TY - JOUR T1 - Adding <em>MASP1</em> to the lectin pathway – leprosy association puzzle: hints from gene polymorphisms and protein levels JF - bioRxiv DO - 10.1101/666909 SP - 666909 AU - Hellen Weinschutz Mendes AU - Angelica Winter Boldt AU - Ewalda Stahlke AU - Jens Christian Jensenius AU - Steffen Thiel AU - Iara J. Taborda Messias-Reason Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/06/11/666909.abstract N2 - Background Deposition of complement factors on Mycobacterium leprae may enhance phagocytosis. Such deposition may occur through the lectin pathway of complement. Three proteins of the lectin pathway are produced from the gene MASP1: Mannan-binding lectin-associated serine protease 1 (MASP-1) and MASP-3 and mannan-binding lectin-associated protein of 44 kDa (MAp44). Despite their obvious importance, the roles played by these proteins have never been investigated in leprosy disease.Methodology We haplotyped five MASP1 polymorphisms by multiplex sequence-specific PCR (intronic rs7609662*G&gt;A and rs13064994*C&gt;T, exon 12 3’-untranslated rs72549262*C&gt;G, rs1109452*C&gt;T and rs850314*G&gt;A) and measured MASP-1, MASP-3 and MAp44 serum levels in 196 leprosy patients (60%, lepromatous) and 193 controls.Principal findings Lower MASP-3 and MAp44 levels were observed in patients, compared with controls (P=0.0002 and P&lt;0.0001, respectively) and in lepromatous, compared with non-lepromatous patients (P=0.008 and P=0.002, respectively). Higher MASP-3 levels occurred in controls carrying variants/haplotypes associated with leprosy resistance (rs13064994*T, rs1109452_rs850314*CG within GT_CCG and rs850314*A: OR=0.5-0.6, Pcorr=0.01-0.04). Controls with rs1109452*T, included in susceptibility haplotypes (GT_GTG/GT_CTG: OR=2.0, Pcorr=0.03), had higher MASP-1 and lower MASP-3 levels (P≤0.009). Those with GC_CCG, presented increasing susceptibility (OR=1.7, Pcorr=0.006) and had higher MAp44 levels (P=0.015). MASP-3 expression decreased in patients, compared with controls carrying rs1109452_rs850314*CA or CG (P≤0.02), which may rely on exon 12 CpG methylation and/or miR-2861/miR-3181 mRNA binding.Conclusion Polymorphisms regulating MASP-3/MAp44 availability in serum modulate leprosy susceptibility, underlining the importance of lectin pathway regulation against pathogens that exploit phagocytosis to parasitize host macrophages.Author summary Since immemorial times, Mycobacterium leprae inflicts permanent injuries in human kind, within a wide symptomatic spectrum ranging from insensitive skin patches to disabling physical lesions. Innate resistance to this parasite is well recognized, but poorly understood. The complement system is one of the most important arms of the innate response, and several lines of evidence indicate that it may be usurped by the parasite to enhance its entrance into host cells. These include our recent work on genetic association of the disease with lectin pathway components and the complement receptor CR1, whose polymorphisms modulate susceptibility to infection and clinical presentation. Here, we add another pivotal piece in the leprosy parasite-host interaction puzzle: polymorphisms and serum levels of three different lectin pathway proteins, all encoded by the same gene, namely mannan-binding lectin-associated serine protease 1 (MASP1). We found lower levels of two of these proteins, MASP-3 and MAp44, in leprosy patients. Higher MASP-3/lower MASP-1 levels were associated with protective haplotypes, containing two side-by-side polymorphisms located in the exclusive untranslated region of MASP-3 exon 12, which may regulate exon splicing and/or translation efficiency. The associations revealed in this study reflect the pleiotropic nature of this gene. They further illustrate the complexity of the response mounted against the parasite, which places MASP1 products in the regulatory crossroad between the innate and adaptive arms of the immunological system, modulating leprosy susceptibility. ER -