Mannose-binding lectin alleles in sub-Saharan Africans and relation with susceptibility to infections

Mombo, Landry‐Erik; Lu, Changyuan; Ossari, Simon; Bedjabaga, I; Sica, Lucas; Krishnamoorthy, R. V.; Lapouméroulie, Claudine

doi:10.1038/sj.gene.6363979

Cited by 43 publications

(32 citation statements)

References 34 publications

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“…Among the 455 selected women (n ϭ 401 selected plus 54 women monitored throughout pregnancy), 66.8% were homozygous wild type (A/A), 31.7% were A/C, and 1.5% were C/C ( Table 2). The overall allelic frequency of the C variant was 17.5%, which is in agreement with that reported in the Cameroonian population (26). The frequency was marginally outside of Hardy-Weinberg equilibrium (P ϭ 0.09, chi-square test).…”

Section: Resultssupporting

confidence: 79%

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Genetic Polymorphisms of Mannose-Binding Lectin Do Not Influence Placental Malaria but Are Associated with Preterm Deliveries

et al. 2009

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During pregnancy, Plasmodium falciparum-infected erythrocytes (IE) sequester in the placenta where they induce pathology and increase the risk of low-birth-weight (LBW) babies. The innate immune mediator, mannose-binding lectin (MBL), enhances phagocytosis of pathogens. Since MBL is reported to bind to IE, we hypothesized that it might aid in clearance of IE from the placenta, thereby reducing the risk of LBW babies. To test this hypothesis, molecular genotyping was used to detect polymorphisms at codon 57 (A/C) in exon 1 of MBL2 in 401 pregnant Cameroonian women, with or without placental malaria, who had LBW and normal-weight babies. Polymorphisms in the promoter region at positions ؊550 (H/L), ؊221 (X/Y), and ؉4 (P/Q) were also determined, and plasma MBL levels were measured during pregnancy and at delivery. The expected correlation between genotype and plasma MBL levels was confirmed. However, asymptomatic infections were not associated with an increase in MBL levels in the peripheral blood, and MBL levels were similar in the placental and cord blood of women with or without placental malaria at delivery. There was no evidence that MBL levels at delivery were associated with malaria-related poor pregnancy outcomes. Women with the LXPA haplotype, however, were more likely to have LBW babies, but the risk was not related to malaria. These results do not support the hypothesis that MBL aids in the clearance of parasites from the placenta but suggest that Cameroonian women with LXPA are at risk of having LBW babies due to other causes.Women who become infected with Plasmodium falciparum during pregnancy are at an increased risk of anemia and poor pregnancy outcomes (5, 25). One reason for these complications is that P. falciparum-infected erythrocytes (IE) sequester in the intervillous space (IVS) of the placenta (9). As a result, monocytes and macrophages are attracted to the IVS (30, 36), where they stimulate an inflammatory response, produce placental pathology (42), and increase the risk of low-birth-weight (LBW) babies due to intrauterine growth reduction and premature deliveries (reviewed in reference 6). Thus, elimination of IE from the IVS is of great importance.Little is known about the role of innate immune cells and factors in eliminating IE from the IVS. An acute-phase protein that might be important is mannose-binding lectin (MBL), since it promotes opsonophagocytosis and activates the MBL pathway upon binding to oligosaccharides on pathogens (12,17). MBL is reported to bind to the surface of IE and possibly merozoites, although the ligand involved remains undefined (10, 15). In addition, MBL2 genetic deficiencies in children are associated with severe malaria (4, 11). Therefore, it is possible that MBL aids in eliminating IE by enhancing phagocytosis, leading to reduced pathology and risk of LBW babies.Plasma levels of MBL are influenced by three functional single nucleotide polymorphisms (SNPs) in exon 1 of the MBL2 gene at codons 52, 54, and 57 (D, B, and C, respectively) (18,20,21,35). These SNP...

