Mannose-Binding Lectin Genotype and Invasive Pneumococcal Infection

doi:10.1016/j.humimm.2006.04.014

Human Immunology

Volume 67, Issue 8, August 2006, Pages 605-611

https://doi.org/10.1016/j.humimm.2006.04.014 Get rights and content

Abstract

Invasive pneumococcal disease is a serious infection that primarily affects young children and elderly or immunocompromised persons, but it also can affect healthy persons. Mannose-binding lectin (MBL) is a mediator of innate host immunity that activates the complement pathway and directly opsonizes pathogens. Variant structural codon and promoter MBL alleles have been associated with susceptibility to infections. Sixty-three Belgian patients with invasive pneumococcal disease and 162 healthy Belgian controls were genotyped for MBL alleles. We found a nonsignificant increased risk between the MBL structural codon variants (52, 54, and 57) and invasive pneumococcal disease. Combining our data with similar data from Kronberg et al. (J Infect Dis 2002;185:1517-20) indicated that MBL structural variants contributed to a small but significant increased risk of invasive pneumococcal disease. On the other hand, the -221 and -550 promoter allele distribution and the prevalence of the combined MBL structural and promoter -221 variant alleles were not significantly different between the patient group and the control group.

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.

Section snippets

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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Mannose-Binding Lectin Genotype and Invasive Pneumococcal Infection

Abstract

Introduction

Section snippets

Patients and Controls

Results

Discussion

Lancet Infect Dis

Lancet

Lancet

J Immunol Methods

J Immunol Methods

Curr Opin Immunol

J Allergy Clin Immunol

Clin Immunol

Infections caused by Streptococcus pneumoniaeclinical spectrum, pathogenesis, immunity, and treatment

Clin Inf Dis

Purification and characterization of two mannan-binding lectins from mouse serum

J Immunol

A second serine protease associated with mannan-binding lectin that activates complement

Nature

Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease

J Exp Med

Mannose binding lectin (MBL) genotype distributions with relations to serum levels in UK Caucasoids

Eur J Immunogenet

Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein

J Immunol

Variant mannose-binding lectin alleles are not associated with susceptibility to or outcome of invasive pneumococcal infection in randomly included patients

J Infect Dis

A population-based study of morbidity and mortality in mannose binding lectin deficiency

J Exp Med

MBL deficiency does not associate with recurrent pneumococcal infections in a group of Colombian children

J Trop Pediatr