helix OpCo LLC, San Mateo, California, United States of America
| | - James T. Lu
- Helix OpCo LLC, San Mateo, California, United States of America
| | | | - Eco J. C. de Geus
- Department of Biological Psychology, FGB, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Amsterdam Public Health research institute, Amsterdam UMC, Amsterdam, The Netherlands
| | - Patrick Deelen
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - H. Marike Boezen
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Lude H. Franke
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| |
Collapse
|
|
9
|
Hodel F, Chong AY, Scepanovic P, Xu ZM, Naret O, Thorball CW, Rüeger S, Marques-Vidal P, Vollenweider P, Begemann M, Ehrenreich H, Brenner N, Bender N, Waterboer T, Mentzer AJ, Hill AVS, Hammer C, Fellay J. Human genomics of the humoral immune response against polyomaviruses. Virus Evol 2021; 7:veab058. [PMID: 34532061 PMCID: PMC8438875 DOI: 10.1093/ve/veab058] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 04/30/2021] [Accepted: 06/09/2021] [Indexed: 12/21/2022] Open
Abstract
Human polyomaviruses are widespread in humans and can cause severe disease in immunocompromised individuals. To identify human genetic determinants of the humoral immune response against polyomaviruses, we performed genome-wide association studies and meta-analyses of qualitative and quantitative immunoglobulin G responses against BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), Merkel cellpolyomavirus (MCPyV), WU polyomavirus (WUPyV), and human polyomavirus 6 (HPyV6) in 15,660 individuals of European ancestry from three independent studies. We observed significant associations for all tested viruses: JCPyV, HPyV6, and MCPyV associated with human leukocyte antigen class II variation, BKPyV and JCPyV with variants in FUT2, responsible for secretor status, MCPyV with variants in STING1, involved in interferon induction, and WUPyV with a functional variant in MUC1, previously associated with risk for gastric cancer. These results provide insights into the genetic control of a family of very prevalent human viruses, highlighting genes and pathways that play a modulating role in human humoral immunity.
Collapse
Affiliation(s)
| | - A Y Chong
- The Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom
| | - P Scepanovic
- Roche Pharmaceutical Research and Early Development, F. Hoffmann-La Roche Ltd, Headquarters Grenzacherstrasse 124, CH-4070 Basel, Switzerland
| | - Z M Xu
- Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland,Swiss Institute of Bioinformatics, Quartier UNIL-Sorge, CH-1015 Lausanne, Switzerland
| | - O Naret
- Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland,Swiss Institute of Bioinformatics, Quartier UNIL-Sorge, CH-1015 Lausanne, Switzerland
| | - C W Thorball
- Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland,Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland
| | - S Rüeger
- Institute for Molecular Medicine Finland, Institute of Life Science HiLIFE, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland
| | - P Marques-Vidal
- Department of Medicine, Internal Medicine, Lausanne University Hospital and University of Lausanne, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland
| | | | - M Begemann
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine, DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Hermann-Rein-Straße 3, 37075 Göttingen, Germany
| | - H Ehrenreich
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine, DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Hermann-Rein-Straße 3, 37075 Göttingen, Germany
| | - N Brenner
- Infections and Cancer Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - N Bender
- Infections and Cancer Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - T Waterboer
- Infections and Cancer Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | | | - A V S Hill
- The Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom,The Jenner Institute, University of Oxford, Old Road Campus Research Build, Roosevelt Dr, Oxford OX1 2JD, United Kingdom
| | | | | |
Collapse
|
|
10
|
Mescheriakova JY, van Nierop GP, van der Eijk AA, Kreft KL, Hintzen RQ. EBNA-1 titer gradient in families with multiple sclerosis indicates a genetic contribution. NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION 2020; 7:7/6/e872. [PMID: 32796079 PMCID: PMC7428359 DOI: 10.1212/nxi.0000000000000872] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 07/07/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVE In multiplex MS families, we determined the humoral immune response to Epstein-Barr virus nuclear antigen 1 (EBNA-1)-specific immunoglobulin γ (IgG) titers in patients with MS, their healthy siblings, and biologically unrelated healthy spouses and investigated the role of specific genetic loci on the antiviral IgG titers. METHODS IgG levels against EBNA-1 and varicella zoster virus (VZV) as control were measured. HLA-DRB1*1501 and HLA-A*02 tagging single-nucleotide polymorphisms (SNPs) were genotyped. We assessed the associations between these SNPs and antiviral IgG titers. RESULTS OR for abundant EBNA-1 IgG was the highest in patients with MS and intermediate in their siblings compared with spouses. We confirmed that HLA-DRB1*1501 is associated with abundant EBNA-1 IgG. After stratification for HLA-DRB1*1501, the EBNA-1 IgG gradient was still significant in patients with MS and young siblings compared with spouses. HLA-A*02 was not explanatory for EBNA-1 IgG titer gradient. No associations for VZV IgG were found. CONCLUSIONS In families with MS, the EBNA-1 IgG gradient being the highest in patients with MS, intermediate in their siblings, and lowest in biologically unrelated spouses indicates a genetic contribution to EBNA-1 IgG levels that is only partially explained by HLA-DRB1*1501 carriership.
Collapse
Affiliation(s)
- Julia Y Mescheriakova
- From the Department of Neurology (J.Y.M., K.L.K.); Department of Viroscience (G.P.N., A.A.E.), Erasmus MC, University Medical Center, Rotterdam, the Netherlands; and Department of Neurology, MS Centre ErasMS, Erasmus MC, Rotterdam, the Netherlands (J.Y.M., K.L.K.)
| | - Gijsbert P van Nierop
- From the Department of Neurology (J.Y.M., K.L.K.); Department of Viroscience (G.P.N., A.A.E.), Erasmus MC, University Medical Center, Rotterdam, the Netherlands; and Department of Neurology, MS Centre ErasMS, Erasmus MC, Rotterdam, the Netherlands (J.Y.M., K.L.K.)
| | - Annemiek A van der Eijk
- From the Department of Neurology (J.Y.M., K.L.K.); Department of Viroscience (G.P.N., A.A.E.), Erasmus MC, University Medical Center, Rotterdam, the Netherlands; and Department of Neurology, MS Centre ErasMS, Erasmus MC, Rotterdam, the Netherlands (J.Y.M., K.L.K.)
