Programmed cell death: the pathways to severe COVID-19?

Bader, Stefanie; Cooney, James P.; Pellegrini, Marc; Doerflinger, Marcel

doi:10.1042/bcj20210602

Cited by 38 publications

(39 citation statements)

References 193 publications

(267 reference statements)

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“…Other studies also showed increased expression of genes associated with inflammation in macrophages challenged with SARS-CoV-2 (Abdelmoaty et al 2021) and associated with the caspase pathway and apoptosis (Cardinez et al 2018). It is reported that the inflammasome (NLRP3, associated with IL-18 activation) is activated during SARS-CoV-2 infection, being proposed as an indicator of COVID-19 disease severity, predicting the release of pro-inflammatory cytokines that lead to dysregulated immune responses and tissue damage (Bader et al 2022).…”

Section: Discussionmentioning

confidence: 99%

Generation of Cytotoxic T cells and Dysfunctional CD8 T Cells in Severe COVID19 Patients

Gozzi-Silva¹,

Oliveira²,

Alberca³

et al. 2022

Preprint

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COVID-19, the infectious disease caused by SARS-CoV-2, has spread on a pandemic scale. The virus infection can evolve asymptomatically or generate severe symptoms, influenced by the presence of comorbidities. Lymphopenia in patients affected with COVID-19 according to the severity of symptoms is frequent. However, the profile of CD4+ and CD8+ T-cells regarding cytotoxicity and antiviral factor expression has not yet been completely elucidated in acute SARS-CoV-2 infections. The purpose of this study is to evaluate the phenotypic and functional profile of T-lymphocytes in patients with moderate and severe/critical COVID-19. During this pandemic period, we analyzed a cohort of 62 confirmed patients with SARS-CoV-2 (22 moderate cases and 40 severe/critical cases). Albeit lymphopenia, we observed an increase in the expression of CD28, co-stimulator molecule, and activation markers (CD38 and HLA-DR) in T-lymphocytes as well as an increase in the frequency of CD4+ T-cells, CD8+ T-cells, and NK cells that express the immunological checkpoint protein, PD-1, in patients with severe/critical condition compared to healthy controls. Regarding the cytotoxic profile of peripheral blood mononuclear cells, an increase in the response of CD4+ T-cells already at baseline level was observed, scarcely changed upon PMA and Ionomycin stimulation. Meanwhile, CD8+ T-lymphocytes decreased cytotoxic response, evidencing a profile of exhaustion in patients with severe COVID-19. As observed in the t-SNE technique CD4+ T-cytotoxic and CD8+ T with low granzyme production evidencing their dysfunctionality in severe/critical conditions. In addition, purified CD8+ T-lymphocytes from patients with severe COVID-19 showed an increased constitutive expression of differentially expressed genes associated with the caspase pathway, inflammasome, and antiviral factors, and curiously, reduced expression of TNF-α. The cytotoxic profile, by CD4+ T-cells, may compensate for the dysfunction/exhaustion of TCD8+ in acute SARS-CoV-2 infection. These findings may provide an understanding of the interplay of cytotoxicity between CD4+ T-cells and CD8+ T-cells in the severity of acute COVID-19 infection.

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Section: Discussionmentioning

confidence: 99%

Generation of Cytotoxic T cells and Dysfunctional CD8 T Cells in Severe COVID19 Patients

Gozzi-Silva¹,

Oliveira²,

Alberca³

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…The replication of coronaviruses in cells is regulated by many host factors, which can induce drastic structural and physiological changes in cells ( 2 ). During infection, SARS-CoV-2 could induce diverse cell death pathways ( 31 , 32 ), such as apoptosis, necroptosis, pyroptosis, and NETosis in the host cells ( Figure 1B ).…”

Section: Multiple Cell Death Pathways Were Induced In Sars-cov-2 Infe...mentioning

confidence: 99%

Therapy Targets SARS-CoV-2 Infection-Induced Cell Death

Zhu

Shi

et al. 2022

Front. Immunol.

