Adding MASP1 to the lectin pathway—Leprosy association puzzle: Hints from gene polymorphisms and protein levels

Mendes, Hellen Weinschutz; Boldt, Angelica Beate Winter; Stahlke, Ewalda Von Rosen Seeling; Jensenius, Jens Christian; Thiel, Steffen; Messias-Reason, Iara

doi:10.1371/journal.pntd.0007534

Cited by 7 publications

(8 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Polymorphisms of both MBL-associated serine protease-encoding genes were associated with HBV infection. We also confirmed the recently published association with leprosy disease and the MASP1*GC_CCG haplotype, obtained with the same group of patients (OR = 1.81 [95%CI = 1.25–2.64], P = 0.002) ( 29 ). Furthermore, we identified an opposite association with the MASP1*GC_CCA haplotype, with leprosy resistance (OR = 0.50 [95%CI = 0.28–0.89], P = 0.019).…”

Section: Resultssupporting

confidence: 91%

“…Instead, it cleaves pro-factor D from the PRM-independent alternative pathway (AP) in “resting” blood (under non-inflammatory conditions) [reviewed by ( 62 )]. The MASP1*AC_CC haplotype associated with higher susceptibility to HBV infection presents a 3′UTR combination in exon 12 that possibly acts as a target for miRNAs, being also associated with higher MASP-3 and lower MASP-1 levels ( 29 ). Thus, the association of this MASP1 haplotype with HBV susceptibility may be explained by blockage/hindered LP activation, as well as excessive AP activation.…”

Section: Discussionmentioning

confidence: 99%

“…Serum MASP-1, MASP-3, and MAp44 levels were measured with time-resolved immunofluorimetric assays (TRIFMA), as published ( 29 ). In the MASP-3 and MAp44 TRIFMA, the bound protein is detected by a specific biotin-labeled monoclonal antibody, recognized by europium-labeled streptavidin.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Hepatitis B Virus Infection Among Leprosy Patients: A Case for Polymorphisms Compromising Activation of the Lectin Pathway and Complement Receptors

et al. 2021

Self Cite

View full text Add to dashboard Cite

Thousands of leprosy patients not only suffer from physical deformities, but also either have or have had hepatitis B virus (HBV) coinfection. Polymorphisms of the complement system modulate susceptibility to leprosy, but genetic susceptibility to past or present HBV infection is unknown. We used sequencing and multiplex sequence-specific PCR to genotype 72 polymorphisms of seven genes (MBL2, FCN1, FCN2, FCN3, MASP1, MASP2, C3) encoding components of the lectin pathway, and two genes encoding complement receptors (CR1, VSIG4) in 190 patients, of which 74 were positive for HBsAg and/or anti-HBc (HBV+, 93.2% with a resolved infection) and 116 lepromatous patients, and 408 HBV-blood donors. In addition, we tested for levels of proteins of the lectin pathway. We found no difference between serum concentrations of mannan-binding lectin (MBL), MBL-associated serine proteins (MASP-1, MASP-2, MASP-3, MAp44), ficolin-3 (FCN-3), soluble complement receptor 1 (sCR1) and MBL mediated C4 activation, measured by ELISA or TRIFMA in up to 167 HBV+ and HBV− patients. Haplotypes lowering protein levels or encoding dysfunctional proteins increased susceptibility to HBV infection: MBL2*LYQC (OR = 3.4, p = 0.02), MASP1*AC_CC (OR = 4.0, p = 0.015) and MASP2*1C2-l (OR = 5.4, p = 0.03). Conversely, FCN1*3C2 haplotype, associated with higher gene expression, was protective (OR = 0.56, P = 0.033). Other haplotypes associated with HBV susceptibility were: MASP2*2B1-i (OR = 19.25, P = 0.003), CR1*3A (OR = 2.65, P = 0.011) and VSIG4*TGGRCG (OR = 12.55, P = 0.014). Some polymorphisms in ficolin genes associated with lower protein levels increased susceptibility to leprosy/HBV infection: FCN*1 (OR = 1.66, P = 0.029), FCN2*GGGCAC (OR = 6.73, P = 0.008), and FCN3*del_del_C (OR = 12.54, P = 0.037), and to lepromatous disease/HBV infection: FCN2*TA (OR = 2.5, P = 0.009), whereas FCN2*MAG was associated with increased FCN-2 expression and resistance against coinfection (OR = 0.29, P = 0.026). These associations were independent of demographic factors and did not increase susceptibility to leprosy per se, except MASP2*1C2-l. Associations for FCN2, FCN3, MASP1, MASP2, and VSIG4 variants were also independent of each other. In conclusion, polymorphisms compromising activation of the lectin pathway of complement increase susceptibility to HBV infection, with ficolin polymorphisms playing a major role in modulating the susceptibility among leprosy patients.

