Genome-Wide Association Studies Identify an Association of Transferrin Binding Protein B Variation and Invasive Serogroup Y Meningococcal Disease in Older Adults

Abstract Background Neisseria meningitidis serogroup Y, especially ST-23 clonal complex (Y:cc23), represents a larger proportion of invasive meningococcal disease (IMD) in older adults compared to younger individuals. This study explored the meningococcal genetic variation underlying this association. Methods Maximum-likelihood phylogenies and the pangenome were analyzed using whole-genome sequence (WGS) data from 200 Y:cc23 isolates in the Neisseria PubMLST database. Genome-wide association studies (GWAS) were performed on WGS data from 250 Y:cc23 isolates from individuals with IMD aged ≥65 years versus < 65 years. Results Y:cc23 meningococcal variants did not cluster by age group or disease phenotype in phylogenetic analyses. Pangenome comparisons found no differences in presence or absence of genes in IMD isolates from the different age groups. GWAS identified differences in nucleotide polymorphisms within the transferrin-binding protein B (tbpB) gene in isolates from individuals ≥65 years of age. TbpB structure modelling suggests these may impact binding of human transferrin. Conclusions These data suggest differential iron scavenging capacity amongst Y:cc23 meningococci isolated from older compared to younger patients. Iron acquisition is essential for many bacterial pathogens including the meningococcus. These polymorphisms may facilitate colonization, thereby increasing the risk of disease in vulnerable older people with altered nasopharyngeal microbiomes and nutritional status.

[1]  J. Bray,et al.  Impact of meningococcal ACWY conjugate vaccines on pharyngeal carriage in adolescents: evidence for herd protection from the UK MenACWY programme. , 2022, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[2]  P. Bork,et al.  Interactive Tree Of Life (iTOL) v5: an online tool for phylogenetic tree display and annotation , 2021, Nucleic Acids Res..

[3]  A. Deghmane,et al.  Difference in virulence between Neisseria meningitidis serogroups W and Y in transgenic mice , 2020, BMC Microbiology.

[4]  K. Koskinen,et al.  The microbiome of the upper respiratory tract in health and disease , 2019, BMC Biology.

[5]  Keith A Jolley,et al.  Open-access bacterial population genomics: BIGSdb software, the PubMLST.org website and their applications , 2018, Wellcome open research.

[6]  L. Ferrucci,et al.  Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty , 2018, Nature Reviews Cardiology.

[7]  A. Booth,et al.  More evidence is needed. Iron, incident cognitive decline and dementia: a systematic review , 2018, Therapeutic advances in chronic disease.

[8]  Xavier Didelot,et al.  A phylogenetic method to perform genome-wide association studies in microbes that accounts for population structure and recombination , 2017, bioRxiv.

[9]  S. Jacobsson,et al.  Clinical presentation of invasive disease caused by Neisseria meningitidis serogroup Y in Sweden, 1995 to 2012 , 2017, Epidemiology and Infection.

[10]  Ola Brynildsrud,et al.  Erratum to: Rapid scoring of genes in microbial pan-genome-wide association studies with Scoary , 2016, Genome Biology.

[11]  I. Feavers,et al.  Investigation into the Antigenic Properties and Contributions to Growth in Blood of the Meningococcal Haemoglobin Receptors, HpuAB and HmbR , 2015, PloS one.

[12]  M. Kuusi,et al.  Meningococcal serogroup Y disease in Europe: Continuation of high importance in some European regions in 2013 , 2015, Human vaccines & immunotherapeutics.

[13]  Andrew J. Page,et al.  Roary: rapid large-scale prokaryote pan genome analysis , 2015, bioRxiv.

[14]  M. Unemo,et al.  Genome-Based Characterization of Emergent Invasive Neisseria meningitidis Serogroup Y Isolates in Sweden from 1995 to 2012 , 2015, Journal of Clinical Microbiology.

[15]  A. Schryvers,et al.  Patterns of structural and sequence variation within isotype lineages of the Neisseria meningitidis transferrin receptor system , 2015, MicrobiologyOpen.

[16]  Daniel J. Wilson,et al.  ClonalFrameML: Efficient Inference of Recombination in Whole Bacterial Genomes , 2015, PLoS Comput. Biol..

[17]  Anne Jamet,et al.  A New Family of Secreted Toxins in Pathogenic Neisseria Species , 2015, PLoS pathogens.

