A double edged-sword - The Complement System during SARS-CoV-2 infection

Santiesteban-Lores, Lazara Elena; Amamura, Thaís Akemi; Silva, Tiago Francisco da; Midon, Leonardo Moura; Carneiro, Milena Carvalho; Isaac, Lourdes; Bavia, Lorena

doi:10.1016/j.lfs.2021.119245

Cited by 32 publications

(27 citation statements)

References 104 publications

(87 reference statements)

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“…The complement system inhibitors, including eculizumab, ravulizumab, tesidolumab, and vilobelimab (IFX-1), may be considered as essential therapeutic drug candidates to control the unregulated release of inflammatory cytokines or inflammatory response [ 130 , 131 , 132 , 133 ]. Among the range of complement system inhibitors mentioned above, tesidolumab, a C5-blocking monoclonal antibody that prevents the formation of C5a and the membrane attack complex, was found to be effective in reducing the exaggerated inflammatory reaction and promoting clinical improvement in patients suffering from COVID-19 with severe disease [ 132 ].…”

Section: Immunomodulatory and Immunotherapeutic Approaches To Counter Cytokine Stormmentioning

confidence: 99%

“…Moreover, the involvement of complement system in the poor prognosis of the disease is yet to be explained as several scientists believe that the complement system may be protective against SARS-CoV-2 infection [ 197 ]. A complement system, for instance, can suppress SARS-CoV-2 infection in asymptomatic or moderate cases; however, due to its significant pro-inflammatory activity, it can also exacerbate local and systemic damage in some patients with severe COVID-19 [ 133 ].…”

Section: Key Elements Of Innate and Adaptive Immune Responsesmentioning

confidence: 99%

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Diverse Immunological Factors Influencing Pathogenesis in Patients with COVID-19: A Review on Viral Dissemination, Immunotherapeutic Options to Counter Cytokine Storm and Inflammatory Responses

et al. 2021

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The pathogenesis of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still not fully unraveled. Though preventive vaccines and treatment methods are out on the market, a specific cure for the disease has not been discovered. Recent investigations and research studies primarily focus on the immunopathology of the disease. A healthy immune system responds immediately after viral entry, causing immediate viral annihilation and recovery. However, an impaired immune system causes extensive systemic damage due to an unregulated immune response characterized by the hypersecretion of chemokines and cytokines. The elevated levels of cytokine or hypercytokinemia leads to acute respiratory distress syndrome (ARDS) along with multiple organ damage. Moreover, the immune response against SARS-CoV-2 has been linked with race, gender, and age; hence, this viral infection’s outcome differs among the patients. Many therapeutic strategies focusing on immunomodulation have been tested out to assuage the cytokine storm in patients with severe COVID-19. A thorough understanding of the diverse signaling pathways triggered by the SARS-CoV-2 virus is essential before contemplating relief measures. This present review explains the interrelationships of hyperinflammatory response or cytokine storm with organ damage and the disease severity. Furthermore, we have thrown light on the diverse mechanisms and risk factors that influence pathogenesis and the molecular pathways that lead to severe SARS-CoV-2 infection and multiple organ damage. Recognition of altered pathways of a dysregulated immune system can be a loophole to identify potential target markers. Identifying biomarkers in the dysregulated pathway can aid in better clinical management for patients with severe COVID-19 disease. A special focus has also been given to potent inhibitors of proinflammatory cytokines, immunomodulatory and immunotherapeutic options to ameliorate cytokine storm and inflammatory responses in patients affected with COVID-19.

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Section: Immunomodulatory and Immunotherapeutic Approaches To Counter Cytokine Stormmentioning

confidence: 99%

Section: Key Elements Of Innate and Adaptive Immune Responsesmentioning

confidence: 99%

Diverse Immunological Factors Influencing Pathogenesis in Patients with COVID-19: A Review on Viral Dissemination, Immunotherapeutic Options to Counter Cytokine Storm and Inflammatory Responses

et al. 2021

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“…In particular, the clinical presentation and progress of coronavirus disease 19 , caused by SARS-CoV-2 and responsible for the current global pandemic, might significantly depend on the fine balance between different degrees of complement activation. For example, an excessive and unrestrained complement activation might favour the development of a systemic pro-inflammatory, pro-oxidant, and pro-coagulant state with multi-organ dysfunction and increased risk of adverse clinical outcomes (4)(5)(6). The measurement of specific components, e.g., the complement proteins C3 and C4, using immunoassays is routinely used in clinical practice to determine and monitor complement activation.…”

Section: Introductionmentioning

confidence: 99%

“…In the setting of viral infections, additional effects mediated by the activation of the complement system include virus aggregation-mediated neutralization, phagocytosis, and lysis of viruses and virus-infected cells ( 3 ). While these processes suggest an overall beneficial effect against viruses, complement activation might also increase the risk of adverse clinical outcomes, in virtue of the sustained release of pro-inflammatory mediators with additional toxic effects at the cellular and tissue level ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

Serum Complement C3 and C4 and COVID-19 Severity and Mortality: A Systematic Review and Meta-Analysis With Meta-Regression

Zinellu

Mangoni

2021

Front. Immunol.

