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Published on: July 15, 2011
Adding MASP1 to the lectin pathway-Leprosy association puzzle: Hints from gene polymorphisms and protein levels
Hellen Weinschutz Mendes1, Angelica Beate Winter Boldt1,2, Ewalda von Rosen Seeling Stahlke3
1Laboratory of Molecular Immunopathology, Department of Clinical Pathology, Clinical Hospital, Federal University of Paraná, Curitiba, Brazil.
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>A and rs13064994*C>T, exon 12 3'-untranslated rs72549262*C>G, rs1109452*C>T and rs850314*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 were present 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 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.
Insights
MASP1 gene variants and lower MASP-3/MAp44 serum levels are linked to increased leprosy susceptibility. These findings highlight the lectin pathway
Area of Science:
- Immunology
- Genetics
- Infectious Diseases
Background:
- Complement factors deposited on Mycobacterium leprae can enhance phagocytosis via the lectin complement pathway.
- The MASP1 gene produces three key lectin pathway proteins: Mannan-binding lectin-associated serine protease 1 (MASP-1), MASP-3, and mannan-binding lectin-associated protein of 44 kDa (MAp44).
- The specific roles of MASP-1, MASP-3, and MAp44 in leprosy pathogenesis remain uninvestigated.
Purpose of the Study:
- To investigate the association between MASP1 gene polymorphisms and serum levels of MASP-1, MASP-3, and MAp44 in leprosy patients.
- To determine the role of these lectin pathway proteins in modulating susceptibility to leprosy.
Main Methods:
- Haplotype analysis of five MASP1 polymorphisms using multiplex sequence-specific PCR.
- Quantification of serum MASP-1, MASP-3, and MAp44 levels in 196 leprosy patients and 193 controls.
- Comparison of genetic variants and protein levels between patient and control groups, and between lepromatous and non-lepromatous leprosy.
Main Results:
- Lower serum levels of MASP-3 and MAp44 were observed in leprosy patients compared to controls.
- Lepromatous leprosy patients exhibited lower MASP-3 and MAp44 levels than non-lepromatous patients.
- Specific MASP1 variants and haplotypes were associated with altered MASP-1, MASP-3, and MAp44 levels, influencing leprosy susceptibility and resistance.
Conclusions:
- MASP1 gene polymorphisms that affect MASP-3 and MAp44 serum concentrations play a role in modulating leprosy susceptibility.
- The regulation of the lectin pathway is crucial in combating pathogens like Mycobacterium leprae that utilize phagocytosis for host cell invasion.