| | - Karim L Kreft
- From the Department of Neurology (J.Y.M., K.L.K.); Department of Viroscience (G.P.N., A.A.E.), Erasmus MC, University Medical Center, Rotterdam, the Netherlands; and Department of Neurology, MS Centre ErasMS, Erasmus MC, Rotterdam, the Netherlands (J.Y.M., K.L.K.).
| | - Rogier Q Hintzen
- From the Department of Neurology (J.Y.M., K.L.K.); Department of Viroscience (G.P.N., A.A.E.), Erasmus MC, University Medical Center, Rotterdam, the Netherlands; and Department of Neurology, MS Centre ErasMS, Erasmus MC, Rotterdam, the Netherlands (J.Y.M., K.L.K.).
| |
Collapse
|
|
11
|
Kępińska AP, Iyegbe CO, Vernon AC, Yolken R, Murray RM, Pollak TA. Schizophrenia and Influenza at the Centenary of the 1918-1919 Spanish Influenza Pandemic: Mechanisms of Psychosis Risk. Front Psychiatry 2020; 11:72. [PMID: 32174851 PMCID: PMC7054463 DOI: 10.3389/fpsyt.2020.00072] [Citation(s) in RCA: 121] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 01/28/2020] [Indexed: 12/13/2022] Open
Abstract
Associations between influenza infection and psychosis have been reported since the eighteenth century, with acute "psychoses of influenza" documented during multiple pandemics. In the late 20th century, reports of a season-of-birth effect in schizophrenia were supported by large-scale ecological and sero-epidemiological studies suggesting that maternal influenza infection increases the risk of psychosis in offspring. We examine the evidence for the association between influenza infection and schizophrenia risk, before reviewing possible mechanisms via which this risk may be conferred. Maternal immune activation models implicate placental dysfunction, disruption of cytokine networks, and subsequent microglial activation as potentially important pathogenic processes. More recent neuroimmunological advances focusing on neuronal autoimmunity following infection provide the basis for a model of infection-induced psychosis, potentially implicating autoimmunity to schizophrenia-relevant protein targets including the N-methyl-D-aspartate receptor. Finally, we outline areas for future research and relevant experimental approaches and consider whether the current evidence provides a basis for the rational development of strategies to prevent schizophrenia.
Collapse
Affiliation(s)
- Adrianna P. Kępińska
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Conrad O. Iyegbe
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Anthony C. Vernon
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
- MRC Centre for Neurodevelopmental Disorders, King’s College London, London, United Kingdom
| | - Robert Yolken
- Stanley Laboratory of Developmental Neurovirology, Johns Hopkins Medical Center, Baltimore, MD, United States
| | - Robin M. Murray
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Thomas A. Pollak
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| |
Collapse
|
|
12
|
Hayward TA, Zhu G, Warrington NM, Wong Y, Ryan RYM, Murray AM, Haigh O, Martin NG, Miles JJ, Evans DM. Antibody response to common human viruses is shaped by genetic factors. J Allergy Clin Immunol 2018; 143:1640-1643. [PMID: 30578878 DOI: 10.1016/j.jaci.2018.11.039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 11/22/2018] [Accepted: 11/30/2018] [Indexed: 11/15/2022]
Affiliation(s)
- Tanisha A Hayward
- University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia; QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Gu Zhu
- QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Nicole M Warrington
- University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia
| | - Yide Wong
- QIMR Berghofer Medical Research Institute, Brisbane, Australia; Faculty of Medicine, University of Queensland, Brisbane, Australia; Centre for Biodiscovery and Molecular Development of Therapeutics, AITHM, James Cook University, Cairns, Australia
| | - Rachael Y M Ryan
- QIMR Berghofer Medical Research Institute, Brisbane, Australia; Centre for Biodiscovery and Molecular Development of Therapeutics, AITHM, James Cook University, Cairns, Australia; School of Natural Sciences, Griffith University, Brisbane, Australia
| | - Abella M Murray
- Faculty of Medicine, University of Queensland, Brisbane, Australia
| | - Oscar Haigh
- QIMR Berghofer Medical Research Institute, Brisbane, Australia; IDMIT CEA-Université Paris Sud, Fontenay-aux-Roses, France
| | | | - John J Miles
- QIMR Berghofer Medical Research Institute, Brisbane, Australia; Faculty of Medicine, University of Queensland, Brisbane, Australia; Centre for Biodiscovery and Molecular Development of Therapeutics, AITHM, James Cook University, Cairns, Australia; School of Natural Sciences, Griffith University, Brisbane, Australia
| | - David M Evans
- University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia; QIMR Berghofer Medical Research Institute, Brisbane, Australia; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
| |
Collapse
|
|
13
|
Toyoshima O, Nishizawa T, Sakitani K, Yamakawa T, Takahashi Y, Yamamichi N, Hata K, Seto Y, Koike K, Watanabe H, Suzuki H. Serum anti- Helicobacter pylori antibody titer and its association with gastric nodularity, atrophy, and age: A cross-sectional study. World J Gastroenterol 2018; 24:4061-4068. [PMID: 30254410 PMCID: PMC6148426 DOI: 10.3748/wjg.v24.i35.4061] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 08/02/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To clarify the role of serum anti-Helicobacter pylori (H. pylori) antibody titers in gastric cancer. METHODS In this cross-sectional study, the effect of patients' baseline characteristics and endoscopic findings on their serum antibody titers were assessed. We evaluated consecutive patients who underwent esophagogastroduodenoscopy and their first evaluation for H. pylori infection using a serum antibody test. We excluded patients with a history of eradication therapy. The participants were divided into four groups according to their E-plate serum antibody titer. Patients with serum antibody titers < 3, 3-9.9, 10-49.9, and ≥ 50 U/mL were classified into groups A, B, C, and D, respectively. RESULTS In total, 874 participants were analyzed with 70%, 16%, 8.7%, and 5.1% of them in the groups A, B, C, and D, respectively. Patients in group C were older than patients in groups A and B. Gastric open-type atrophy, intestinal metaplasia, enlarged folds, diffuse redness, and duodenal ulcers were associated with a high titer. Regular arrangements of collecting venules, fundic gland polyps, superficial gastritis, and gastroesophageal reflux disease were related to a low titer. Multivariate analysis revealed that nodularity (P = 0.0094), atrophy (P = 0.0076), and age 40-59 years (vs age ≥ 60 years, P = 0.0090) were correlated with a high serum antibody titer in H. pylori-infected patients. Intestinal metaplasia and atrophy were related to age ≥ 60 years in group C and D. CONCLUSION Serum antibody titer changes with age, reflects gastric mucosal inflammation, and is useful in predicting the risk of gastric cancer.
