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

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.

SUBMITTER: Bumiller-Bini V

PROVIDER: S-EPMC7982787 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAbnormal coagulation is a common feature of glioma. There is a strong correlation between coagulation and the complement system, named complement and coagulation cascades (CCC). However, the role of CCC genes in lower-grade glioma (LGG) remains unclear. This study aimed to investigate the role of CCC genes in LGG.MethodsIn total, 5,628 differential expressed genes were identified between 498 LGG tissues from The Cancer Genome Atlas (TCGA) and 207 normal brain tissues from Genotype-Tissue Expression Project (GTEx). Among them, 20 overlapped CCC genes were identified as differentially expressed CCC genes. Then, comprehensive bioinformatics analysis was used to investigate the role of CCC genes in LGG; 271 LGG tissues from the Chinese Glioma Genome Atlas (CGGA) were used as the validation dataset. Cell Counting Kit-8 (CCK8) proliferation assay, colony formation assay, and wound healing assay were conducted to explore the anti-glioma effect of the sensitive drugs we predicted.ResultsWe constructed a risk signature consisting of six CCC genes, including F2R, SERPINA1, TFPI, C1QC, C2, and C3AR1. The CCC gene-based risk signature could accurately predict the prognosis of patients with LGG. In addition, we found that the JAK-STAT, NOD-like receptor, Notch, PI3K-Akt, and Rap1 signaling pathways might be activated and had crosstalk with CCC in the high-risk group. Our findings analyses demonstrated that samples in high- and low-risk groups had different immune landscapes. Moreover, patients in the high-risk group might have greater resistance to immunotherapy. We validated the accuracy of the risk signature in predicting immunotherapy response in two public immunotherapy cohorts, GSE135222 and GSE78220. By means of oncoPredict, MG-132, BMS-536924, PLX-4720, and AZD6482 were identified as potential sensitive drugs for high-risk patients, of which MG-132 was particularly recommended for high-risk patients. We performed in vitro experiments to explore the anti-glioma effect of MG-132, and the results demonstrated MG-132 could inhibit the proliferation and migration of glioma cells.ConclusionsOur findings show that CCC genes are associated with the prognosis and immune infiltration of LGG and provide possible immunotherapeutic and novel chemotherapeutic strategies for patients with LGG based on the risk signature.

Project description:Over 5 million people around the world have tested positive for the beta coronavirus SARS-CoV-2 as of May 29, 2020, a third of which are in the United States alone. These infections are associated with the development of a disease known as COVID-19, which is characterized by several symptoms, including persistent dry cough, shortness of breath, chills, muscle pain, headache, loss of taste or smell, and gastrointestinal distress. COVID-19 has been characterized by elevated mortality (over 100 thousand people have already died in the US alone), mostly due to thromboinflammatory complications that impair lung perfusion and systemic oxygenation in the most severe cases. While the levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) have been associated with the severity of the disease, little is known about the impact of IL-6 levels on the proteome of COVID-19 patients. The present study provides the first proteomics analysis of sera from COVID-19 patients, stratified by circulating levels of IL-6, and correlated to markers of inflammation and renal function. As a function of IL-6 levels, we identified significant dysregulation in serum levels of various coagulation factors, accompanied by increased levels of antifibrinolytic components, including several serine protease inhibitors (SERPINs). These were accompanied by up-regulation of the complement cascade and antimicrobial enzymes, especially in subjects with the highest levels of IL-6, which is consistent with an exacerbation of the acute phase response in these subjects. Although our results are observational, they highlight a clear increase in the levels of inhibitory components of the fibrinolytic cascade in severe COVID-19 disease, providing potential clues related to the etiology of coagulopathic complications in COVID-19 and paving the way for potential therapeutic interventions, such as the use of pro-fibrinolytic agents. Raw data for this study are available through ProteomeXchange with identifier PXD020601.

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

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