Role of CD39 in COVID-19 Severity: Dysregulation of Purinergic Signaling and Thromboinflammation

Díaz‐García, Elena; García-Tovar, Sara; Alfaro, Enrique; Zamarrón, Ester; Mangas, Alberto; Galera, Raúl; Ruiz-Hernández, J.J.; Solé‐Violán, Jordi; Rodríguez-Gallego, Carlos; Rym, Ana Van Den; Pérez-de-Diego, Rebeca; Nanwani-Nanwani, Kapil; López-Collazo, Eduardo; García‐Río, Francisco; Cubillos‐Zapata, Carolina

doi:10.3389/fimmu.2022.847894

Cited by 26 publications

(26 citation statements)

References 41 publications

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“…Interestingly, Wang, Veurich, Kalbasi, Graham, et al ( 2021 ) identified increased CD39 expression in the lung, liver, spleen, and PBMCs from severe COVID‐19 patients, which correlated with days in the hospital, days in intensive care unit (ICU), and markers of coagulation, indicating associations between ectonucleotidases and disease progression. Similarly, CD39 messenger RNA (mRNA) as upregulated in peripheral blood leukocytes in association with higher soluble CD39 levels in severe COVID‐19 patients, which were related to the length of hospital day and ICU admission (Díaz‐García et al, 2022 ). Furthermore, upregulation in CD39 expression in late‐stage COVID‐19 was associated with heightened levels of STAT‐3 and HIF‐1α, but decreased levels of CD39‐antisense RNA, possibly a purinergic imbalance that contributes to metabolic changes and T‐cell dysfunction (Wang, Veurich, Kalbasi, Shaefi, et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, CD39 messenger RNA (mRNA) as upregulated in peripheral blood leukocytes in association with higher soluble CD39 levels in severe COVID-19 patients, which were related to the length of hospital day and ICU admission (Díaz-García et al, 2022). Furthermore, upregulation in CD39 expression in late-stage COVID-19 was associated with heightened levels of STAT-3 and HIF-1α, but decreased levels of CD39-antisense RNA, possibly a purinergic imbalance that contributes to metabolic changes and T-cell dysfunction (Wang, Veurich, Kalbasi, Shaefi, et al, 2021).…”

Section: In Vitro Adenosine Treatment Reduces Nuclear Factor-κb (Nf-κ...mentioning

confidence: 99%

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Alterations in CD39/CD73 axis of T cells associated with COVID‐19 severity

Dorneles

Teixeira

Silva

et al. 2022

Journal Cellular Physiology

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Purinergic signaling modulates immune function and is involved in the immunopathogenesis of several viral infections. This study aimed to investigate alterations in purinergic pathways in coronavirus disease 2019 (COVID-19) patients. Mild and severe COVID-19 patients had lower extracellular adenosine triphosphate and adenosine levels, and higher cytokines than healthy controls. Mild COVID-19 patients presented lower frequencies of CD4 + CD25 + CD39 + (activated/memory regulatory T cell [mTreg]) and increased frequencies of high-differentiated (CD27 − CD28 − ) CD8 + T cells compared with healthy controls. Severe COVID-19 patients also showed higher frequencies of CD4 + CD39 + , CD4 + CD25 − CD39 + (memory T effector cell), and high-differentiated CD8 + T cells (CD27 − CD28 − ), and diminished frequencies of CD4 + CD73 + , CD4 + CD25 + CD39 + mTreg cell, CD8 + CD73 + , and low-differentiated CD8 + T cells (CD27 + CD28 + ) in the blood in relation to mild COVID-19 patients and controls. Moreover, severe COVID-19 patients presented higher expression of PD-1 on low-differentiated CD8 + T cells. Both severe and mild COVID-19 patients presented higher frequencies of CD4 + Annexin-V + and CD8 + Annexin-V + T cells, indicating increased T-cell apoptosis. Plasma samples collected from severe COVID-19 patients were able to decrease the expression of CD73 on CD4 + and CD8 + T cells of a healthy donor. Interestingly, the in vitro incubation of peripheral blood mononuclear cell from severe COVID-19 patients with adenosine

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Section: Discussionmentioning

confidence: 99%

Section: In Vitro Adenosine Treatment Reduces Nuclear Factor-κb (Nf-κ...mentioning

confidence: 99%

Alterations in CD39/CD73 axis of T cells associated with COVID‐19 severity

Dorneles

Teixeira

Silva

et al. 2022

Journal Cellular Physiology

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“…Purinergic signaling molecules, such as eATP and eADP bind to P2Y 12 on platelets and induce platelet aggregation and coagulation. Hypoxia- and viral-induced increased CD39 expression on T cells and NK cells in COVID-19 patients with pneumonia was observed by Díaz-García and colleagues ( 180 ). Moreover, soluble active CD39 (sCD39) levels in plasma of COVID-19 patients was associated with longer hospitalisation times, necessity of mechanical ventilation, ICU admission, and death, suggesting sCD39 as a marker for disease severity in COVID-19 patients.…”

