Genome-wide association studies reveal the role of polymorphisms affecting factor H binding protein expression in host invasion by Neisseria meningitidis

Abstract

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.

Publication DOI: https://doi.org/10.1371/journal.ppat.1009992
Divisions: College of Health & Life Sciences > School of Biosciences
Additional Information: © 2021 Earle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Uncontrolled Keywords: Antigens, Bacterial/genetics,Bacterial Proteins/genetics,Genome-Wide Association Study,Humans,Meningococcal Infections/genetics,Neisseria meningitidis/genetics,Polymorphism, Single Nucleotide
Publication ISSN: 1553-7374
Last Modified: 20 May 2024 07:37
Date Deposited: 13 Jan 2022 15:22
Full Text Link:
Related URLs: https://journal ... al.ppat.1009992 (Publisher URL)
PURE Output Type: Article
Published Date: 2021-10-18
Accepted Date: 2021-09-29
Authors: Earle, Sarah G
Lobanovska, Mariya
Lavender, Hayley
Tang, Changyan
Exley, Rachel M
Ramos-Sevillano, Elisa
Browning, Douglas F (ORCID Profile 0000-0003-4672-3514)
Kostiou, Vasiliki
Harrison, Odile B
Bratcher, Holly B
Varani, Gabriele
Tang, Christoph M
Wilson, Daniel J
Maiden, Martin C J

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