Abstract
Structural variants of the Mannose Binding Lectin (MBL) cause quantitative and qualitative functional deficiencies, which are associated with various patterns of susceptibility to infectious diseases and other disorders. We determined genetic MBL variants in 2010 Ghanaian patients with pulmonary tuberculosis (TB) and 2346 controls and characterized the mycobacterial isolates of the patients. Assuming a recessive mode of inheritance, we found a protective association between TB and the MBL2 G57E variant (odds ratio 0.60, confidence interval 0.4–0.9, P 0.008) and the corresponding LYQC haplotype (P corrected 0.007) which applied, however, only to TB caused by M. africanum but not to TB caused by M. tuberculosis. In vitro, M. africanum isolates bound recombinant human MBL more efficiently than did isolates of M. tuberculosis. We conclude that MBL binding may facilitate the uptake of M. africanum by macrophages, thereby promoting infection and that selection by TB may have favoured the spread of functional MBL deficiencies in regions endemic for M. africanum.
Highlights
Mannose-binding lectin (MBL) is a plasma opsonin of the collectin family
We found in a recessive mode of inheritance that the MBL2 lowproducer haplotype LYQC including the structural variant G57E was associated with protection from TB caused by M. africanum/M. bovis but not from TB caused by M. tuberculosis
The observation in the genetic analysis was corroborated by MBL binding studies that were performed with M. tuberculosis and M. africanum isolates originating from Ghanaian TB patients and with the laboratory strain H37Rv
Summary
Mannose-binding lectin (MBL) is a plasma opsonin of the collectin family. Its monomer consists of a 228-amino-acid polypeptide chain. The heterozygous occurrence of the B allele was found negatively associated with tuberculous meningitis in South Africa [8], and the B allele was less frequent in Afro-American pulmonary TB cases than in controls [9]. The frequency of the B allele was significantly higher in Afro-American TB patients than in controls [9]. In South India, a positive association of the B allele with disease was observed [11], and likewise, the C allele was found to be more frequent among HIV-positive TB patients than among HIV-negative controls in Malawi [12]. We have studied the influence of MBL2 variants on susceptibility and resistance to TB by comparing HIV-negative patients with smear- and/or culture-positive pulmonary TB to unaffected and unrelated control individuals in Ghana, West Africa. Genotyping of MTBC isolates allowed to stratify in the association study for the infecting MTBC strains and to search for a contribution of pathogen variability
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