Invasive meningococcal disease and genome databases
Authors: Jens Karlsson, Hannes Eichner, Edmund Loh
Journal: The Lancet Microbe (2021)

Neisseria meningitidis (meningococcus) is a human-restricted bacterium and a common coloniser of the nasopharynx. The bacterium is often harmless, but can in rare cases cause life-threatening meningitis and sepsis, commonly referred to as invasive meningococcal disease (IMD). Because of the rapid onset of disease and the risk of severe morbidity and mortality, antibiotics are administered promptly to patients where there is suspicion of IMD. Although vaccination programmes against the meningococcus have substantially reduced IMD worldwide, disease burden remains a challenge, particularly in low-income and middle-income countries.1Bizri AR Althaqafi A Kaabi N Obeidat N Al Akoury N Haridy H The burden of invasive vaccine-preventable diseases in adults in the Middle East and North Africa (MENA) region.Infect Dis Ther. 2021; 10: 663-685Crossref PubMed Scopus (2) Google ScholarThe surveillance network for IMD in Europe started in 1999 as part of the Invasive Bacterial Infections Surveillance project. The aims of the network are to improve the epidemiological information on IMD in Europe, to characterise meningococcal isolates, and to foster international collaborations. This project facilitated the complete genome mapping of two meningococcal strains in 2000.2Tettelin H Saunders NJ Heidelberg J et al.Complete genome sequence of Neisseria meningitidis serogroup B strain MC58.Science. 2000; 287: 1809-1815Crossref PubMed Scopus (953) Google Scholar, 3Parkhill J Achtman M James KD et al.Complete DNA sequence of a serogroup A strain of Neisseria meningitidis Z2491.Nature. 2000; 404: 502-506Crossref PubMed Scopus (610) Google Scholar Since 2009, the Meningitis Research Foundation further commissioned the creation of a publicly available online library of the genomes of all meningococcal disease isolates in the UK, pioneering the public databases for molecular typing and microbial genome diversity (PubMLST).4Jolley KA Bray JE Maiden MCJ Open-access bacterial population genomics: BIGSdb software, the PubMLST.org website and their applications.Wellcome Open Res. 2018; 3: 124Crossref PubMed Scopus (760) Google Scholar With the rapid advancement of next-generation sequencing, whole-genome sequencing has now become the gold standard in outbreak investigation and surveillance of IMD in many countries. Generated whole-genome sequencing data are often annotated and deposited in the meningococcal PubMLST.Although there is an extensive meningococcal database, its usage in scientific research has been scarce. The meningococcus has a few tested animal models but they are all only specifically for unique virulence factors and there is no suitable animal model to investigate IMD resembling the human body, which further hinders the investigation process. Publications have highlighted that comparative molecular epidemiological investigation utilising the PubMLST could provide valuable information in assisting the identification of novel meningococcal virulence factors and their association with IMD.The mucosal membranes in the nasopharynx that the meningococcus colonises are often replete with secretory IgA. Meningococci can degrade these IgA using their IgA1-specific serine protease. Our study has shown that the IgA1 serine protease could further facilitate meningococcal immune evasion by opposing serum IgG3.5Spoerry C Karlsson J Aschtgen MS Loh E Neisseria meningitidis IgA1-specific serine protease exhibits novel cleavage activity against IgG3.Virulence. 2021; 12: 389-403Crossref PubMed Scopus (4) Google Scholar Through molecular characterisation, it was shown that meningococcal IgA1-specific serine protease of cleavage type 1 degrades both IgG3 and IgA, whereas cleavage type 2 only degrades IgA. Comparative epidemiological analysis of more than 7000 clinical meningococcal isolates from the PubMLST shows a significantly higher proportion of cleavage type 1 among isolates from invasive cases compared with carrier cases.The meningococcus has several other strategies to evade complement-mediated killing, such as the production of a polysaccharide capsule and surface-exposed Factor H binding protein (fHbp). Both of these factors are major components of the current meningococcal vaccines (Menveo, a quadrivalent polysaccharide conjugate vaccine; and Bexsero, a recombinant protein vaccine for Meningitis B). The expressions of both virulence factors are temperature dependent and are mediated by regulatory RNAs.6Loh E Kugelberg E Tracy A et al.Temperature triggers immune evasion by Neisseria meningitidis.Nature. 2013; 502: 237-240Crossref PubMed Scopus (101) Google Scholar Our study further identified sequence variants within a regulatory RNA that induces hypercapsulation phenotype that confers better protection against complement-mediated killing.7Karlsson J Eichner H Andersson C Jacobsson S Loh E Novel hypercapsulation RNA thermosensor variants in Neisseria meningitidis and their association with invasive meningococcal disease: a genetic and phenotypic investigation and molecular epidemiological study.Lancet Microbe. 