Section: The Pathophysiological Influence Of Platelet-net Interplay I...mentioning

confidence: 60%

“…Moreover, soluble active CD39 (sCD39) levels in plasma of COVID-19 patients was associated with longer hospitalisation times, necessity of mechanical ventilation, ICU admission, and death, suggesting sCD39 as a marker for disease severity in COVID-19 patients. Elevated eATP and eADP, as well as decreased adenosine plasma levels may be responsible for increased sCD39, with eATP activating the NLRP-3 inflammasome and eADP activating the procoagulant P2Y 12 receptor on platelets ( 180 ).…”

Section: The Pathophysiological Influence Of Platelet-net Interplay I...mentioning

confidence: 99%

Platelets in the NETworks interweaving inflammation and thrombosis

2022

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Platelets are well characterized for their indispensable role in primary hemostasis to control hemorrhage. Research over the past years has provided a substantial body of evidence demonstrating that platelets also participate in host innate immunity. The surface expression of pattern recognition receptors, such as TLR2 and TLR4, provides platelets with the ability to sense bacterial products in their environment. Platelet α-granules contain microbicidal proteins, chemokines and growth factors, which upon release may directly engage pathogens and/or contribute to inflammatory signaling. Additionally, platelet interactions with neutrophils enhance neutrophil activation and are often crucial to induce a sufficient immune response. In particular, platelets can activate neutrophils to form neutrophil extracellular traps (NETs). This specific neutrophil effector function is characterized by neutrophils expelling chromatin fibres decorated with histones and antimicrobial proteins into the extracellular space where they serve to trap and kill pathogens. Until now, the mechanisms and signaling pathways between platelets and neutrophils inducing NET formation are still not fully characterized. NETs were also detected in thrombotic lesions in several disease backgrounds, pointing towards a role as an interface between neutrophils, platelets and thrombosis, also known as immunothrombosis. The negatively charged DNA within NETs provides a procoagulant surface, and in particular NET-derived proteins may directly activate platelets. In light of the current COVID-19 pandemic, the topic of immunothrombosis has become more relevant than ever, as a majority of COVID-19 patients display thrombi in the lung capillaries and other vascular beds. Furthermore, NETs can be found in the lung and other tissues and are associated with an increased mortality. Here, virus infiltration may lead to a cytokine storm that potently activates neutrophils and leads to massive neutrophil infiltration into the lung and NET formation. The resulting NETs presumably activate platelets and coagulation factors, further contributing to the subsequent emergence of microthrombi in pulmonary capillaries. In this review, we will discuss the interplay between platelets and NETs and the potential of this alliance to influence the course of inflammatory diseases. A better understanding of the underlying molecular mechanisms and the identification of treatment targets is of utmost importance to increase patients’ survival and improve the clinical outcome.

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“…We observed that BK1-8 was positively and significantly related to inflammation, suggesting a potential role of this peptide in inflammation in patients with COVID-19. Interestingly, inflammatory condition of patients with COVID-19 has been related to NLRP3 inflammasome (30)(31)(32)(33). Further study of the KKS is quite interesting, especially in the context of thromboinflammation and pulmonary edema complications; in fact, therapeutical targeting on this pathway has been addressed (15).…”

Section: Discussionmentioning

confidence: 99%

Impaired Kallikrein-Kinin System in COVID-19 Patients' Severity

Alfaro¹,

Díaz‐García²,

García-Tovar³

et al. 2022

Front. Immunol.

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COVID-19 has emerged as a devastating disease in the last 2 years. Many authors appointed to the importance of kallikrein-kinin system (KKS) in COVID-19 pathophysiology as it is involved in inflammation, vascular homeostasis, and coagulation. We aim to study the bradykinin cascade and its involvement in severity of patients with COVID-19. This is an observational cohort study involving 63 consecutive patients with severe COVID-19 pneumonia and 27 healthy subjects as control group. Clinical laboratory findings and plasma protein concentration of KKS peptides [bradykinin (BK), BK1-8], KKS proteins [high–molecular weight kininogen (HK)], and KKS enzymes [carboxypeptidase N subunit 1 (CPN1), kallikrein B1 (KLKB1), angiotensin converting enzyme 2 (ACE2), and C1 esterase inhibitor (C1INH)] were analyzed. We detected dysregulated KKS in patients with COVID-19, characterized by an accumulation of BK1-8 in combination with decreased levels of BK. Accumulated BK1-8 was related to severity of patients with COVID-19. A multivariate logistic regression model retained BK1-8, BK, and D-dimer as independent predictor factors to intensive care unit (ICU) admission. A Youden’s optimal cutoff value of −0.352 was found for the multivariate model score with an accuracy of 92.9%. Multivariate model score-high group presented an odds ratio for ICU admission of 260.0. BK1-8 was related to inflammation, coagulation, and lymphopenia. Our data suggest that BK1-8/BK plasma concentration in combination with D-dimer levels might be retained as independent predictors for ICU admission in patients with COVID-19. Moreover, we reported KKS dysregulation in patients with COVID-19, which was related to disease severity by means of inflammation, hypercoagulation, and lymphopenia.

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Role of CD39 in COVID-19 Severity: Dysregulation of Purinergic Signaling and Thromboinflammation

Cited by 26 publications

References 41 publications

Alterations in CD39/CD73 axis of T cells associated with COVID‐19 severity

Alterations in CD39/CD73 axis of T cells associated with COVID‐19 severity

Platelets in the NETworks interweaving inflammation and thrombosis

Impaired Kallikrein-Kinin System in COVID-19 Patients' Severity

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