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...

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Autores principales:	Sarah G Earle, Mariya Lobanovska, Hayley Lavender, Changyan Tang, Rachel M Exley, Elisa Ramos-Sevillano, Douglas F Browning, Vasiliki Kostiou, Odile B Harrison, Holly B Bratcher, Gabriele Varani, Christoph M Tang, Daniel J Wilson, Martin C J Maiden
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/0b6f3dfc4de74b43a1339c59c7591f44
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spelling	oai:doaj.org-article:0b6f3dfc4de74b43a1339c59c7591f442021-12-02T20:00:00ZGenome-wide association studies reveal the role of polymorphisms affecting factor H binding protein expression in host invasion by Neisseria meningitidis.1553-73661553-737410.1371/journal.ppat.1009992https://doaj.org/article/0b6f3dfc4de74b43a1339c59c7591f442021-10-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009992https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Many 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.Sarah G EarleMariya LobanovskaHayley LavenderChangyan TangRachel M ExleyElisa Ramos-SevillanoDouglas F BrowningVasiliki KostiouOdile B HarrisonHolly B BratcherGabriele VaraniChristoph M TangDaniel J WilsonMartin C J MaidenPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 10, p e1009992 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Sarah G Earle Mariya Lobanovska Hayley Lavender Changyan Tang Rachel M Exley Elisa Ramos-Sevillano Douglas F Browning Vasiliki Kostiou Odile B Harrison Holly B Bratcher Gabriele Varani Christoph M Tang Daniel J Wilson Martin C J Maiden Genome-wide association studies reveal the role of polymorphisms affecting factor H binding protein expression in host invasion by Neisseria meningitidis.
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	article
author	Sarah G Earle Mariya Lobanovska Hayley Lavender Changyan Tang Rachel M Exley Elisa Ramos-Sevillano Douglas F Browning Vasiliki Kostiou Odile B Harrison Holly B Bratcher Gabriele Varani Christoph M Tang Daniel J Wilson Martin C J Maiden
author_facet	Sarah G Earle Mariya Lobanovska Hayley Lavender Changyan Tang Rachel M Exley Elisa Ramos-Sevillano Douglas F Browning Vasiliki Kostiou Odile B Harrison Holly B Bratcher Gabriele Varani Christoph M Tang Daniel J Wilson Martin C J Maiden
author_sort	Sarah G Earle
title	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_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_sort	genome-wide association studies reveal the role of polymorphisms affecting factor h binding protein expression in host invasion by neisseria meningitidis.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/0b6f3dfc4de74b43a1339c59c7591f44
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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.

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