Collapse
Affiliation(s)
- Osamu Toyoshima
- Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo 157-0066, Japan
| | | | - Kosuke Sakitani
- Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo 157-0066, Japan
| | | | | | - Nobutake Yamamichi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Keisuke Hata
- Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Yasuyuki Seto
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | | | - Hidekazu Suzuki
- Medical Education Center, Keio University School of Medicine, Tokyo 160-8582, Japan
| |
Collapse
|
|
14
|
Scepanovic P, Alanio C, Hammer C, Hodel F, Bergstedt J, Patin E, Thorball CW, Chaturvedi N, Charbit B, Abel L, Quintana-Murci L, Duffy D, Albert ML, Fellay J. Human genetic variants and age are the strongest predictors of humoral immune responses to common pathogens and vaccines. Genome Med 2018; 10:59. [PMID: 30053915 PMCID: PMC6063007 DOI: 10.1186/s13073-018-0568-8] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 07/10/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Humoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses. Here, we evaluated the impact of intrinsic (age and sex), environmental, and genetic factors on the variability of humoral response to common pathogens and vaccines. METHODS We characterized the serological response to 15 antigens from common human pathogens or vaccines, in an age- and sex-stratified cohort of 1000 healthy individuals (Milieu Intérieur cohort). Using clinical-grade serological assays, we measured total IgA, IgE, IgG, and IgM levels, as well as qualitative (serostatus) and quantitative IgG responses to cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1 and 2, varicella zoster virus, Helicobacter pylori, Toxoplasma gondii, influenza A virus, measles, mumps, rubella, and hepatitis B virus. Following genome-wide genotyping of single nucleotide polymorphisms and imputation, we examined associations between ~ 5 million genetic variants and antibody responses using single marker and gene burden tests. RESULTS We identified age and sex as important determinants of humoral immunity, with older individuals and women having higher rates of seropositivity for most antigens. Genome-wide association studies revealed significant associations between variants in the human leukocyte antigen (HLA) class II region on chromosome 6 and anti-EBV and anti-rubella IgG levels. We used HLA imputation to fine map these associations to amino acid variants in the peptide-binding groove of HLA-DRβ1 and HLA-DPβ1, respectively. We also observed significant associations for total IgA levels with two loci on chromosome 2 and with specific KIR-HLA combinations. CONCLUSIONS Using extensive serological testing and genome-wide association analyses in a well-characterized cohort of healthy individuals, we demonstrated that age, sex, and specific human genetic variants contribute to inter-individual variability in humoral immunity. By highlighting genes and pathways implicated in the normal antibody response to frequently encountered antigens, these findings provide a basis to better understand disease pathogenesis. TRIALS REGISTRATION ClinicalTrials.gov , NCT01699893.
Collapse
Affiliation(s)
- Petar Scepanovic
- School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Cécile Alanio
- Immunobiology of Dendritic Cell Unit, Institut Pasteur, Paris, France.,Center for Translational Research, Institut Pasteur, Paris, France.,Inserm U1223, Institut Pasteur, Paris, France
| | - Christian Hammer
- School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Swiss Institute of Bioinformatics, Lausanne, Switzerland.,Department of Cancer Immunology, Genentech, South San Francisco, CA, USA
| | - Flavia Hodel
- School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Jacob Bergstedt
- Department of Automatic Control, Lund University, Lund, Sweden
| | - Etienne Patin
- Unit of Human Evolutionary Genetics, Department of Genomes and Genetics, Institut Pasteur, Paris, France.,Centre National de la Recherche Scientifique, URA 3012, Paris, France.,Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, 75015, Paris, France
| | - Christian W Thorball
- School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Nimisha Chaturvedi
- School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Bruno Charbit
- Center for Translational Research, Institut Pasteur, Paris, France
| | - Laurent Abel
- Laboratory of Human Genetics of Infectious Diseases, Necker branch, Inserm U1163, Paris, France.,Imagine Institute, Paris Descartes University, Paris, France.,St Giles laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Lluis Quintana-Murci
- Unit of Human Evolutionary Genetics, Department of Genomes and Genetics, Institut Pasteur, Paris, France.,Centre National de la Recherche Scientifique, URA 3012, Paris, France.,Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, 75015, Paris, France
| | - Darragh Duffy
- Immunobiology of Dendritic Cell Unit, Institut Pasteur, Paris, France.,Center for Translational Research, Institut Pasteur, Paris, France.,Inserm U1223, Institut Pasteur, Paris, France
| | - Matthew L Albert
- Department of Cancer Immunology, Genentech, South San Francisco, CA, USA.
| | - Jacques Fellay
- School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. .,Swiss Institute of Bioinformatics, Lausanne, Switzerland. .,Precision Medicine Unit, Lausanne University Hospital, Lausanne, Switzerland.
| | | |
Collapse
|
|
15
|
Toyoshima O, Nishizawa T, Arita M, Kataoka Y, Sakitani K, Yoshida S, Yamashita H, Hata K, Watanabe H, Suzuki H. Helicobacter pylori infection in subjects negative for high titer serum antibody. World J Gastroenterol 2018; 24:1419-1428. [PMID: 29632423 PMCID: PMC5889822 DOI: 10.3748/wjg.v24.i13.1419] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Revised: 03/13/2018] [Accepted: 03/18/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the clinicopathological features of the patients testing negative for high titer serum anti-Helicobacter pylori (H. pylori) antibody. METHODS The antibody titers were measured using antigens derived from Japanese individuals. 13C-urea breath test-positive individuals were defined as having H. pylori infection. We investigated the demographic characteristics, laboratory data, endoscopic findings including Kyoto classification of gastritis, and histology in negative-high titer patients without H. pylori eradication therapy. Kyoto classification consisted of scores for gastric atrophy, intestinal metaplasia, enlarged folds, nodularity, and redness. RESULTS Of the 136 subjects enrolled, 23 (17%) had H. pylori infection. Kyoto classification had an excellent area under the receiver operating characteristics curve (0.886, 95% confidence interval: 0.803-0.968, P = 3.7 × 10-20) for predicting H. pylori infection with a cut-off value of 2. Further, Kyoto classification, H. pylori density, and neutrophil activity had high accuracies (89.7%, 96.3%, and 94.1%, respectively). Kyoto classification was independent of the demographic and laboratory parameters in multivariate analysis. CONCLUSION Endoscopic Kyoto classification of gastritis is a useful predictor of H. pylori infection in negative-high titer antibody patients.
