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

Sarah G Earle,Gabriele Varani,Douglas F Browning,Rachel M Exley,Changyan Tang,Hayley Lavender,Odile B Harrison,Vasiliki Kostiou,Martin C J Maiden,Christoph M Tang,Daniel J Wilson,Mariya Lobanovska,Elisa Ramos-Sevillano,Holly B Bratcher,Xavier Nassif

doi:10.1371/journal.ppat.1009992

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.

Highlights

Many normally harmless members of the human microbiota can cause invasive disease in certain circumstances
Whilst controlling for population structure as a confounder, we identified multiple genes apparently contributing to invasion and identified a signal around the gene encoding an important component of some meningococcal vaccines, called factor H binding protein
Given that human DNA variation in complement factor H increases the risk of meningococcal invasion, this highlights the important connection between human and bacterial genetic variation and helps explain why some people infected with meningococci suffer meningococcal disease whilst others do not

Summary

Introduction

Many normally harmless members of the human microbiota can cause invasive disease in certain circumstances. Given the complexity of relationships between commensal and symbiotic bacteria and their hosts, there are numerous factors that promote the disruption of asymptomatic interactions, resulting in host tissue invasion, including genetic polymorphisms and phenotypic changes in hosts and infecting microbes. These diseases present both an evolutionary puzzle, as host invasion is often a dead-end for transmission, and an epidemiological challenge, as the aetiological agent circulates widely undetected, striking seemingly at random. As hyperinvasive meningococci spread through populations in asymptomatic carriage, the nature and incidence of IMD changes [3,8]

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