Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
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
_version_ 1784591524807311360
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
work_keys_str_mv AT earlesarahg genomewideassociationstudiesrevealtheroleofpolymorphismsaffectingfactorhbindingproteinexpressioninhostinvasionbyneisseriameningitidis
AT lobanovskamariya genomewideassociationstudiesrevealtheroleofpolymorphismsaffectingfactorhbindingproteinexpressioninhostinvasionbyneisseriameningitidis
AT lavenderhayley genomewideassociationstudiesrevealtheroleofpolymorphismsaffectingfactorhbindingproteinexpressioninhostinvasionbyneisseriameningitidis
AT tangchangyan genomewideassociationstudiesrevealtheroleofpolymorphismsaffectingfactorhbindingproteinexpressioninhostinvasionbyneisseriameningitidis
AT exleyrachelm genomewideassociationstudiesrevealtheroleofpolymorphismsaffectingfactorhbindingproteinexpressioninhostinvasionbyneisseriameningitidis
AT ramossevillanoelisa genomewideassociationstudiesrevealtheroleofpolymorphismsaffectingfactorhbindingproteinexpressioninhostinvasionbyneisseriameningitidis
AT browningdouglasf genomewideassociationstudiesrevealtheroleofpolymorphismsaffectingfactorhbindingproteinexpressioninhostinvasionbyneisseriameningitidis
AT kostiouvasiliki genomewideassociationstudiesrevealtheroleofpolymorphismsaffectingfactorhbindingproteinexpressioninhostinvasionbyneisseriameningitidis
AT harrisonodileb genomewideassociationstudiesrevealtheroleofpolymorphismsaffectingfactorhbindingproteinexpressioninhostinvasionbyneisseriameningitidis
AT bratcherhollyb genomewideassociationstudiesrevealtheroleofpolymorphismsaffectingfactorhbindingproteinexpressioninhostinvasionbyneisseriameningitidis
AT varanigabriele genomewideassociationstudiesrevealtheroleofpolymorphismsaffectingfactorhbindingproteinexpressioninhostinvasionbyneisseriameningitidis
AT tangchristophm genomewideassociationstudiesrevealtheroleofpolymorphismsaffectingfactorhbindingproteinexpressioninhostinvasionbyneisseriameningitidis
AT wilsondanielj genomewideassociationstudiesrevealtheroleofpolymorphismsaffectingfactorhbindingproteinexpressioninhostinvasionbyneisseriameningitidis
AT maidenmartincj genomewideassociationstudiesrevealtheroleofpolymorphismsaffectingfactorhbindingproteinexpressioninhostinvasionbyneisseriameningitidis