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Genomic diversification of Neisseria meningitidis during clonal waves of colonization and disease and its potential role in immune evasion

English title Genomic diversification of Neisseria meningitidis during clonal waves of colonization and disease and its potential role in immune evasion
Applicant Pluschke Gerd
Number 152840
Funding scheme Project funding (Div. I-III)
Research institution Swiss Tropical and Public Health Institute
Institution of higher education University of Basel - BS
Main discipline Genetics
Start/End 01.04.2014 - 31.03.2016
Approved amount 170'000.00
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Keywords (2)

Neisseria meningitidis; comparative genomics

Lay Summary (German)

Lead
Neisseria meningitidis ist ein Gram-negatives Bakterium, das über Tröpfcheninfektionen übertragen wird. Besonders im sogenannten “Meningitis-Gürtel” Afrikas ruft es immer wieder grosse Hirnhautentzündungs-Epidemien hervor. Um die Ursachen und die Dynamik der Epidemien besser zu verstehen, ist es das Ziel unserer vergleichenden Genom-Analysen, aufzuklären, wie N. meningitidis der Immunantwort des Wirtes ausweicht.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Bakterielle Hirnhautentzündung (Meningitis) ist eine lebensbedrohliche Erkrankung, die häufig von Meningokokken (Neisseria meningitidis) hervorgerufen wird. Das einzige Erregerreservoir für Meningokokken ist der Mensch. Die Bakterien besiedeln den Nasen-Rachenraum und werden durch Tröpfcheninfektion übertragen. Meningokokken sind genetisch hochvariabel, wobei einzelne Klone eine erhöhte Virulenz aufweisen, andere dagegen keine Erkrankungen hervorrufen. Weiterhin entwickeln nur wenige Personen, die von einem hypervirulenten Stamm kolonisiert sind, eine Meningokokkenerkrankung.

Im sogenannten Meningitisgürtel in Afrika südlich der Sahara sind in den letzten 100 Jahren alle fünf bis zehn Jahre von Meningokokken hervorgerufene Meningitis-Epidemien aufgetreten. Diese Epidemien beginnen in der Trockenzeit, enden während der Regenzeit und können in den Trockenzeiten über drei bis vier Jahre hin wieder aufflammen. Unsere Langzeitstudien in Ghana und Burkina Faso haben gezeigt, dass immer wieder neue Meningokokken-Klone für die Epidemien verantwortlich sind. Die hypervirulenten Klone breiten sich in einer Population aus, rufen in einem Teil der Kolonisierten eine invasive Erkrankung hervor und verschwinden nach etwa fünf Jahren vollständig aus der betroffenen Region. Im Rahmen des SNF-geförderten Forschungsprojektes werden wir vergleichende Genomanalysen  mit einer einzigartigen Sammlung von N. meningitidis Kolonisations- und Krankheits-Isolaten durchführen, die wir im Zuge unserer Feldstudien systematisch gesammelt haben. Ziel ist es zu verstehen, warum es neuen Klonen gelingt, eine menschliche Population zu kolonisieren, obwohl ein nahe verwandter Klon kurze Zeit zuvor durch die Entwicklung einer mukosalen Herdenimmunität eliminiert worden ist.

Key words

Neisseria meningitidis, Meningitisepidemien, Genomanalyse, Impfstoffentwicklung, Microevolution

 

April 2, 2014

Direct link to Lay Summary Last update: 14.04.2014

Lay Summary (English)

Lead
Neisseria meningitidis, a Gram-negative bacterium transmitted by the spread of respiratory secretions is causing in particular in the so-called “meningitis belt” of sub-Saharan Africa severe meningitis epidemics. Goals of our comparative genomic studies are to gain better insight into immune evasion mechanisms of N. meningitidis and to provide a deeper understanding of the dynamics of meningococcal epidemics.
Lay summary

Goals of the research project

Meningococcal meningitis epidemics in the African meningitis belt are caused by hypervirulent clones of N. meningitidis that colonize a population, cause invasive disease in some of the colonized individuals and disappear after a few years. Within the framework of the project we will conduct comparative genomic analyses with a unique collection of N. meningitidis colonization and disease strains that we have isolated in longitudinal studies in Ghana and Burkina Faso. With these analyses we want to understand, why new clones can colonize the nasopharynx of a host population shortly after the disappearance of a closely related N. meningitidis clone. We hypothesize that development of herd immunity in the host population is responsible for the complete disappearance of meningococcal clones after a few years of colonization. We expect that we can identify crucial targets of protective immune response by characterizing the genomic regions that are hot spots of genetic diversification. That way we will gain insight into immune evasion mechanisms of N. meningitidis and provide a deeper understanding of the dynamics of meningococcal epidemics. By identifying new target antigens, our results will have major implications for protein subunit vaccine design.