Collapse
Affiliation(s)
- Osamu Toyoshima
- Department of Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo 1570066, Japan
| | - Toshihiro Nishizawa
- Department of Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo 1570066, Japan
| | - Masahide Arita
- Department of Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo 1570066, Japan
| | - Yosuke Kataoka
- Department of Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo 1570066, Japan
| | - Kosuke Sakitani
- Department of Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo 1570066, Japan
| | - Shuntaro Yoshida
- Department of Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo 1570066, Japan
| | - Hiroharu Yamashita
- Department of Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo 1570066, Japan
| | - Keisuke Hata
- Department of Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo 1570066, Japan
| | - Hidenobu Watanabe
- Department of Pathology, Pathology and Cytology Laboratory Japan, Tokyo 1660003, Japan
| | - Hidekazu Suzuki
- Medical Education Center, Keio University School of Medicine, Tokyo 1608582, Japan
| |
Collapse
|
|
16
|
Carignano HA, Roldan DL, Beribe MJ, Raschia MA, Amadio A, Nani JP, Gutierrez G, Alvarez I, Trono K, Poli MA, Miretti MM. Genome-wide scan for commons SNPs affecting bovine leukemia virus infection level in dairy cattle. BMC Genomics 2018; 19:142. [PMID: 29439661 PMCID: PMC5812220 DOI: 10.1186/s12864-018-4523-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 02/01/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Bovine leukemia virus (BLV) infection is omnipresent in dairy herds causing direct economic losses due to trade restrictions and lymphosarcoma-related deaths. Milk production drops and increase in the culling rate are also relevant and usually neglected. The BLV provirus persists throughout a lifetime and an inter-individual variation is observed in the level of infection (LI) in vivo. High LI is strongly correlated with disease progression and BLV transmission among herd mates. In a context of high prevalence, classical control strategies are economically prohibitive. Alternatively, host genomics studies aiming to dissect loci associated with LI are potentially useful tools for genetic selection programs tending to abrogate the viral spreading. The LI was measured through the proviral load (PVL) set-point and white blood cells (WBC) counts. The goals of this work were to gain insight into the contribution of SNPs (bovine 50KSNP panel) on LI variability and to identify genomics regions underlying this trait. RESULTS We quantified anti-p24 response and total leukocytes count in peripheral blood from 1800 cows and used these to select 800 individuals with extreme phenotypes in WBCs and PVL. Two case-control genomic association studies using linear mixed models (LMMs) considering population stratification were performed. The proportion of the variance captured by all QC-passed SNPs represented 0.63 (SE ± 0.14) of the phenotypic variance for PVL and 0.56 (SE ± 0.15) for WBCs. Overall, significant associations (Bonferroni's corrected -log10p > 5.94) were shared for both phenotypes by 24 SNPs within the Bovine MHC. Founder haplotypes were used to measure the linkage disequilibrium (LD) extent (r2 = 0.22 ± 0.27 at inter-SNP distance of 25-50 kb). The SNPs and LD blocks indicated genes potentially associated with LI in infected cows: i.e. relevant immune response related genes (DQA1, DRB3, BOLA-A, LTA, LTB, TNF, IER3, GRP111, CRISP1), several genes involved in cell cytoskeletal reorganization (CD2AP, PKHD1, FLOT1, TUBB5) and modelling of the extracellular matrix (TRAM2, TNXB). Host transcription factors (TFs) were also highlighted (TFAP2D; ABT1, GCM1, PRRC2A). CONCLUSIONS Data obtained represent a step forward to understand the biology of BLV-bovine interaction, and provide genetic information potentially applicable to selective breeding programs.
Collapse
Affiliation(s)
- Hugo A. Carignano
- Instituto Nacional de Tecnología Agropecuaria (INTA). Centro de Investigaciones en Ciencias Veterinarias y Agronómicas (CICVyA). Instituto de Genética, B1686 Hurlingham, Argentina
| | - Dana L. Roldan
- Instituto Nacional de Tecnología Agropecuaria (INTA). Centro de Investigaciones en Ciencias Veterinarias y Agronómicas (CICVyA). Instituto de Genética, B1686 Hurlingham, Argentina
| | - María J. Beribe
- Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Pergamino, B2700 Pergamino, Argentina
| | - María A. Raschia
- Instituto Nacional de Tecnología Agropecuaria (INTA). Centro de Investigaciones en Ciencias Veterinarias y Agronómicas (CICVyA). Instituto de Genética, B1686 Hurlingham, Argentina
| | - Ariel Amadio
- Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela, S2300, Rafaela, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), C1033AAJ Ciudad Autónoma de Buenos Aires, Argentina
| | - Juan P. Nani
- Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela, S2300, Rafaela, Argentina
| | - Gerónimo Gutierrez
- Instituto Nacional de Tecnología Agropecuaria (INTA). Centro de Investigaciones en Ciencias Veterinarias y Agronómicas (CICVyA). Instituto de Virología, B686 Hurlingham, Argentina
| | - Irene Alvarez
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), C1033AAJ Ciudad Autónoma de Buenos Aires, Argentina
- Instituto Nacional de Tecnología Agropecuaria (INTA). Centro de Investigaciones en Ciencias Veterinarias y Agronómicas (CICVyA). Instituto de Virología, B686 Hurlingham, Argentina
| | - Karina Trono
- Instituto Nacional de Tecnología Agropecuaria (INTA). Centro de Investigaciones en Ciencias Veterinarias y Agronómicas (CICVyA). Instituto de Virología, B686 Hurlingham, Argentina
| | - Mario A. Poli
- Instituto Nacional de Tecnología Agropecuaria (INTA). Centro de Investigaciones en Ciencias Veterinarias y Agronómicas (CICVyA). Instituto de Genética, B1686 Hurlingham, Argentina
| | - Marcos M. Miretti
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), C1033AAJ Ciudad Autónoma de Buenos Aires, Argentina
- Grupo de Investigación en Genética Aplicada, Instituto de Biología Subtropical (GIGA - IBS), Universidad Nacional de Misiones, N3300 Posadas, Argentina
| |
Collapse
|
|
17
|
Sallah N, Carstensen T, Wakeham K, Bagni R, Labo N, Pollard MO, Gurdasani D, Ekoru K, Pomilla C, Young EH, Fatumo S, Asiki G, Kamali A, Sandhu M, Kellam P, Whitby D, Barroso I, Newton R. Whole-genome association study of antibody response to Epstein-Barr virus in an African population: a pilot. Glob Health Epidemiol Genom 2017; 2:e18. [PMID: 29868224 PMCID: PMC5870407 DOI: 10.1017/gheg.2017.16] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 10/19/2017] [Accepted: 10/24/2017] [Indexed: 02/02/2023] Open
Abstract
Epstein Barr virus (EBV) infects 95% of the global population and is associated with up to 2% of cancers globally. Immunoglobulin G (IgG) antibody levels to EBV have been shown to be heritable and associated with developing malignancies. We, therefore, performed a pilot genome-wide association analysis of anti-EBV IgG traits in an African population, using a combined approach including array genotyping, whole-genome sequencing and imputation to a panel with African sequence data. In 1562 Ugandans, we identify a variant in human leukocyte antigen (HLA)-DQA1, rs9272371 (p = 2.6 × 10-17) associated with anti-EBV nuclear antigen-1 responses. Trans-ancestry meta-analysis and fine-mapping with European-ancestry individuals suggest the presence of distinct HLA class II variants driving associations in Uganda. In addition, we identify four putative, novel, very rare African-specific loci with preliminary evidence for association with anti-viral capsid antigen IgG responses which will require replication for validation. These findings reinforce the need for the expansion of such studies in African populations with relevant datasets to capture genetic diversity.
