Interrogation of global mutagenesis data with a genome scale model of Neisseria meningitidis to assess gene fitness in vitro and in sera

Tom A. Mendum, Jane Newcombe (Collaborator), Ahmad A Mannan (Collaborator), Andrzej M Kierzek (Collaborator), Johnjoe McFadden (Corresponding Author)

Research output: Contribution to journalArticle

21 Citations (Scopus)
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Abstract

Background
Neisseria meningitidis is an important human commensal and pathogen that causes several thousand deaths each year, mostly in young children. How the pathogen replicates and causes disease in the host is largely unknown, particularly the role of metabolism in colonization and disease. Completed genome sequences are available for several strains but our understanding of how these data relate to phenotype remains limited.

Results
To investigate the metabolism of N. meningitidis we generated and then selected a representative Tn5 library on rich medium, a minimal defined medium and in human serum to identify genes essential for growth under these conditions. To relate these data to a systems-wide understanding of the pathogen's biology we constructed a genome-scale metabolic network: Nmb_iTM560. This model was able to distinguish essential and non-essential genes as predicted by the global mutagenesis. These essentiality data, the library and the Nmb_iTM560 model are powerful and widely applicable resources for the study of meningococcal metabolism and physiology. We demonstrate the utility of these resources by predicting and demonstrating metabolic requirements on minimal medium, such as a requirement for phosphoenolpyruvate carboxylase, and by describing the nutritional and biochemical status of N. meningitidis when grown in serum, including a requirement for both the synthesis and transport of amino acids.

Conclusions
This study describes the application of a genome scale transposon library combined with an experimentally validated genome-scale metabolic network of N. meningitidis to identify essential genes and provide novel insight into the pathogen's metabolism both in vitro and during infection.
Original languageEnglish
Article numberR127
Number of pages15
JournalGenome Biology
Volume12
DOIs
Publication statusPublished - 30 Dec 2011

Keywords

  • neisseria-meningitidis
  • genome scale model
  • global mutagenesis

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