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Genome-wide association studies reveal the role of polymorphisms affecting factor H binding protein expression in host invasion by Neisseria meningitidis
Many invasive bacterial diseases are caused by organisms that are ordinarily harmless components of the human microbiome. Effective interventions against these microbes require an understanding of the processes whereby symbiotic or commensal relationships transition into pathology. Here, we describe...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553145/ https://www.ncbi.nlm.nih.gov/pubmed/34662348 http://dx.doi.org/10.1371/journal.ppat.1009992 |
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author | Earle, Sarah G. Lobanovska, Mariya Lavender, Hayley Tang, Changyan Exley, Rachel M. Ramos-Sevillano, Elisa Browning, Douglas F. Kostiou, Vasiliki Harrison, Odile B. Bratcher, Holly B. Varani, Gabriele Tang, Christoph M. Wilson, Daniel J. Maiden, Martin C. J. |
author_facet | Earle, Sarah G. Lobanovska, Mariya Lavender, Hayley Tang, Changyan Exley, Rachel M. Ramos-Sevillano, Elisa Browning, Douglas F. Kostiou, Vasiliki Harrison, Odile B. Bratcher, Holly B. Varani, Gabriele Tang, Christoph M. Wilson, Daniel J. Maiden, Martin C. J. |
author_sort | Earle, Sarah G. |
collection | PubMed |
description | Many invasive bacterial diseases are caused by organisms that are ordinarily harmless components of the human microbiome. Effective interventions against these microbes require an understanding of the processes whereby symbiotic or commensal relationships transition into pathology. Here, we describe bacterial genome-wide association studies (GWAS) of Neisseria meningitidis, a common commensal of the human respiratory tract that is nevertheless a leading cause of meningitis and sepsis. An initial GWAS discovered bacterial genetic variants, including single nucleotide polymorphisms (SNPs), associated with invasive meningococcal disease (IMD) versus carriage in several loci across the meningococcal genome, encoding antigens and other extracellular components, confirming the polygenic nature of the invasive phenotype. In particular, there was a significant peak of association around the fHbp locus, encoding factor H binding protein (fHbp), which promotes bacterial immune evasion of human complement by recruiting complement factor H (CFH) to the meningococcal surface. The association around fHbp with IMD was confirmed by a validation GWAS, and we found that the SNPs identified in the validation affected the 5’ region of fHbp mRNA, altering secondary RNA structures, thereby increasing fHbp expression and enhancing bacterial escape from complement-mediated killing. This finding is consistent with the known link between complement deficiencies and CFH variation with human susceptibility to IMD. These observations demonstrate the importance of human and bacterial genetic variation across the fHbp:CFH interface in determining IMD susceptibility, the transition from carriage to disease. |
format | Online Article Text |
id | pubmed-8553145 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-85531452021-10-29 Genome-wide association studies reveal the role of polymorphisms affecting factor H binding protein expression in host invasion by Neisseria meningitidis Earle, Sarah G. Lobanovska, Mariya Lavender, Hayley Tang, Changyan Exley, Rachel M. Ramos-Sevillano, Elisa Browning, Douglas F. Kostiou, Vasiliki Harrison, Odile B. Bratcher, Holly B. Varani, Gabriele Tang, Christoph M. Wilson, Daniel J. Maiden, Martin C. J. PLoS Pathog Research Article Many invasive bacterial diseases are caused by organisms that are ordinarily harmless components of the human microbiome. Effective interventions against these microbes require an understanding of the processes whereby symbiotic or commensal relationships transition into pathology. Here, we describe bacterial genome-wide association studies (GWAS) of Neisseria meningitidis, a common commensal of the human respiratory tract that is nevertheless a leading cause of meningitis and sepsis. An initial GWAS discovered bacterial genetic variants, including single nucleotide polymorphisms (SNPs), associated with invasive meningococcal disease (IMD) versus carriage in several loci across the meningococcal genome, encoding antigens and other extracellular components, confirming the polygenic nature of the invasive phenotype. In particular, there was a significant peak of association around the fHbp locus, encoding factor H binding protein (fHbp), which promotes bacterial immune evasion of human complement by recruiting complement factor H (CFH) to the meningococcal surface. The association around fHbp with IMD was confirmed by a validation GWAS, and we found that the SNPs identified in the validation affected the 5’ region of fHbp mRNA, altering secondary RNA structures, thereby increasing fHbp expression and enhancing bacterial escape from complement-mediated killing. This finding is consistent with the known link between complement deficiencies and CFH variation with human susceptibility to IMD. These observations demonstrate the importance of human and bacterial genetic variation across the fHbp:CFH interface in determining IMD susceptibility, the transition from carriage to disease. Public Library of Science 2021-10-18 /pmc/articles/PMC8553145/ /pubmed/34662348 http://dx.doi.org/10.1371/journal.ppat.1009992 Text en © 2021 Earle et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Earle, Sarah G. Lobanovska, Mariya Lavender, Hayley Tang, Changyan Exley, Rachel M. Ramos-Sevillano, Elisa Browning, Douglas F. Kostiou, Vasiliki Harrison, Odile B. Bratcher, Holly B. Varani, Gabriele Tang, Christoph M. Wilson, Daniel J. Maiden, Martin C. J. Genome-wide association studies reveal the role of polymorphisms affecting factor H binding protein expression in host invasion by Neisseria meningitidis |
title | Genome-wide association studies reveal the role of polymorphisms affecting factor H binding protein expression in host invasion by Neisseria meningitidis |
title_full | Genome-wide association studies reveal the role of polymorphisms affecting factor H binding protein expression in host invasion by Neisseria meningitidis |
title_fullStr | Genome-wide association studies reveal the role of polymorphisms affecting factor H binding protein expression in host invasion by Neisseria meningitidis |
title_full_unstemmed | Genome-wide association studies reveal the role of polymorphisms affecting factor H binding protein expression in host invasion by Neisseria meningitidis |
title_short | Genome-wide association studies reveal the role of polymorphisms affecting factor H binding protein expression in host invasion by Neisseria meningitidis |
title_sort | genome-wide association studies reveal the role of polymorphisms affecting factor h binding protein expression in host invasion by neisseria meningitidis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553145/ https://www.ncbi.nlm.nih.gov/pubmed/34662348 http://dx.doi.org/10.1371/journal.ppat.1009992 |
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