Mannose-Binding Lectin Genotype and Invasive Pneumococcal Infection
Introduction
Streptococcus pneumoniae is an important pathogen causing severe and invasive disease such as pneumonia, bacteremia, meningitis, and sepsis. These infections are common throughout the world and are an important cause of mortality and morbidity, especially among young children, immunocompromised patients, and elderly who suffer from chronic illness [1]. A key component of the host defense against S. pneumoniae is opsonophagocytosis of the microorganism [2]. A number of components of the immune system involved in the immune response to Streptococcus pneumoniae are polymorphic. Polymorphisms are variant forms of genes, and the extent to which such genetic variants might influence susceptibility to invasive pneumococcal disease is unknown, because studies are limited and evidence conflicting.
Mannose-binding lectin (MBL) is an acute-phase protein that is synthesized in the liver. It recognizes and binds to glycoconjugates containing mannose, N-acetylmannoseamine, L-fucose, glucose, and N-acetyl-glucosamine present on microbial surfaces [3]. On binding, the protein activates the complement system via the lectin pathway independently of antibody [4, 5]. In addition, by binding to bacteria, MBL opsonizes bacteria and thereby facilitates opsonophagocytosis.
Deficiencies of MBL are known to be caused by point mutations within exon 1 of the MBL gene at codons 52, 54, and 57 (which are also called structural alleles and are designated D, B and C variants, respectively, and the wild type allele is designated A). The mutations lead to amino acid substitutions, disrupting the normal structure of the protein and resulting in enzymatic degradation and functional deficiency of MBL [6]. Concentrations of MBL in serum are about 20% lower in persons who are heterozygous for any codon variant compared with persons with none of the mutations, and they are very low (<2%) or absent in homozygote mutants or compound heterozygote mutants (persons who are heterozygous for two different codon mutations), described as O/O. Also, variations in the promoter region at position –221 and -550 have a significant effect on the MBL serum concentration, with the Y and H genotypes having high MBL-expressing activity and the X and L genotypes having low MBL-expressing activity. The haplotypes HY, LY, and LX were found to be associated with high, intermediate, and low plasma levels of MBL, respectively [7].
It has been reported by Roy et al. [8] that homozygote mutants for MBL codon variants, which represent about 5% of north Europeans and North Americans, could be at substantially increased risk of invasive pneumococcal disease. This is at variance with a report of Kronborg et al. [9] who found no association but only a nonsignificant increased risk between MBL genotypes and invasive pneumococcal disease in randomly included adult Danish patients. Combining the data of the two studies in a meta-analysis indicated that homozygosity for MBL variant alleles contributed to a small but significant increased risk of invasive pneumococcal disease [10].
We performed a Belgian case-control study in which we genotyped the MBL structural and promoter alleles, using a previously described allelic discrimination method [11], to investigate the possible influence of MBL deficiency on the susceptibility to invasive pneumococcal disease.
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Patients and Controls
We studied a Caucasian group of patients (47 adults and 16 children, n = 63) with invasive pneumococcal disease who were consecutively recruited at the University Hospital Gasthuisberg Leuven, Belgium. Invasive pneumococcal disease was defined by the isolation of S. pneumoniae from a normally sterile site (e.g., blood, cerebrospinal fluid, joint fluid). Patients with immune defects that might have caused an increased susceptibility to pneumococcal infections (e.g., corticoid therapy,
Results
Sixty-three patients (40 males and 23 females) with invasive pneumococcal disease and 162 controls (77 males and 85 females) were enrolled in the study. The median age of the patients was 67 years, with a range of 4 months to 92 years. The age distribution of the control population was between 9 months and 66 years with a median age of 30 years. The Streptococcus pneumoniae serotype was identified in 53 patients, and the most frequent serotypes isolated were 1, 9, and 14. Nine patients (14.3%)
Discussion
A broad variety of microorganisms including S. pneumoniae can colonize the nasopharynx. Every person is likely to be colonized at least once during life. In some cases, colonization is followed by disease [2]. The reasons that some people are more susceptible than others to invasive pneumococcal disease are complex and not entirely understood.
Two previous studies have addressed the question of whether variant MBL alleles are associated with increased susceptibility to invasive pneumococcal
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