Collapse
Affiliation(s)
- N. Sallah
- Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK
- Department of Virus Genomics, Wellcome Trust Sanger Institute, Hinxton, UK
| | - T. Carstensen
- Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - K. Wakeham
- MRC/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - R. Bagni
- Protein Expression Lab, Cancer Research Technology Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - N. Labo
- Viral Oncology Section, Aids and Cancer Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - M. O. Pollard
- Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - D. Gurdasani
- Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - K. Ekoru
- Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - C. Pomilla
- Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - E. H. Young
- Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - S. Fatumo
- Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK
- Department of Medicine, University of Cambridge, Cambridge, UK
- H3Africa Bioinformatics Network (H3ABioNet) Node, National Biotechnology Development Agency (NABDA), Federal Ministry of Science and Technology (FMST), Abuja, Nigeria
| | - G. Asiki
- MRC/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda
| | - A. Kamali
- MRC/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda
| | - M. Sandhu
- Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - P. Kellam
- Department of Virus Genomics, Wellcome Trust Sanger Institute, Hinxton, UK
| | - D. Whitby
- Viral Oncology Section, Aids and Cancer Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - I. Barroso
- Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK
| | - R. Newton
- MRC/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda
| |
Collapse
|
|
18
|
Szczubiałka K, Pyrć K, Nowakowska M. In search for effective and definitive treatment of herpes simplex virus type 1 (HSV-1) infections. RSC Adv 2016. [DOI: 10.1039/c5ra22896d] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Herpes Simplex Virus type 1 (HSV-1) is a nuclear replicating enveloped virus.
Collapse
Affiliation(s)
| | - Krzysztof Pyrć
- Faculty of Biochemistry, Biophysics and Biotechnology
- Jagiellonian University
- 30-387 Kraków
- Poland
| | | |
Collapse
|
|
19
|
Abstract
The strategies employed in vaccinology have improved since the seminal work of Edward Jenner in the eighteenth century. Stimulated by failure to develop vaccines for cancers and chronic infectious diseases as well as an emergence of a multitude of new technologies not available earlier, vaccinology has moved from a largely experimental art to a new phase of innovation. Currently, immune reactions can be predicted and modeled before they occur and formulations can be optimized in advance for genetic background, age, sex, lifestyle, environmental factors, and microbiome. A multitude of scientific insights and technological advancements have led us to this current status, yet possibly none of the recent developments is individually more promising to achieve these goals than the interdisciplinary science of systems vaccinology. This review summarizes current trends and applications of systems vaccinology, including technically tangible areas of vaccine and immunology research which allow the transformative process into a truly broad understanding of vaccines, thereby effectively modeling interaction of vaccines with health and disease. It is becoming clear that a multitude of factors have to be considered to understand inter-patient variability of vaccine responses including those characterized from the interfaces between the immune system, microbiome, metabolome, and the nervous system.
Collapse
|
|
20
|
Hammer C, Begemann M, McLaren PJ, Bartha I, Michel A, Klose B, Schmitt C, Waterboer T, Pawlita M, Schulz TF, Ehrenreich H, Fellay J. Amino Acid Variation in HLA Class II Proteins Is a Major Determinant of Humoral Response to Common Viruses. Am J Hum Genet 2015; 97:738-43. [PMID: 26456283 PMCID: PMC4667104 DOI: 10.1016/j.ajhg.2015.09.008] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Accepted: 09/21/2015] [Indexed: 02/02/2023] Open
Abstract
The magnitude of the human antibody response to viral antigens is highly variable. To explore the human genetic contribution to this variability, we performed genome-wide association studies of the immunoglobulin G response to 14 pathogenic viruses in 2,363 immunocompetent adults. Significant associations were observed in the major histocompatibility complex region on chromosome 6 for influenza A virus, Epstein-Barr virus, JC polyomavirus, and Merkel cell polyomavirus. Using local imputation and fine mapping, we identified specific amino acid residues in human leucocyte antigen (HLA) class II proteins as the most probable causal variants underlying these association signals. Common HLA-DRβ1 haplotypes showed virus-specific patterns of humoral-response regulation. We observed an overlap between variants affecting the humoral response to influenza A and EBV and variants previously associated with autoimmune diseases related to these viruses. The results of this study emphasize the central and pathogen-specific role of HLA class II variation in the modulation of humoral immune response to viral antigens in humans.
