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. 2021 Mar 17;44(1 Suppl 1):e20200199.
doi: 10.1590/1678-4685-GMB-2020-0199. eCollection 2021.

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

Valéria Bumiller-Bini  1   2 , Camila de Freitas Oliveira-Toré  3 , Tamyres Mingorance Carvalho  4   2 , Gabriela Canalli Kretzschmar  1   2 , Letícia Boslooper Gonçalves  5   2 , Nina de Moura Alencar  6 , Miguel Angelo Gasparetto Filho  1 , Marcia Holsbach Beltrame  1 , Angelica Beate Winter Boldt  1
Affiliations

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

Valéria Bumiller-Bini et al. Genet Mol Biol. .

Abstract

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.

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Conflict of interest statement

Conflicts of Interest: Authors declare no conflict of interest.

Figures

Figure 1 -
Figure 1 -. Complement pathways in SARS-CoV-2 infection. The activation of the classical pathway occurs through the C1 complex, after recognition of antibodies complexed to SARS-CoV-2. This leads to the cleavage of the C2 component into C2a and C2b. C2a joins the common pathway of the three complement pathways to form the C3 convertase. Activation of the lectin pathway by the virus via the MBL/MASP-1/MASP-2 complex has already been demonstrated, however the activation by ficolins or colectin is not shown (with a question mark). After binding of MBL/MASP complexes to the surface of pathogens, MASP-1 autoativates, transactivates MASP-2, and C2 and C4 components are cleaved (C2 and C4 by MASP-2 and C2 by MASP-1), generating the C3 convertase. The alternative pathway is initiated by the spontaneous hydrolysis of component C3, generating C3a and C3b. C3b binds to factor B and is cleaved by factor D, forming the C3 convertase of the alternative pathway. After this step, the three pathways converge into a single pathway. The C3 convertase enzyme cleaves component C3 into C3a and C3b. C3a and C4a are anaphylatoxins that contribute to an increase in inflammatory processes and to the chemotaxis of neutrophils and macrophages (red arrows), while C3b performs viral opsonization. The formation of C5 convertase occurs in different ways through the three pathways, but all generate C5a and C5b. C5a is an anaphylatoxin (as also C3a) that contributes to inflammatory processes, while C5b joins the last C6-C9 components of the cascade and forms the membrane attack complex. The MASP-3, MAp44, and probably MAp19 proteins inhibit the lectin pathway. MASP-3 also participates in the cleavage of pro-factor D into factor D, of the alternative pathway. The elements of the figure are not shown in their actual proportions.
Figure 2 -
Figure 2 -. MASP1 and MASP2 genes. The MASP1 gene (ENSG00000127241) generates three proteins by alternative splicing: MASP-1 (ENST00000337774.9), MASP-3 (ENST00000296280.11) and MAp44 (ENST00000169293.10). MASP-1 and MASP-3 share the regulatory domains (CUB1-EGF-CUB2-CCP1-CCP2), but differ in the serine protease domain (SP); MASP-1 SP is encoded by exons 13 to 18, whereas the MASP-3 SP is encoded only by exon 12. MAp44 lacks the SP domain but shares the first four domains with MASP-1 and MASP-3 (CUB1-EGF-CUB2-CCP1). This protein has no protease function. The MASP2 gene (ENSG00000009724) encodes two proteins: MASP-2 (ENST00000400897.8) and MAp19 (ENST00000400898.3). MASP-2 and MAp19 share only two regulatory domains (CUB1-EGF). MASP-2 has a SP domain, but MAp19 lacks this domain. Genetic polymorphisms in these two genes can alter protein expression (see Tables 1 and 2), and many have already been associated with the most diverse disease models. Exons and introns are represented figuratively, not reflecting their actual size. The same colors represent the domains and their respective exons. Figure adapted from Boldt et al. (2016).
Figure 3 -
Figure 3 -. MASPs in the coagulation cascade during COVID-19. The participation of MASPs in coagulation contributes significantly to the formation of clots, and cleavage of intermediate components of the cascade. On the right side of the figure, MASP-1 activates endothelial cells through the protease-activated receptor (PAR) 4, 2 and 1. This activation has a characteristic response profile, and different from that stimulated via thrombin: activated endothelial cells start secretin pro-inflammatory cytokines and interleukins 6 and 8 (IL-6 and IL-8). Platelet aggregation also occurs. IL-6 and IL-8 contribute to the chemotaxis of neutrophils and macrophages. On the left, complexes of MASPs and MBL / MASPs participate in the coagulation cascade at different points. Like the factor Xa (FXa) of the coagulation cascade, MASP-2 cleaves prothrombin to thrombin l. MASP-1 participates in the cleavage of prothrombin to thrombin, and the cleavage of fibrinogen to fibrin. MASP-1 cleaves prothrombin in three specific sites: R393, R155, and R271. The sites R155 and R271 are shared with thrombin and factor FXa, respectively, whereas R393 is exclusive of MASP-1. MBL/MASPs complexes form clots directly, without co-participation of other components of coagulation (Gulla et al., 2010). These complexes cleave fibrinogen to fibrin, contributing to formation of clots in the coagulation cascade. MASP-1 has an independent dual role in the coagulation cascade and innate immunity. Its important contribution to the coagulation cascade and the time/structure of the clots can contribute to direct the pathophysiology of COVID-19 to severe conditions.
