AddingMASP1to the lectin pathway – leprosy association puzzle: hints from gene polymorphisms and protein levels

Abstract

38 39 Background: Deposition of complement factors on Mycobacterium leprae 40 may enhance phagocytosis. Such deposition may occur through the lectin 41 pathway of complement. Three proteins of the lectin pathway are produced 42 from the gene MASP1: Mannan-binding lectin-associated serine protease 1 43 (MASP-1) and MASP-3 and mannan-binding lectin-associated protein of 44 44 kDa (MAp44). Despite their obvious importance, the roles played by these 45 proteins have never been investigated in leprosy disease. Methodology: We 46 haplotyped five MASP1 polymorphisms by multiplex sequence-specific PCR 47 (intronic rs7609662*G>A and rs13064994*C>T, exon 12 3'-untranslated 48 rs72549262*C>G, rs1109452*C>T and rs850314*G>A) and measured 49 MASP-1, MASP-3 and MAp44 serum levels in 196 leprosy patients (60%, 50 lepromatous) and 193 controls. Principal findings: Lower MASP-3 and 51 MAp44 levels were observed in patients, compared with controls (P=0.000252 and P<0.0001, respectively) and in lepromatous, compared with non-53 lepromatous patients (P=0.008 and P=0.002, respectively). Higher MASP-3 54 levels occurred in controls carrying variants/haplotypes associated with 55 leprosy resistance (rs13064994*T, rs1109452_rs850314*CG within GT_CCG 56 and rs850314*A: OR=0.5-0.6, Pcorr=0.01-0.04). Controls with rs1109452*T, 57 included in susceptibility haplotypes (GT_GTG/GT_CTG: OR=2.0, 58 Pcorr=0.03), had higher MASP-1 and lower MASP-3 levels (P≤0.009). Those 59 with GC_CCG, presented increasing susceptibility (OR=1.7, Pcorr=0.006) and 60 had higher MAp44 levels (P=0.015). MASP-3 expression decreased in 61 patients, compared with controls carrying rs1109452_rs850314*CA or CG 62 (P≤0.02), which may rely on exon 12 CpG methylation and/or miR-2861/miR-63 3181 mRNA binding. Conclusion: Polymorphisms regulating MASP-3/MAp44 64 availability in serum modulate leprosy susceptibility, underlining the 65 importance of lectin pathway regulation against pathogens that exploit 66 phagocytosis to parasitize host macrophages. 67 68 Author summary 3 69Since immemorial times, Mycobacterium leprae inflicts permanent injuries in 70 human kind, within a wide symptomatic spectrum ranging from insensitive 71 skin patches to disabling physical lesions. Innate resistance to this parasite is 72 well recognized, but poorly understood. The complement system is one of the 73 most important arms of the innate response, and several lines of evidence 74 indicate that it may be usurped by the parasite to enhance its entrance into 75 host cells. These include our recent work on genetic association of the 76 disease with lectin pathway components and the complement receptor CR1, 77 whose polymorphisms modulate susceptibility to infection and clinical 78 presentation. Here, we add another pivotal piece in the leprosy parasite-host 79 interaction puzzle: polymorphisms and serum levels of three different lectin 80 pathway proteins, all encoded by the same gene, namely mannan-binding 81 lectin-associated serine protease 1 (MASP1). We found lower levels of two of 82 these ...

Association of Polymorphisms of MASP1/3, COLEC10, and COLEC11 Genes with 3MC Syndrome

“…Some clinical associations of MASP-1, MASP-3, and MAp44 other than 3MC have been reported. For example, Weinschutz Mendes et al (2020) found that polymorphisms influencing serum concentrations of MASP-3/MAp44 modulate susceptibility to leprosy [ 33 ]. Larsen et al (2019) showed that low MASP-1 concentrations were associated with clotting disorders in patients with septic shock [ 34 ].…”