title: Large scale genomic analysis shows no evidence for pathogen adaptation between the blood and cerebrospinal fluid niches during bacterial meningitis.
abstract: Recent studies have provided evidence for rapid pathogen genome diversification, some of which could potentially affect the course of disease. We have previously described such variation seen between isolates infecting the blood and cerebrospinal fluid (CSF) of a single patient during a case of bacterial meningitis. Here, we performed whole-genome sequencing of paired isolates from the blood and CSF of 869 meningitis patients to determine whether such variation frequently occurs between these two niches in cases of bacterial meningitis. Using a combination of reference-free variant calling approaches, we show that no genetic adaptation occurs in either invaded niche during bacterial meningitis for two major pathogen species,Streptococcus pneumoniaeandNeisseria meningitidis. This study therefore shows that the bacteria capable of causing meningitis are already able to do this upon entering the blood, and no further sequence change is necessary to cross the blood-brain barrier. Our findings place the focus back on bacterial evolution between nasopharyngeal carriage and invasion, or diversity of the host, as likely mechanisms for determining invasiveness.
authors.affiliation: 1​Pathogen Genomics, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Lees
authors.affiliation: 2​Department of Neurology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Philip H C
authors.initials: PHC
authors.lastname: Kremer
authors.affiliation: 3​Department of Genetics, University of Leicester, Leicester, UK.
authors.forename: Ana S
authors.initials: AS
authors.lastname: Manso
authors.affiliation: 4​Department of Infectious Disease Epidemiology, Imperial College London, London, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Croucher
authors.affiliation: 2​Department of Neurology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: Ferwerda
authors.affiliation: 2​Department of Neurology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Mercedes Valls
authors.initials: MV
authors.lastname: Serón
authors.affiliation: 3​Department of Genetics, University of Leicester, Leicester, UK.
authors.forename: Marco R
authors.initials: MR
authors.lastname: Oggioni
authors.affiliation: 1​Pathogen Genomics, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Parkhill
authors.affiliation: 2​Department of Neurology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Matthijs C
authors.initials: MC
authors.lastname: Brouwer
authors.affiliation: 5​Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands.|6​Netherlands Reference Laboratory for Bacterial Meningitis, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Arie
authors.initials: A
authors.lastname: van der Ende
authors.affiliation: 2​Department of Neurology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Diederik
authors.initials: D
authors.lastname: van de Beek
authors.affiliation: 1​Pathogen Genomics, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Bentley
mesh_terms: D000220:Adaptation, Biological / Q000235:genetics*; D001812:Blood-Brain Barrier / Q000382:microbiology*; D002353:Carrier State / Q000382:microbiology; D004269:DNA, Bacterial; D014644:Genetic Variation; D006801:Humans; D008585:Meningitis, Meningococcal / Q000097:blood / Q000134:cerebrospinal fluid / Q000382:microbiology*; D008586:Meningitis, Pneumococcal / Q000097:blood / Q000134:cerebrospinal fluid / Q000382:microbiology*; D009305:Nasopharynx / Q000382:microbiology; D009345:Neisseria meningitidis / Q000235:genetics / Q000472:pathogenicity*; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000472:pathogenicity*; D000073336:Whole Genome Sequencing
chemical_list: D004269:DNA, Bacterial
keywords: Neisseria meningitidis; Streptococcus pneumoniae; ivr locus; meningitis; pan-genome calling; within-host evolution