[18]  Julian Parkhill,et al.  A gene-by-gene population genomics platform: de novo assembly, annotation and genealogical analysis of 108 representative Neisseria meningitidis genomes , 2014, BMC Genomics.

[19]  E. Schadt,et al.  Geroscience: Linking Aging to Chronic Disease , 2014, Cell.

[20]  Torsten Seemann,et al.  Prokka: rapid prokaryotic genome annotation , 2014, Bioinform..

[21]  M. Surette,et al.  The loss of topography in the microbial communities of the upper respiratory tract in the elderly. , 2014, Annals of the American Thoracic Society.

[22]  P. Myint,et al.  Iron status in the elderly , 2014, Mechanisms of Ageing and Development.

[23]  E. Sanders,et al.  Prevalence and Clinical Course in Invasive Infections with Meningococcal Endotoxin Variants , 2012, PloS one.

[24]  David R. Riley,et al.  Whole Genome Sequencing to Investigate the Emergence of Clonal Complex 23 Neisseria meningitidis Serogroup Y Disease in the United States , 2012, PloS one.

[25]  Joenel Alcantara,et al.  The structural basis of transferrin sequestration by transferrin-binding protein B , 2012, Nature Structural &Molecular Biology.

[26]  S. Ladhani,et al.  Invasive Meningococcal Capsular Group Y Disease, England and Wales, 2007–2009 , 2012, Emerging infectious diseases.

[27]  H. Fredlund,et al.  Genetic characterisation of the emerging invasive Neisseria meningitidis serogroup Y in Sweden, 2000 to 2010. , 2011, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[28]  S. McNicholas,et al.  Presenting your structures: the CCP4mg molecular-graphics software , 2011, Acta crystallographica. Section D, Biological crystallography.

[29]  S. Ram,et al.  Meningococcal Group W-135 and Y Capsular Polysaccharides Paradoxically Enhance Activation of the Alternative Pathway of Complement* , 2011, The Journal of Biological Chemistry.

[30]  Martin C. J. Maiden,et al.  BIGSdb: Scalable analysis of bacterial genome variation at the population level , 2010, BMC Bioinformatics.

[31]  G. Weinstock,et al.  Genome Sequencing Reveals Widespread Virulence Gene Exchange among Human Neisseria Species , 2010, PloS one.

[32]  O. Gascuel,et al.  New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. , 2010, Systematic biology.

[33]  M. Maiden,et al.  Meningococcal carriage and disease—Population biology and evolution , 2009, Vaccine.

[34]  Adam P. Arkin,et al.  FastTree: Computing Large Minimum Evolution Trees with Profiles instead of a Distance Matrix , 2009, Molecular biology and evolution.

[35]  E. McLean,et al.  Worldwide prevalence of anaemia 1993-2005: WHO global database on anaemia. , 2008 .

[36]  F. Guillou,et al.  Transgenic Mice Expressing Human Transferrin as a Model for Meningococcal Infection , 2007, Infection and Immunity.

[37]  N. Saunders,et al.  The majority of genes in the pathogenic Neisseria species are present in non-pathogenic Neisseria lactamica, including those designated as 'virulence genes' , 2006, BMC Genomics.

[38]  Jane W. Marsh,et al.  Antigenic shift and increased incidence of meningococcal disease. , 2006, The Journal of infectious diseases.

[39]  I. Stojiljković,et al.  Iron Transport Systems in Neisseria meningitidis , 2004, Microbiology and Molecular Biology Reviews.

[40]  V. Ferriani,et al.  Ontogeny of Complement Regulatory Proteins – Concentrations of Factor H, Factor I, C4b‐Binding Protein, Properdin and Vitronectin in Healthy Children of Different Ages and in Adults , 2003, Scandinavian journal of immunology.

[41]  D. Caugant,et al.  Allelic Diversity of the Two Transferrin Binding Protein B Gene Isotypes among a Collection of Neisseria meningitidisStrains Representative of Serogroup B Disease: Implication for the Composition of a Recombinant TbpB-Based Vaccine , 2000, Infection and Immunity.

[42]  T. Popović,et al.  The changing epidemiology of meningococcal disease in the United States, 1992-1996. , 1999, The Journal of infectious diseases.

[43]  M. Hobbs,et al.  The transferrin receptor expressed by gonococcal strain FA1090 is required for the experimental infection of human male volunteers , 1998, Molecular microbiology.