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Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV-2 has become a global health issue. The clinical presentation of COVID-19 is highly variable, ranging from asymptomatic and mild disease to severe. However, the mechanisms for the high mortality induced by SARS-CoV-2 infection are still not well understood. Recent studies have indicated that the cytokine storm might play an essential role in the disease progression in patients with COVID-19, which is characterized by the uncontrolled release of cytokines and chemokines leading to acute respiratory distress syndrome (ARDS), multi-organ failure, and even death. Cell death, especially, inflammatory cell death, might be the initiation of a cytokine storm caused by SARS-CoV-2 infection. This review summarizes the forms of cell death caused by SARS-CoV-2 in vivo or in vitro and elaborates on the dedication of apoptosis, necroptosis, NETosis, pyroptosis of syncytia, and even SARS-CoV-2 E proteins forming channel induced cell death, providing insights into targets on the cell death pathway for the treatment of COVID-19.

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“…Coronaviruses (CoVs) were first identified at the beginning of 1900 in domestic animals, and their importance rose since 2003 when three severe CoV human diseases emerged: the Severe Acute Respiratory Syndrome (SARS), the Middle East Respiratory Syndrome (MERS) and the SARS-CoV-2 Infection Disease-19 (COVID-19) [ 168 , 169 , 170 ]. COVID-19 symptoms are similar to SARS, including fever, pneumonia, cough, and in severe cases, serious dyspnea and lung infiltration [ 171 ]. The high infectivity of SARS-CoV-2, the pathogen responsible for COVID-19, caused a rapid spread worldwide and over five million deaths in two years after the disease onset.…”

Section: Rnases and Rna Processing As Tumor And Viral Infection Manag...mentioning

confidence: 99%

“…The high infectivity of SARS-CoV-2, the pathogen responsible for COVID-19, caused a rapid spread worldwide and over five million deaths in two years after the disease onset. Despite the fast vaccine development achievement [ 172 ], as well as the recent approvals of virus-directed therapeutics, this pandemic is far from reaching eradication [ 171 ]. In June 2020, the Orgenesis and Leidos Company started a clinical trial with ONC in COVID-19 infections, after U.S. FDA marketing approval ( .…”

Section: Rnases and Rna Processing As Tumor And Viral Infection Manag...mentioning

confidence: 99%

Role of the Ribonuclease ONCONASE in miRNA Biogenesis and tRNA Processing: Focus on Cancer and Viral Infections

Menegazzi

Gotte

2022

IJMS

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The majority of transcribed RNAs do not codify for proteins, nevertheless they display crucial regulatory functions by affecting the cellular protein expression profile. MicroRNAs (miRNAs) and transfer RNA-derived small RNAs (tsRNAs) are effectors of interfering mechanisms, so that their biogenesis is a tightly regulated process. Onconase (ONC) is an amphibian ribonuclease known for cytotoxicity against tumors and antiviral activity. Additionally, ONC administration in patients resulted in clinical effectiveness and in a well-tolerated feature, at least for lung carcinoma and malignant mesothelioma. Moreover, the ONC therapeutic effects are actually potentiated by cotreatment with many conventional antitumor drugs. This review not only aims to describe the ONC activity occurring either in different tumors or in viral infections but also to analyze the molecular mechanisms underlying ONC pleiotropic and cellular-specific effects. In cancer, data suggest that ONC affects malignant phenotypes by generating tRNA fragments and miRNAs able to downregulate oncogenes expression and upregulate tumor-suppressor proteins. In cells infected by viruses, ONC hampers viral spread by digesting the primer tRNAs necessary for viral DNA replication. In this scenario, new therapeutic tools might be developed by exploiting the action of ONC-elicited RNA derivatives.

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Programmed cell death: the pathways to severe COVID-19?

Cited by 38 publications

References 193 publications

Generation of Cytotoxic T cells and Dysfunctional CD8 T Cells in Severe COVID19 Patients

Generation of Cytotoxic T cells and Dysfunctional CD8 T Cells in Severe COVID19 Patients

Therapy Targets SARS-CoV-2 Infection-Induced Cell Death

Role of the Ribonuclease ONCONASE in miRNA Biogenesis and tRNA Processing: Focus on Cancer and Viral Infections

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