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Activation of the complement system has been observed in coronavirus disease 19 (COVID-19). We conducted a systematic review and meta-analysis with meta-regression to investigate possible differences in the serum concentrations of two routinely measured complement components, C3 and C4, in COVID-19 patients with different severity and survival status. We searched PubMed, Web of Science and Scopus, between January 2020 and February 2021, for studies reporting serum complement C3 and C4, measures of COVID-19 severity, and survival. Eligibility criteria were a) reporting continuous data on serum C3 and C4 concentrations in COVID-19 patients, -b) investigating COVID-19 patients with different disease severity and/or survival status, c) adult patients, d) English language, e) ≥10 patients, and f) full-text available. Using a random-effects model, standardized mean differences (SMD) with 95% confidence intervals (CIs) were calculated to evaluate differences in serum C3 and C4 concentrations between COVID-19 patients with low vs. high severity or survivor vs. non-survivor status. Risk of bias was assessed using the Newcastle-Ottawa scale whereas publication bias was assessed with the Begg’s and Egger’s tests. Certainty of evidence was assessed using GRADE. Nineteen studies in 3,764 COVID-19 patients were included in the meta-analysis. Both C3 and C4 concentrations were significantly lower in patients with high disease severity or non-survivor status than patients with low severity or survivor status (C3 SMD=-0.40, 95% CI -0.60 to -0.21, p<0.001; C4 SMD=-0.29, 95% CI -0.49 to -0.09, p=0.005; moderate certainty of evidence). Extreme between-study heterogeneity was observed (C3, I2 = 82.1%; C4, I2 = 84.4%). Sensitivity analysis, performed by sequentially removing each study and re-assessing the pooled estimates, showed that the magnitude and direction of the effect size was not modified. There was no publication bias. In meta-regression, the SMD of C3 was significantly associated with white blood cell count, C-reactive protein (CRP), and pro-thrombin time, whereas the SMD of C4 was significantly associated with CRP, pro-thrombin time, D-dimer, and albumin. In conclusion, lower concentrations of C3 and C4, indicating complement activation, were significantly associated with higher COVID-19 severity and mortality. C3 and C4 might be useful to predict adverse clinical consequences in these patients.Systematic Review Registration: PROSPERO, Registration number: CRD42021239634.

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“…The balance between Tregs and Th17 cell differentiation appears to be regulated by STAT5 and STAT3 [ 145 ]. In addition, researchers have found that impaired adaptive immune responses in patients with COVID-19, as a result of infection with SARS-CoV-2, lead to immune system dysregulation [ 146 ]. This involves increased levels of Th17 cells and a decrease in the number of Treg cells [ 127 ].…”

Section: T Cellsmentioning

confidence: 99%

The Role of Immune Cells in Recurrent Spontaneous Abortion

Zheng

Zhao

et al. 2021

Reprod. Sci.

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Recurrent spontaneous abortion affects approximately 1–2% of women of childbearing, and describes a condition in which women suffer from three or more continuous spontaneous miscarriages. However, the origin of recurrent spontaneous abortion (RSA) remains unknown, preventing effective treatment and placing stress upon patients. It has been acknowledged that successful pregnancy necessitates balanced immune responses. Therefore, immunological aberrancy may be considered a root cause of poor pregnancy outcomes. Considerable published studies have investigated the relationship between various immune cells and RSA. Here, we review current knowledge on this area, and discuss the five main categories of immune cells involved in RSA; these include innate lymphocytes (ILC), macrophages, decidual dendritic cells (DCs), and T cells. Furthermore, we sought to summarize the impact of the multiple interactions of various immune cells on the emergence of RSA. A good understanding of pregnancy-induced immunological alterations could reveal new therapeutic strategies for favorable pregnancy outcomes.

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A double edged-sword - The Complement System during SARS-CoV-2 infection

Cited by 32 publications

References 104 publications

Diverse Immunological Factors Influencing Pathogenesis in Patients with COVID-19: A Review on Viral Dissemination, Immunotherapeutic Options to Counter Cytokine Storm and Inflammatory Responses

Diverse Immunological Factors Influencing Pathogenesis in Patients with COVID-19: A Review on Viral Dissemination, Immunotherapeutic Options to Counter Cytokine Storm and Inflammatory Responses

Serum Complement C3 and C4 and COVID-19 Severity and Mortality: A Systematic Review and Meta-Analysis With Meta-Regression

The Role of Immune Cells in Recurrent Spontaneous Abortion

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