Collapse
Affiliation(s)
- Christian Hammer
- School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
| | - Martin Begemann
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany
| | - Paul J McLaren
- School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
| | - István Bartha
- School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
| | - Angelika Michel
- Division of Molecular Diagnostics of Oncogenic Infections, Infections and Cancer Program, German Cancer Research Center, 69120 Heidelberg, Germany
| | - Beate Klose
- Institute of Virology, Hannover Medical School, 30625 Hannover, Germany
| | - Corinna Schmitt
- Institute of Virology, Hannover Medical School, 30625 Hannover, Germany
| | - Tim Waterboer
- Division of Molecular Diagnostics of Oncogenic Infections, Infections and Cancer Program, German Cancer Research Center, 69120 Heidelberg, Germany
| | - Michael Pawlita
- Division of Molecular Diagnostics of Oncogenic Infections, Infections and Cancer Program, German Cancer Research Center, 69120 Heidelberg, Germany
| | - Thomas F Schulz
- Institute of Virology, Hannover Medical School, 30625 Hannover, Germany
| | - Hannelore Ehrenreich
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany; DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain, 37075 Göttingen, Germany
| | - Jacques Fellay
- School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
| |
Collapse
|
|
21
|
Rubicz R, Yolken R, Drigalenko E, Carless MA, Dyer TD, Kent Jr J, Curran JE, Johnson MP, Cole SA, Fowler SP, Arya R, Puppala S, Almasy L, Moses EK, Kraig E, Duggirala R, Blangero J, Leach CT, Göring HHH. Genome-wide genetic investigation of serological measures of common infections. Eur J Hum Genet 2015; 23:1544-8. [PMID: 25758998 PMCID: PMC4613484 DOI: 10.1038/ejhg.2015.24] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Revised: 12/09/2014] [Accepted: 01/27/2015] [Indexed: 12/16/2022] Open
Abstract
Populations and individuals differ in susceptibility to infections because of a number of factors, including host genetic variation. We previously demonstrated that differences in antibody titer, which reflect infection history, are significantly heritable. Here we attempt to identify the genetic factors influencing variation in these serological phenotypes. Blood samples from >1300 Mexican Americans were quantified for IgG antibody level against 12 common infections, selected on the basis of their reported role in cardiovascular disease risk: Chlamydia pneumoniae; Helicobacter pylori; Toxoplasma gondii; cytomegalovirus; herpes simplex I virus; herpes simplex II virus; human herpesvirus 6 (HHV6); human herpesvirus 8 (HHV8); varicella zoster virus; hepatitis A virus (HAV); influenza A virus; and influenza B virus. Pathogen-specific quantitative antibody levels were analyzed, as were three measures of pathogen burden. Genome-wide linkage and joint linkage and association analyses were performed using ~1 million SNPs. Significant linkage (lod scores >3.0) was obtained for HHV6 (on chromosome 7), HHV8 (on chromosome 6), and HAV (on chromosome 13). SNP rs4812712 on chromosome 20 was significantly associated with C. pneumoniae (P=5.3 × 10(-8)). However, no genome-wide significant loci were obtained for the other investigated antibodies. We conclude that it is possible to localize host genetic factors influencing some of these antibody traits, but that further larger-scale investigations will be required to elucidate the genetic mechanisms contributing to variation in antibody levels.
Collapse
Affiliation(s)
- Rohina Rubicz
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Robert Yolken
- Stanley Division of Developmental Neurovirology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Eugene Drigalenko
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Melanie A Carless
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Thomas D Dyer
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Jack Kent Jr
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Joanne E Curran
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Matthew P Johnson
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Shelley A Cole
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Sharon P Fowler
- Division of Clinical Epidemiology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Rector Arya
- Division of Endocrinology and Diabetes, Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Sobha Puppala
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Laura Almasy
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Eric K Moses
- Center for Genetic Epidemiology and Biostatistics, The University of Western Australia, Perth, WA, Australia
| | - Ellen Kraig
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | | | - John Blangero
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Charles T Leach
- Department of Pediatrics, Section of Infectious Diseases, Baylor College of Medicine/Children's Hospital of San Antonio, San Antonio, TX, USA
| | - Harald HH Göring
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
| |
Collapse
|
|
22
|
Abstract
PURPOSE OF REVIEW Transmission of hepatitis A virus (HAV) infection is primarily fecal-oral. Symptomatic hepatitis, severe disease, and death are more likely to occur when infection occurs at an older age. Improvements in socioeconomic and hygienic conditions have led to a change in its epidemiology worldwide. RECENT FINDINGS In the last two decades, improved hygiene in several resource-poor countries has led to reduced transmission of HAV, an increase in average age at infection, and, consequently, a paradoxical increase in morbidity and mortality because of hepatitis A. In Argentina, introduction of one dose (instead of the conventional two doses, to reduce costs) of inactivated HAV vaccine at 12-month age in a universal childhood immunization program during such 'epidemiologic transition' has markedly reduced the incidence of symptomatic hepatitis A, and of fulminant hepatitis and liver transplantation caused by HAV infection. The monetary value of medical and nonmedical benefits of this strategy outweighed the expenditure on vaccination. These excellent results were possibly contingent upon a high vaccination coverage. SUMMARY Resource-poor countries should closely monitor the epidemiology of HAV infection and periodically undertake cost-effectiveness analyses of HAV immunization strategies. This should allow timely identification of epidemiologic transition and introduction of preventive strategies before HAV infection becomes a public health problem.
Collapse
Affiliation(s)
- Rakesh Aggarwal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | | |
Collapse
|
|
23
|
Kishikawa H, Kimura K, Takarabe S, Kaida S, Nishida J. Helicobacter pylori Antibody Titer and Gastric Cancer Screening. DISEASE MARKERS 2015; 2015:156719. [PMID: 26494936 PMCID: PMC4606161 DOI: 10.1155/2015/156719] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Accepted: 09/06/2015] [Indexed: 02/07/2023]
Abstract
The "ABC method" is a serum gastric cancer screening method, and the subjects were divided based on H. pylori serology and atrophic gastritis as detected by serum pepsinogen (PG): Group A [H. pylori (-) PG (-)], Group B [H. pylori (+) PG (-)], Group C [H. pylori (+) PG (+)], and Group D [H. pylori (-) PG (+)]. The risk of gastric cancer is highest in Group D, followed by Groups C, B, and A. Groups B, C, and D are advised to undergo endoscopy, and the recommended surveillance is every three years, every two years, and annually, respectively. In this report, the reported results with respect to further risk stratification by anti-H. pylori antibody titer in each subgroup are reviewed: (1) high-negative antibody titer subjects in Group A, representing posteradicated individuals with high risk for intestinal-type cancer; (2) high-positive antibody titer subjects in Group B, representing active inflammation with high risk for diffuse-type cancer; and (3) low-positive antibody titer subjects in Group C, representing advanced atrophy with increased risk for intestinal-type cancer. In these subjects, careful follow-up with intervals of surveillance of every three years in (1), every two years in (2), and annually in (3) should be considered.
