Bacterial genetics in meningitis: Associating meningococcal and pneumococcal genes with clinical outcome

The objective of this thesis is to provide more insight in the association of bacterial genetics with clinical characteristics of patients with bacterial meningitis. In a genetic association study using a cohort of 258 meningococcal meningitis patients, we show that specific meningococcal clonal complexes, meningococcal factor H binding protein (fHbp) types and meningococcal two-partner secretion system distribution are associated with clinical outcome. In a study contributing to vaccine research, we describe the genetic distribution of the 3 meningococcal antigens that are included in the serogroup B meningococcal vaccine in meningococcal isolates collected in the Netherlands over a period of 50 years. We report the availability of the N. meningitidis serogroup B H44/76 genome sequence, a strain widely used in molecular genetics studies. Also we analyze the genome of a clinical meningococcal meningitis isolate without lipopolysaccharide (LPS) and show that a mutation located in lpxH, which encodes an enzyme in the lipid A biosynthesis pathway, explains its LPS-deficiency. Finally we identified pneumococcal arginine biosynthesis genes to be associated with clinical outcome in patients with pneumococcal meningitis, using a clinical phenotype-based approach combined with bacterial whole-genome sequencing. This thesis, in which more than half of our analyses are based on newly sequenced bacterial whole genome sequences, serves as a proof of principle that bacterial whole-genome sequencing can give answers to research questions that previously remained unanswered. This thesis has contributed to a better understanding of the role of bacterial genetics in the clinical course and outcome of bacterial meningitis.