show abstract

Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Hepatitis B Virus Infection Among Leprosy Patients: A Case for Polymorphisms Compromising Activation of the Lectin Pathway and Complement Receptors

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…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].…”

Section: Biological Activities Of the Masp-1 Masp-3 And Map44mentioning

confidence: 99%

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

Gajek

Świerzko

Cedzyński

2020

IJMS

View full text Add to dashboard Cite

The Malpuech, Michels, Mingarelli, Carnevale (3MC) syndrome is a rare, autosomal recessive genetic- disorder associated with mutations in the MASP1/3, COLEC1,1 or COLEC10 genes. The number of 3MC patients with known mutations in these three genes reported so far remains very small. To date, 16 mutations in MASP-1/3, 12 mutations in COLEC11 and three in COLEC10 associated with 3MC syndrome have been identified. Their products play an essential role as factors involved in the activation of complement via the lectin or alternative (MASP-3) pathways. Recent data indicate that mannose-binding lectin-associated serine protease-1 (MASP-1), MASP-3, collectin kidney-1 (collectin-11) (CL-K1), and collectin liver-1 (collectin-10) (CL-L1) also participate in the correct migration of neural crest cells (NCC) during embryogenesis. This is supported by relationships between MASP1/3, COLEC10, and COLEC11 gene mutations and the incidence of 3MC syndrome, associated with craniofacial abnormalities such as radioulnar synostosis high-arched eyebrows, cleft lip/palate, hearing loss, and ptosis.

show abstract

“…In fact, lower MASP-2, MASP-3 and MAp44 levels occur in leprosy and lepromatous disease, probably due to its consumption in the inflammatory response. On the other hand, MASP1 haplotypes associated with lower MASP-1 and higher MASP-3 levels at baseline were associated with leprosy resistance, probably by decreasing mycobacteria infection, which relies on successful complement-driven opsonization and phagocytosis ( Boldt et al ., 2013 ; Weinschutz Mendes et al ., 2020 ). Thus, the investigation of MASP levels in COVID-19 is also highly relevant, especially in the context of comorbidities.…”

Section: Introductionmentioning

confidence: 99%

MASPs at the crossroad between the complement and the coagulation cascades - the case for COVID-19

et al. 2021

View full text Add to dashboard Cite

Components of the complement system and atypical parameters of coagulation were reported in COVID-19 patients, as well as the exacerbation of the inflammation and coagulation activity. Mannose binding lectin (MBL)-associated serine proteases (MASPs) play an important role in viral recognition and subsequent activation of the lectin pathway of the complement system and blood coagulation, connecting both processes. Genetic variants of MASP1 and MASP2 genes are further associated with different levels and functional efficiency of their encoded proteins, modulating susceptibility and severity to diseases. Our review highlights the possible role of MASPs in SARS-COV-2 binding and activation of the lectin pathway and blood coagulation cascades, as well as their associations with comorbidities of COVID-19. MASP-1 and/or MASP-2 present an increased expression in patients with COVID-19 risk factors: diabetes, arterial hypertension and cardiovascular disease, chronic kidney disease, chronic obstructive pulmonary disease, and cerebrovascular disease. Based also on the positive results of COVID-19 patients with anti-MASP-2 antibody, we propose the use of MASPs as a possible biomarker of the progression of COVID-19 and the investigation of new treatment strategies taking into consideration the dual role of MASPs, including MASP inhibitors as promising therapeutic targets against COVID-19.

show abstract

Adding MASP1 to the lectin pathway—Leprosy association puzzle: Hints from gene polymorphisms and protein levels

Cited by 7 publications

References 49 publications

Hepatitis B Virus Infection Among Leprosy Patients: A Case for Polymorphisms Compromising Activation of the Lectin Pathway and Complement Receptors

Hepatitis B Virus Infection Among Leprosy Patients: A Case for Polymorphisms Compromising Activation of the Lectin Pathway and Complement Receptors

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

MASPs at the crossroad between the complement and the coagulation cascades - the case for COVID-19

Contact Info

Product

Resources

About