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Section: Resultssupporting

confidence: 79%

“…Our results agree with previous reports on the prevalence of the exon 1 codon 57 SNP of MBL2 in Cameroonians and other African populations (22,26). The results also verify the influence of SNPs on MBL levels (Tables 2 and 3) (21,22).…”

Section: Discussionsupporting

confidence: 83%

Genetic Polymorphisms of Mannose-Binding Lectin Do Not Influence Placental Malaria but Are Associated with Preterm Deliveries

et al. 2009

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“…MBL deficiencies have been demonstrated to increase susceptibility to HIV infection, but a relationship between MBL levels and/or polymorphism and susceptibility to cryptococcal infection has not been investigated (14). Interestingly, an MBL polymorphism that results in malformation of the MBL oligomer has been demonstrated to be unique to regions of subSaharan Africa, correlating geographically with a high prevalence of cryptococcosis in HIV-infected populations (1,27).…”

Section: Discussionmentioning

confidence: 99%

Binding of Serum Mannan Binding Lectin to a Cell Integrity-DefectiveCryptococcus neoformans ccr4Δ Mutant

et al. 2007

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Mannan binding lectin (MBL) is an innate immune mediator belonging to the collectin family known to bind to the surfaces of many viruses, bacteria, and fungi. However, pathogenic strains of the fungus Cryptococcus neoformans are resistant to MBL binding. To dissect the mechanism of cryptococcal resistance to MBL, we compared MBL binding to an encapsulated wild-type strain, an encapsulated ccr4⌬ mutant defective in cell integrity, and an acapsular cap60⌬ strain. No MBL binding was detected on wild-type C. neoformans. In contrast, the ccr4⌬ mutant bound MBL to the cell wall, predominantly at the ends of enlarged buds, whereas the acapsular strain bound MBL only at the bud neck and bud scars. In addition, the ccr4⌬ mutant was sensitive to the cell wall-active antifungal caspofungin and other cell wall stress inducers, and its virulence was reduced in a mouse model of cryptococcosis. Interestingly, treatment of wild-type cells with caspofungin also increased MBL binding to C. neoformans. These results suggest that both the presence of capsule and wild-type cell wall architecture preclude MBL binding to C. neoformans.

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“…Also, among the Gujarati Indians in London, vitamin D receptor gene polymorphisms were correlated with tuberculosis infection (68). Several studies have indicated a partially protective effect of heterozygosity for mannan binding lectin variant alleles against TB (23,29), whereas others have pointed toward an increased susceptibility for TB in homozygous carriers of mannan binding lectin variant alleles (47). In general, a genetically determined impairment of release or response to gamma interferon (IFN-␥) or interleukin 12 (IL-12) is associated with an enhanced risk of developing tuberculosis (15,17).…”

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confidence: 99%

Genetically Determined Susceptibility to Tuberculosis in Mice Causally Involves Accelerated and Enhanced Recruitment of Granulocytes

Hoffmann²,

et al. 2006

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Classical twin studies and recent linkage analyses of African populations have revealed a potential involvement of host genetic factors in susceptibility or resistance to Mycobacterium tuberculosis infection. In order to identify the candidate genes involved and test their causal implication, we capitalized on the mouse model of tuberculosis, since inbred mouse strains also differ substantially in their susceptibility to infection. Two susceptible and two resistant mouse strains were aerogenically infected with 1,000 CFU of M. tuberculosis, and the regulation of gene expression was examined by Affymetrix GeneChip U74A array with total lung RNA 2 and 4 weeks postinfection. Four weeks after infection, 96 genes, many of which are involved in inflammatory cell recruitment and activation, were regulated in common. One hundred seven genes were differentially regulated in susceptible mouse strains, whereas 43 genes were differentially expressed only in resistant mice. Data mining revealed a bias towards the expression of genes involved in granulocyte pathophysiology in susceptible mice, such as an upregulation of those for the neutrophil chemoattractant LIX (CXCL5), interleukin 17 receptor, phosphoinositide kinase 3 delta, or gamma interferon-inducible protein 10. Following M. tuberculosis challenge in both airways or peritoneum, granulocytes were recruited significantly faster and at higher numbers in susceptible than in resistant mice. When granulocytes were efficiently depleted by either of two regimens at the onset of infection, only susceptible mice survived aerosol challenge with M. tuberculosis significantly longer than control mice. We conclude that initially enhanced recruitment of granulocytes contributes to susceptibility to tuberculosis.

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Mannose-binding lectin alleles in sub-Saharan Africans and relation with susceptibility to infections

Cited by 43 publications

References 34 publications

Genetic Polymorphisms of Mannose-Binding Lectin Do Not Influence Placental Malaria but Are Associated with Preterm Deliveries

Genetic Polymorphisms of Mannose-Binding Lectin Do Not Influence Placental Malaria but Are Associated with Preterm Deliveries

Binding of Serum Mannan Binding Lectin to a Cell Integrity-DefectiveCryptococcus neoformans ccr4Δ Mutant

Genetically Determined Susceptibility to Tuberculosis in Mice Causally Involves Accelerated and Enhanced Recruitment of Granulocytes

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