2020; 1: e319-e327Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar Through comparative molecular epidemiological analysis of isolates from the PubMLST, we showed that hypercapsulated variants have higher serum survival and are almost two-times more common in IMD than in carrier isolates. Another study published in 2021 identified and characterised specific polymorphisms in the main regulatory regions of the fHbp gene that are driving fHbp production. By comparing whole-genome sequencing of almost 6000 clinical meningococcal isolates from the PubMLST, the authors discovered that isolates that produce more fHbp were significantly increased in IMD compared with the carrier state.8Spinsanti M Brignoli T Bodini M et al.Deconvolution of intergenic polymorphisms determining high expression of Factor H binding protein in meningococcus and their association with invasive disease.PLoS Pathog. 2021; 17e1009461Crossref PubMed Google ScholarComparative molecular epidemiology utilised in these studies has shown specific meningococcal virulence factors with an augmented propensity in IMD. However, due to a low availability of whole-genome sequencing from carrier isolates within the PubMLST, these studies were not able to assert stronger causation between the virulence factors of carrier and invasive isolates. Considering the ongoing COVID-19 pandemic, the implementation of lockdown policy has had a positive impact on the epidemiology of IMD. An international surveillance study published in 2021 has shown that there has been a significant reduction in the incidence of invasive respiratory disease including IMD during the COVID-19 pandemic.9Brueggemann AB Jansen van Rensburg MJ Shaw D et al.Changes in the incidence of invasive disease due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis during the COVID-19 pandemic in 26 countries and territories in the Invasive Respiratory Infection Surveillance Initiative: a prospective analysis of surveillance data.Lancet Digit Health. 2021; 3: e360-e370Summary Full Text Full Text PDF PubMed Scopus (86) Google Scholar Another case study has shown that a patient suffered IMD and concurrently showed positive RT-PCR for SARS-CoV-2.10Gallacher SD Seaton A Meningococcal meningitis and COVID-19 co-infection.BMJ Case Rep. 2020; 13e237366Crossref PubMed Scopus (14) Google Scholar However, the meningococcus co-infection with SARS-CoV-2 remains unclear and requires further investigation.Another potential positive outcome from the COVID-19 pandemic is a renewed public interest in infectious disease research. This increased interest could encourage participation in carrier studies of the meningococcus and create a larger pool of carrier isolate whole-genome sequencing, which would increase the overall capability of databases like PubMLST in finding new important virulence factors related to IMD. With international collaborations among national surveillance centres, epidemiologists, clinicians, and molecular researchers, the identification and characterisation of meningococcal virulence factors and potential diagnostic and therapeutic tools could be made, ultimately preventing and creating better treatments for IMD. Neisseria meningitidis (meningococcus) is a human-restricted bacterium and a common coloniser of the nasopharynx. The bacterium is often harmless, but can in rare cases cause life-threatening meningitis and sepsis, commonly referred to as invasive meningococcal disease (IMD). Because of the rapid onset of disease and the risk of severe morbidity and mortality, antibiotics are administered promptly to patients where there is suspicion of IMD. Although vaccination programmes against the meningococcus have substantially reduced IMD worldwide, disease burden remains a challenge, particularly in low-income and middle-income countries.1Bizri AR Althaqafi A Kaabi N Obeidat N Al Akoury N Haridy H The burden of invasive vaccine-preventable diseases in adults in the Middle East and North Africa (MENA) region.Infect Dis Ther. 2021; 10: 663-685Crossref PubMed Scopus (2) Google Scholar The surveillance network for IMD in Europe started in 1999 as part of the Invasive Bacterial Infections Surveillance project. The aims of the network are to improve the epidemiological information on IMD in Europe, to characterise meningococcal isolates, and to foster international collaborations. This project facilitated the complete genome mapping of two meningococcal strains in 2000.2Tettelin H Saunders NJ Heidelberg J et al.Complete genome sequence of Neisseria meningitidis serogroup B strain MC58.Science. 2000; 287: 1809-1815Crossref PubMed Scopus (953) Google Scholar, 3Parkhill J Achtman M James KD et al.Complete DNA sequence of a serogroup A strain of Neisseria meningitidis Z2491.Nature. 2000; 404: 502-506Crossref PubMed Scopus (610) Google Scholar Since 2009, the Meningitis Research Foundation further commissioned the creation of a publicly available online library of the genomes of all meningococcal disease isolates in the UK, pioneering the public databases for molecular typing and microbial genome diversity (PubMLST).4Jolley KA Bray JE Maiden MCJ Open-access bacterial population genomics: BIGSdb software, the PubMLST.org website and their applications.Wellcome Open Res. 2018; 3: 124Crossref PubMed Scopus (760) Google Scholar With the rapid advancement of next-generation sequencing, whole-genome sequencing has now become the gold standard in outbreak investigation and surveillance of IMD in many countries. Generated whole-genome sequencing data are often annotated and deposited in the meningococcal PubMLST. Although there is an extensive meningococcal database, its usage in scientific research has been scarce. The meningococcus has a few tested animal models but they are all only specifically for unique virulence factors and there is no suitable animal model to investigate IMD resembling the human body, which further hinders the investigation process. Publications have highlighted that comparative molecular epidemiological investigation utilising the PubMLST could provide valuable information in assisting the identification of novel meningococcal virulence factors and their association with IMD. The mucosal membranes in the nasopharynx that the meningococcus colonises are often replete with secretory IgA. Meningococci can degrade these IgA using their IgA1-specific serine protease. Our study has shown that the IgA1 serine protease could further facilitate meningococcal immune evasion by opposing serum IgG3.5Spoerry C Karlsson J Aschtgen MS Loh E Neisseria meningitidis IgA1-specific serine protease exhibits novel cleavage activity against IgG3.Virulence. 