Search

Introduction: While complement is a contributor to disease severity in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, all three complement pathways might be activated by the virus. Lectin pathway activation occurs through different pattern recognition molecules, including mannan binding lectin (MBL), a protein shown to interact with SARS-CoV-2 proteins. However, the exact role of lectin pathway activation and its key pattern recognition molecule MBL in COVID-19 is still not fully understood., Methods: We therefore investigated activation of the lectin pathway in two independent cohorts of SARS-CoV-2 infected patients, while also analysing MBL protein levels and potential effects of the six major single nucleotide polymorphisms (SNPs) found in the MBL2 gene on COVID-19 severity and outcome., Results: We show that the lectin pathway is activated in acute COVID-19, indicated by the correlation between complement activation product levels of the MASP-1/C1-INH complex (p=0.0011) and C4d (p<0.0001) and COVID-19 severity. Despite this, genetic variations in MBL2 are not associated with susceptibility to SARS-CoV-2 infection or disease outcomes such as mortality and the development of Long COVID., Conclusion: In conclusion, activation of the MBL-LP only plays a minor role in COVID-19 pathogenesis, since no clinically meaningful, consistent associations with disease outcomes were noted., Competing Interests: Author ET is an employee of Hycult Biotech. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hurler, Szilágyi, Mescia, Bergamaschi, Mező, Sinkovits, Réti, Müller, Iványi, Gál, Gopcsa, Reményi, Szathmáry, Lakatos, Szlávik, Bobek, Prohászka, Förhécz, Csuka, Kajdácsi, Cervenak, Kiszel, Masszi, Vályi-Nagy, Würzner, Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration, Lyons, Toonen and Prohászka.)

Objectives: Uncontrolled thromboinflammation plays an important role in the pathogenesis of coronavirus disease (COVID-19) caused by SARS-CoV-2 virus. Complement was implicated as key contributor to this process, therefore we hypothesized that markers of the complement profile, indicative for the activation state of the system, may be related to the severity and mortality of COVID-19., Methods: In this prospective cohort study samples of 102 hospitalized and 26 outpatients with PCR-confirmed COVID-19 were analyzed. Primary outcome was in-hospital, COVID-19 related mortality, and secondary outcome was COVID-19 severity as assessed by the WHO ordinal scale. Complement activity of alternative and classical pathways, its factors, regulators, and activation products were measured by hemolytic titration, turbidimetry, or enzyme-immunoassays. Clinical covariates and markers of inflammation were extracted from hospital records., Results: Increased complement activation was characteristic for hospitalized COVID-19 patients. Complement activation was significantly associated with markers of inflammation, such as interleukin-6, C-reactive protein, and ferritin. Twenty-five patients died during hospital stay due to COVID-19 related illness. Patients with uncontrolled complement activation leading to consumption of C3 and decrease of complement activity were more likely to die, than those who had complement activation without consumption. Cox models identified anaphylatoxin C3a, and C3 overactivation and consumption (ratio of C3a/C3) as predictors of in-hospital mortality [HR of 3.63 (1.55-8.45, 95% CI) and 6.1 (2.1-17.8), respectively]., Conclusion: Increased complement activation is associated with advanced disease severity of COVID-19. Patients with SARS-CoV-2 infection are more likely to die when the disease is accompanied by overactivation and consumption of C3. These results may provide observational evidence and further support to studies on complement inhibitory drugs for the treatment of COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sinkovits, Mező, Réti, Müller, Iványi, Gál, Gopcsa, Reményi, Szathmáry, Lakatos, Szlávik, Bobek, Prohászka, Förhécz, Csuka, Hurler, Kajdácsi, Cervenak, Kiszel, Masszi, Vályi-Nagy and Prohászka.)

Pentraxin-3 (PTX3) and C-reactive protein (CRP) have been shown to regulate complement activation in vitro , but their role has not been investigated in complement consumption in vivo . Thrombotic microangiopathies (TMA) are often accompanied by complement overactivation and consumption, therefore we analyzed the relation of the systemic pentraxin levels to the complement profile, laboratory parameters and clinical outcome of TMA patients. We determined the PTX3 and CRP levels, complement factor and activation product concentrations in blood samples of 171 subjects with the diagnosis of typical hemolytic uremic syndrome (STEC-HUS) ( N = 34), atypical HUS (aHUS) ( N = 44), secondary TMA ( N = 63), thrombotic thrombocytopenic purpura (TTP) ( N = 30) and 69 age-matched healthy individuals. Clinical data, blood count and chemistry were collected from medical records. To determine the in vitro effect of PTX3 on alternative pathway (AP) activation, sheep red blood cell-based hemolytic assay and AP activity ELISA were used. We found that PTX3 levels were elevated in the acute phase of STEC-HUS, aHUS and secondary TMA, whereas PTX3 elevation was exceptional is TTP. Conversely, a significantly higher median CRP was present in all patient groups compared to controls. PTX3, but not CRP was associated with signs of complement consumption in vivo , and PTX3 significantly decreased the AP hemolytic activity in vitro . Our results provide a detailed description of acute phase-TMA patients' complement profile linked to changes in the systemic pentraxin levels that may support further molecular studies on the function of PTX3 in disease pathogenesis and add to the laboratory assessment of complement consumption in TMA.