Key words

Neisseria meningitidis, meningitis epidemics, comparative genomics, immune evasion

 April 1, 2014

Direct link to Lay Summary Last update: 14.04.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Emergence of a new epidemic Neisseria meningitidis serogroup A Clone in the African meningitis belt: high-resolution picture of genomic changes that mediate immune evasion.
Lamelas Araceli, Harris Simon R., Röltgen Katharina, Dangy Jean-Pierre, Hauser Julia, Kingsley Robert A., Connor Thomas R., Sie Ali, Hodgson Abraham, Dougan Gordon, Parkhill Julian, Bentley Stephen D., Pluschke Gerd (2014), Emergence of a new epidemic Neisseria meningitidis serogroup A Clone in the African meningitis belt: high-resolution picture of genomic changes that mediate immune evasion., in mBio, 5(5), e01974-14.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Institutsseminar Institute for Infectious Diseases, University of Bern Individual talk Clonal waves and genomic diversification: meningococcal and pneumococcal disease in the African meningitis belt 05.02.2016 Bern, Switzerland Pluschke Gerd;
Institutsseminar, Institute for Glycomics, Griffith University Individual talk Genomic epidemiology of meningococcal disease in the African meningitis belt 30.11.2015 Gold Coast, Australia Pluschke Gerd;
Gendrivax meeting Individual talk The genetics of successive waves of Neisseria meningitidis in Africa 04.12.2014 Siena, Italy Pluschke Gerd;
Nineteenth International Pathogenic Neisseria Conference Talk given at a conference Re-emergence of a Neisseria meningitidis serogroup A ST2859 clone in Northern Ghana after transient replacement by serogroup W ST2881 meningococci 12.10.2014 Asheville, North Carolina, United States of America Lamelas Araceli;


Abstract

1. Summary of the Research Proposal Background:Overall aim of the proposed research is to come to a better understanding of meningococcal virulence, immune evasion and the dynamics of meningococcal epidemics. We conduct comparative genomic analyses with a unique collection of N. meningitidis colonization and disease strains that we have isolated in the framework of the first two longitudinal studies of the dynamics of N. meningitidis carriage and disease in the African meningitis belt. During these studies we have demonstrated that clonal waves of colonization and disease are a characteristic feature of the meningitis belt. To gain deeper insight into the microevolution of hypervirulent meningococcal lineages we have in a pilot study focused on the comparative analysis of the genomes of 100 serogroup A strains belonging to two consecutive colonization waves. Our data indicate that new serogroup A clones that can colonize the nasopharynx of the host population shortly after the disappearance of a closely related clone differ in several non-capsular surface structures from the previous clone. Hot spots of fixation of recombination blocks included the pgl locus implicated in protein glycosylation, the NMAA_1914-pilU locus implicated in the regulation of type IV pilus expression and the maf3 locus, which is thought to encode adhesins.Working Hypothesis:We hypothesize that development of herd immunity is responsible for the complete disappearance of meningococcal clones after a few years of colonization of a host population and that comparative genomic analysis allows to identify sets of genes, which are hot spots of diversification through horizontal gene transfer, allowing new clones to evade herd immunity.Specific Aims, Design and Methods:We will broaden our genomic database by analyzing the genomes of an additional 200 N. meningitidis isolates to extend and consolidate identification of gene loci for which horizontal gene transfer-associated recombination is fixed by immune selection. In depth analysis will focus on the maf3 and the pgl locus. Analyses of the maf3 locus will focus on the genetic diversity, cellular location and function of the MafB proteins. To correlate pgl genotype and phenotype, the structure of the O-linked glycans in strains with different allelic constellations of the pgl locus will be determined by mass spectrometry. The function of O-glycosylation in immune evasion will be studied by analyzing immune responses against both the O-linked glycans themselves and against the glycosylated pili. Prototype strains expressing different glycoforms will also be used for comparative analyses of their adhesion and invasion capacity to epithelial cells. Expected Value of the Proposed Project:We expect that results will give insight into immune evasion mechanisms of N. meningitidis and provide a deeper understanding of the dynamics of meningococcal epidemics. Results may have implications for protein subunit vaccine design by identifying new potential oligosaccharide or protein target antigens and by elucidating whether protein antigens may be immunologically masked by changing glycosylation patterns.
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