2021; 12: 389-403Crossref PubMed Scopus (4) Google Scholar Through molecular characterisation, it was shown that meningococcal IgA1-specific serine protease of cleavage type 1 degrades both IgG3 and IgA, whereas cleavage type 2 only degrades IgA. Comparative epidemiological analysis of more than 7000 clinical meningococcal isolates from the PubMLST shows a significantly higher proportion of cleavage type 1 among isolates from invasive cases compared with carrier cases. The meningococcus has several other strategies to evade complement-mediated killing, such as the production of a polysaccharide capsule and surface-exposed Factor H binding protein (fHbp). Both of these factors are major components of the current meningococcal vaccines (Menveo, a quadrivalent polysaccharide conjugate vaccine; and Bexsero, a recombinant protein vaccine for Meningitis B). The expressions of both virulence factors are temperature dependent and are mediated by regulatory RNAs.6Loh E Kugelberg E Tracy A et al.Temperature triggers immune evasion by Neisseria meningitidis.Nature. 2013; 502: 237-240Crossref PubMed Scopus (101) Google Scholar Our study further identified sequence variants within a regulatory RNA that induces hypercapsulation phenotype that confers better protection against complement-mediated killing.7Karlsson J Eichner H Andersson C Jacobsson S Loh E Novel hypercapsulation RNA thermosensor variants in Neisseria meningitidis and their association with invasive meningococcal disease: a genetic and phenotypic investigation and molecular epidemiological study.Lancet Microbe. 2020; 1: e319-e327Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar Through comparative molecular epidemiological analysis of isolates from the PubMLST, we showed that hypercapsulated variants have higher serum survival and are almost two-times more common in IMD than in carrier isolates. Another study published in 2021 identified and characterised specific polymorphisms in the main regulatory regions of the fHbp gene that are driving fHbp production. By comparing whole-genome sequencing of almost 6000 clinical meningococcal isolates from the PubMLST, the authors discovered that isolates that produce more fHbp were significantly increased in IMD compared with the carrier state.8Spinsanti M Brignoli T Bodini M et al.Deconvolution of intergenic polymorphisms determining high expression of Factor H binding protein in meningococcus and their association with invasive disease.PLoS Pathog. 2021; 17e1009461Crossref PubMed Google Scholar Comparative molecular epidemiology utilised in these studies has shown specific meningococcal virulence factors with an augmented propensity in IMD. However, due to a low availability of whole-genome sequencing from carrier isolates within the PubMLST, these studies were not able to assert stronger causation between the virulence factors of carrier and invasive isolates. Considering the ongoing COVID-19 pandemic, the implementation of lockdown policy has had a positive impact on the epidemiology of IMD. An international surveillance study published in 2021 has shown that there has been a significant reduction in the incidence of invasive respiratory disease including IMD during the COVID-19 pandemic.9Brueggemann AB Jansen van Rensburg MJ Shaw D et al.Changes in the incidence of invasive disease due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis during the COVID-19 pandemic in 26 countries and territories in the Invasive Respiratory Infection Surveillance Initiative: a prospective analysis of surveillance data.Lancet Digit Health. 2021; 3: e360-e370Summary Full Text Full Text PDF PubMed Scopus (86) Google Scholar Another case study has shown that a patient suffered IMD and concurrently showed positive RT-PCR for SARS-CoV-2.10Gallacher SD Seaton A Meningococcal meningitis and COVID-19 co-infection.BMJ Case Rep. 2020; 13e237366Crossref PubMed Scopus (14) Google Scholar However, the meningococcus co-infection with SARS-CoV-2 remains unclear and requires further investigation. Another potential positive outcome from the COVID-19 pandemic is a renewed public interest in infectious disease research. This increased interest could encourage participation in carrier studies of the meningococcus and create a larger pool of carrier isolate whole-genome sequencing, which would increase the overall capability of databases like PubMLST in finding new important virulence factors related to IMD. With international collaborations among national surveillance centres, epidemiologists, clinicians, and molecular researchers, the identification and characterisation of meningococcal virulence factors and potential diagnostic and therapeutic tools could be made, ultimately preventing and creating better treatments for IMD. We declare no competing interests.