Collapse
Affiliation(s)
- Hiroshi Kishikawa
- Department of Gastroenterology, Tokyo Dental College, Ichikawa General Hospital, 5-11-13 Sugano, Ichikawa, Chiba 272-8513, Japan
| | - Kayoko Kimura
- Department of Gastroenterology, Tokyo Dental College, Ichikawa General Hospital, 5-11-13 Sugano, Ichikawa, Chiba 272-8513, Japan
| | - Sakiko Takarabe
- Department of Gastroenterology, Tokyo Dental College, Ichikawa General Hospital, 5-11-13 Sugano, Ichikawa, Chiba 272-8513, Japan
| | - Shogo Kaida
- Department of Gastroenterology, Tokyo Dental College, Ichikawa General Hospital, 5-11-13 Sugano, Ichikawa, Chiba 272-8513, Japan
| | - Jiro Nishida
- Department of Gastroenterology, Tokyo Dental College, Ichikawa General Hospital, 5-11-13 Sugano, Ichikawa, Chiba 272-8513, Japan
| |
Collapse
|
|
24
|
Dubuisson O, Day RS, Dhurandhar NV. Accurate identification of neutralizing antibodies to adenovirus Ad36, -a putative contributor of obesity in humans. J Diabetes Complications 2015; 29:83-7. [PMID: 25312598 DOI: 10.1016/j.jdiacomp.2014.09.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 09/04/2014] [Accepted: 09/06/2014] [Indexed: 12/31/2022]
Abstract
BACKGROUND In children and adults, human adenovirus serotype 36 (Ad36) is linked with increased adiposity, and important metabolic alterations. Since this property is not shared by many other human adenovirus serotypes, it is imperative to specifically identify exposure to Ad36. Although serum neutralization assay (SNA) is the gold standard to specifically detect neutralizing antibodies (NA) to Ad36, it requires 2-weeks to complete and considerable training to interpret the results. Whereas, an enzyme-immuno assay (EIA) may provide a quicker and objective determination. OBJECTIVES Evaluate the accuracy of commercially available EIA kits to detect NA to Ad36. Modify SNA to reduce time and increase objectivity. STUDY DESIGN Sera of 15 seropositive or 16 seronegative subjects confirmed by SNA were used to test: 1) reproducibility of SNA to detect Ad36 exposure, by repeating assays twice; 2) an EIA that detects antibodies to all human adenovirus serotypes (NS-EIA) (Abcam-108705); 3) an EIA supposedly specific for Ad36 antibody (Ad36-EIA) (MyBioSource,#MBS705802), and 4) the concordance of SNA with a novel combination of SNA and immune-staining (SN-IS) kit (Cell BioLabs,#VPK-111). RESULTS The SNA showed exact reproducibility. NS-EIA detected adenovirus antibodies in 94% samples, confirming the non-specificity of the assay for Ad36 serotype. All seronegative samples (as determined by SNA) were false positive by Ad36-EIA. In 97% samples, SN-IS showed fidelity with Ad36-antibody status as determined by SNA. CONCLUSIONS The available EIA kits are not specific for detecting NA to Ad36. The modified SNA with immune-staining reduces assay time and increases accuracy of detecting by reducing subjectivity.
Collapse
Affiliation(s)
- Olga Dubuisson
- Infections and Obesity Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808 USA
| | - Rena Sue Day
- Michael & Susan Dell Center for Healthy Living The University of Texas School of Public Health, Houston, TX 77030 USA
| | - Nikhil V Dhurandhar
- Infections and Obesity Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808 USA.
| |
Collapse
|
|
25
|
Lopes AI, Vale FF, Oleastro M. Helicobacter pylori infection - recent developments in diagnosis. World J Gastroenterol 2014; 20:9299-9313. [PMID: 25071324 PMCID: PMC4110561 DOI: 10.3748/wjg.v20.i28.9299] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Considering the recommended indications for Helicobacter pylori (H. pylori) eradication therapy and the broad spectrum of available diagnostic methods, a reliable diagnosis is mandatory both before and after eradication therapy. Only highly accurate tests should be used in clinical practice, and the sensitivity and specificity of an adequate test should exceed 90%. The choice of tests should take into account clinical circumstances, the likelihood ratio of positive and negative tests, the cost-effectiveness of the testing strategy and the availability of the tests. This review concerns some of the most recent developments in diagnostic methods of H. pylori infection, namely the contribution of novel endoscopic evaluation methodologies for the diagnosis of H. pylori infection, such as magnifying endoscopy techniques and chromoendoscopy. In addition, the diagnostic contribution of histology and the urea breath test was explored recently in specific clinical settings and patient groups. Recent studies recommend enhancing the number of biopsy fragments for the rapid urease test. Bacterial culture from the gastric biopsy is the gold standard technique, and is recommended for antibiotic susceptibility test. Serology is used for initial screening and the stool antigen test is particularly used when the urea breath test is not available, while molecular methods have gained attention mostly for detecting antibiotic resistance.
Collapse
|
|
26
|
Antoine TE, Shukla D. Inhibition of myosin light chain kinase can be targeted for the development of new therapies against herpes simplex virus type-1 infection. Antivir Ther 2013; 19:15-29. [PMID: 23813409 DOI: 10.3851/imp2661] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2013] [Indexed: 10/26/2022]
Abstract
BACKGROUND Herpes simplex virus type-1 (HSV-1) is the leading cause of infectious blindness worldwide. Through a multistep process, HSV-1 enters into naturally susceptible human corneal epithelial (HCE) cells where it establishes an optimal environment for viral replication and spread. HSV-1 employment of cytoskeletal proteins, kinases, and cell signalling pathways is crucial for the entry process. METHODS Here we demonstrate that non-muscle myosin IIA (NM-IIA) and/or a myosin activating kinase, myosin light chain kinase (MLCK), can be targeted for the development of new and effective therapies against HSV-1. HCE cells were incubated with MLCK inhibitors ML-7 and ML-9 and NM-IIA inhibitor blebbistatin. Following the application of inhibitors, HSV-1 entry and spread to neighbouring HCE cells was evaluated. RESULTS Upon application of MLCK inhibitors ML-7 and ML-9 and NM-IIA inhibitor blebbistatin, HSV-1 entry into HCE cells was significantly decreased. Furthermore, dramatic impairment of glycoprotein-mediated membrane fusion was seen in cells treated with MLCK inhibitors, thus establishing a role for MLCK activation in cell-to-cell fusion and multinucleated syncytial cell formation. These results also indicate that the activation of motor protein NM-IIA by MLCK is crucial for cytoskeletal changes required for HSV-1 infection of corneal cells. CONCLUSIONS We provide new evidence that NM-IIA and MLCK can be used as effective antiviral targets against ocular herpes.