Figure 4 -
Figure 4 -. Promising therapeutic targets. (A) The clinical symptoms of COVID-19 appear after the first week of infection. In this first week, MASP-2 recognizes the N-SARS-CoV-2 protein and MBL recognizes S-SARS-CoV-2, leading to lectin pathway (LP) activation. Deficiency of C1-INH, proposed as a direct consequence of SARS-CoV-2 infection, leads to loss of physiological control of LP and coagulation, causing hyperinflammation and overcoagulation. During the second week, the symptoms start with activation of the classical pathway (CP) through the production of IgG and IgM antibodies, amplified by the alternative pathway (AP). At this stage of the disease, uncontrolled complement activation of all three pathways contribute to worsen the prognosis of COVID-19. (B) Drugs that inhibit the LP of complement can be considered as promising therapeutic agents against COVID-19. Those that inhibit MASP-1 and/or MASP-2 (Narsoplimab, C1-INH and antithrombin in the presence of low-molecular weight heparin - LMWH) are predicted to block both LP and coagulation, redirecting the clinical course of COVID-19 towards a better prognosis. This may also occur by reducing excessive antibody production, due to lower viral opsonization, phagocytosis and antigen presentation to B lymphocytes. AP - alternative pathway of complement; DIC - disseminated intravascular coagulation; C1-INH - C1 inhibitor; CP - classical pathway of complement; Ig - immunoglobulins; IL - interleukin; LP - lectin pathway of complement; MAC - membrane attack complex; MASP - mannose-binding lectin associated serine protease; NPC - new coronavirus pneumonia. Traced lines - weakened or blocked activation/ production. Solid lines - activation or blockage. Down-pointing arrows - lower production.
Figure 5 -
Figure 5 -. Relationship between MASPs and COVID-19 comorbidities. Changes in MASPs levels have already been associated with COVID-19 risk factors, such as sex, diabetes, kidney, cardiovascular, cerebrovascular, and chronic obstructive pulmonary disease (COPD). Genetic polymorphisms in the MASP1 and MASP2 genes influence the expression levels of these proteins. COPD: high levels in plasma and increased detection in situ, after MASP-2 was associated with risk (thick pink arrow), MASP-1 has not yet been associated/investigated with COPD, but the evidence leads us to suggest that MASP-1 function is also a risk factor to these patients (green arrow). Arterial Hypertension and Cardiovascular Disease (CVD): high levels of MASP-1 and MASP-2 have been associated with risk. The participation of MASP-1 in the coagulation cascade contributes to the formation of clots, worsening CVD. Chronic kidney disease (CKD): high levels of MASP-2 are associated with ischemia-reperfusion injury (IR), and MASP-1 seems to play crucial roles in chronic kidney disease, as well as its associated symptoms and conditions, such as IR and kidney transplantation. Diabetes (DM): the natural hyperglycemic status, uncontrolled activation of the lectin pathway, with elevated MASPs concentration in DM patients, might partially explain why those individuals belong to the group with higher incidence and severity of COVID-19. Immunodeficiency and Immunosuppression: MASPs levels have been associated with the condition and outcome of HIV and immunosuppressed patients, who also can be considered more vulnerable to COVID-19 infection. Apparently, MASP-1 and MASP-2 levels were not associated with susceptibility to infections in patients with immunosuppression, for this reason, the topic is not represented in this figure. Cerebrovascular diseases: MASP-1 and MASP-2 show increased proteolytic activity in the ischemic stroke, inflammation, and clots formation. Sex: About two-thirds of COVID-19 patients are men, who also have a higher expression of MASP-1 and lower expression of MASP-2. The disseminated intravascular coagulation observed in severe COVID-19 are representations such as the formation of clots in the organs where this activity has already been observed. The thickness of the arrows indicates MASP expressions in each comorbidity. The blue arrows correspond to MASP-1 and the pink arrows to MASP-2. The dashed pink line means a decrease in MASP-2 expression.
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