Host genetic determinants of Neisseria meningitidis infections

• Published in: The Lancet infectious diseases Vol. 3; no. 9; pp. 565 - 577
• Main Authors: Emonts, M, Hazelzet, JA, de Groot, R, Hermans, PWM
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.09.2003; Elsevier Limited
• Subjects: Bacterial infections; Child; Complement activation; Cytokines; Cytokines - genetics; Cytokines - physiology; Disease; Enzymes; Fibrinolysis; Gene polymorphism; Genetic diversity; Haplotypes; Humans; Immunology; Infections; Infectious diseases; Inflammation; Inflammatory response; Interleukins; Membrane Glycoproteins - immunology; Meningitis; Meningitis, Meningococcal - classification; Meningitis, Meningococcal - genetics; Meningitis, Meningococcal - physiopathology; Meningococcal disease; Mortality; Neisseria meningitidis; Neisseria meningitidis - genetics; Patients; Permeability; Plasminogen activator inhibitors; Polymorphism; Polymorphism, Genetic; Properdin; Proteins; Receptors; Receptors, Cell Surface - immunology; Sepsis; Septic shock; Severity of Illness Index; Single-nucleotide polymorphism; Tissue Plasminogen Activator - physiology; TLR4 protein; Toll-Like Receptor 4; Toll-Like Receptors; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Tumors; United Kingdom > UK
• ISSN: 1473-3099; 1474-4457
• DOI: 10.1016/S1473-3099(03)00740-0

The clinical presentation of infections caused by Neisseria meningitidis is highly diverse. Some patients develop meningitis, and others present with sepsis or even septic shock. After invasion of the bloodstream by the bacteria, three main cascade pathways are activated. These are the complement system, the inflammatory response, and the coagulation and fibrinolysis pathway. These pathways do not act independently but are able to interact with each other. Genetic polymorphisms among components of these pathways have been shown to be involved in the susceptibility, severity, and outcome of meningococcal disease. We review knowledge of genetic variations associated with susceptibility to and severity of meningococcal infection. Complement deficiencies and defects in sensing or opsonophagocytic pathways, such as the rare Toll-like receptor 4 single nucleotide polymorphisms (SNPs) and combinations of inefficient variants of Fcγ-receptors, seem to have the most important role in genetically established susceptibility. Effect on severity has repeatedly been reported for FcγRIIa and plasminogen activator inhibitor type 1 (PAI1) polymorphisms. Outcome effects have been confirmed for SNPs in properdin deficiencies, PAI1 and combination of the −511C/T SNP in interleukin 1β, and the +2018C/T SNP in interleukin RN. Conflicting results are reported for the effect of the −308G/A promoter polymorphism in tumour necrosis factor (TNF) α. These differences may reflect discrepancies in group definitions between studies or the influence of additional SNPs in the TNFα promoter, which can form haplotypes representing different cytokine production capacity. For several SNPs, the potential effect on susceptibility, severity, or outcome has not yet been confirmed in an independent study.