Collapse
Affiliation(s)
- Thessicar E Antoine
- Department of Ophthalmology & Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | | |
Collapse
|
|
27
|
Rubicz R, Zhu J, Laston S, Cole SA, Voruganti VS, Ebbesson SOE, Howard BV, Maccluer JW, Davidson M, Umans JG, Comuzzie AG, Göring HHH. Statistical genetic analysis of serological measures of common, chronic infections in Alaska Native participants in the GOCADAN study. Genet Epidemiol 2013; 37:751-7. [PMID: 23798484 DOI: 10.1002/gepi.21745] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 05/06/2013] [Accepted: 05/29/2013] [Indexed: 11/09/2022]
Abstract
This paper describes genetic investigations of seroreactivity to five common infectious pathogens in the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study. Antibody titers and seroprevalence were available for 495 to 782 (depending on the phenotype) family members at two time points, approximately 15 years apart, for Chlamydophila pneumoniae, Helicobacter pylori, cytomegalovirus (CMV), herpes simplex virus 1 (HSV-1), and herpes simplex virus 2 (HSV-2). Seroprevalence rates indicate that infections with most of these pathogens are common (≥20% for all of them, >80% for H. pylori, CMV, and HSV-1). Seropositive individuals typically remain seropositive over time, with seroreversion rates of <1% to 10% over ∼15 years. Antibody titers were significantly heritable for most pathogens, with the highest estimate being 0.61 for C. pneumoniae. Significant genome-wide linkage evidence was obtained for C. pneumoniae on chromosome 15 (logarithm of odds, LOD score of 3.13). These results demonstrate that individual host genetic differences influence antibody measures of common infections in this population, and further investigation may elucidate the underlying immunological processes and genes involved.
Collapse
Affiliation(s)
- Rohina Rubicz
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Antoine TE, Park PJ, Shukla D. Glycoprotein targeted therapeutics: a new era of anti-herpes simplex virus-1 therapeutics. Rev Med Virol 2013; 23:194-208. [PMID: 23440920 DOI: 10.1002/rmv.1740] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Revised: 12/14/2012] [Accepted: 12/17/2012] [Indexed: 01/02/2023]
Abstract
Herpes simplex virus type-1 (HSV-1) is among the most common human pathogens worldwide. Its entry into host cells is an intricate process that relies heavily on the ability of the viral glycoproteins to bind host cellular proteins and to efficiently mediate fusion of the virus envelope with the cell membrane. Acquisition of HSV-1 results in a lifelong latent infection. Because of the cycles of reactivation from a latent state, much emphasis has been placed on the management of infection through the use of DNA synthesis inhibitors. However, new methods are needed to provide more effective treatment at earlier phases of the viral infection and to prevent the development of drug resistance by the virus. This review outlines the infection process and the common therapeutics currently used against the fundamental stages of HSV-1 replication and fusion. The remainder of this article will focus on a new approach for HSV-1 infection control and management, the concept of glycoprotein-receptor targeting.
Collapse
Affiliation(s)
- Thessicar E Antoine
- Department of Ophthalmology and Visual Sciences, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | | | | |
Collapse
|
|
29
|
Rubicz R, Yolken R, Drigalenko E, Carless MA, Dyer TD, Bauman L, Melton PE, Kent JW, Harley JB, Curran JE, Johnson MP, Cole SA, Almasy L, Moses EK, Dhurandhar NV, Kraig E, Blangero J, Leach CT, Göring HHH. A genome-wide integrative genomic study localizes genetic factors influencing antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA-1). PLoS Genet 2013; 9:e1003147. [PMID: 23326239 PMCID: PMC3542101 DOI: 10.1371/journal.pgen.1003147] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2012] [Accepted: 10/23/2012] [Indexed: 12/20/2022] Open
Abstract
Infection with Epstein-Barr virus (EBV) is highly prevalent worldwide, and it has been associated with infectious mononucleosis and severe diseases including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal lymphoma, and lymphoproliferative disorders. Although EBV has been the focus of extensive research, much still remains unknown concerning what makes some individuals more sensitive to infection and to adverse outcomes as a result of infection. Here we use an integrative genomics approach in order to localize genetic factors influencing levels of Epstein Barr virus (EBV) nuclear antigen-1 (EBNA-1) IgG antibodies, as a measure of history of infection with this pathogen, in large Mexican American families. Genome-wide evidence of both significant linkage and association was obtained on chromosome 6 in the human leukocyte antigen (HLA) region and replicated in an independent Mexican American sample of large families (minimum p-value in combined analysis of both datasets is 1.4×10(-15) for SNPs rs477515 and rs2516049). Conditional association analyses indicate the presence of at least two separate loci within MHC class II, and along with lymphocyte expression data suggest genes HLA-DRB1 and HLA-DQB1 as the best candidates. The association signals are specific to EBV and are not found with IgG antibodies to 12 other pathogens examined, and therefore do not simply reveal a general HLA effect. We investigated whether SNPs significantly associated with diseases in which EBV is known or suspected to play a role (namely nasopharyngeal lymphoma, Hodgkin lymphoma, systemic lupus erythematosus, and multiple sclerosis) also show evidence of associated with EBNA-1 antibody levels, finding an overlap only for the HLA locus, but none elsewhere in the genome. The significance of this work is that a major locus related to EBV infection has been identified, which may ultimately reveal the underlying mechanisms by which the immune system regulates infection with this pathogen.
Collapse
Affiliation(s)
- Rohina Rubicz
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|