AddingMASP1to the lectin pathway – leprosy association puzzle: hints from gene polymorphisms and protein levels
Authors: Mendes Hellen Weinschutz , Boldt Angelica Winter , Stahlke Ewalda , Jensenius Jens Christian , Thiel Steffen , Messias-Reason Iara J. Taborda 
Published: June 2019

Background

Deposition of complement factors onMycobacterium lepraemay enhance phagocytosis. Such deposition may occur through the lectin pathway of complement. Three proteins of the lectin pathway are produced from the geneMASP1: 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 fiveMASP1polymorphisms by multiplex sequence-specific PCR (intronicrs7609662*G>Aandrs13064994*C>T, exon 12 3’-untranslatedrs72549262*C>G, rs1109452*C>Tandrs850314*G>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<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*CGwithinGT_CCGandrs850314*A: OR=0.5-0.6, Pcorr=0.01-0.04). Controls withrs1109452*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 carryingrs1109452_rs850314*CAorCG(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 lepraeinflicts 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 placesMASP1products in the regulatory crossroad between the innate and adaptive arms of the immunological system, modulating leprosy susceptibility.