Consideration of Pannexin 1 channels in COVID-19 pathology and treatment

Swayne, Leigh Anne; Johnstone, Scott R.; Ng, Chen Seng; Sanchez-Arias, Juan C.; Good, Miranda E.; Peñuela, Silvia; Lohman, Alexander W.; Wolpe, Abigail G.; Laubach, Victor E.; Koval, Michael; Isakson, Brant E.

doi:10.1152/ajplung.00146.2020

Cited by 25 publications

(21 citation statements)

References 69 publications

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“…Furthermore, P2Y 2 R is known to cooperate with pannexin-1 (PANX-1) channel protein that mediates passive transport of ATP, which triggers lung inflammation and regulates the life cycle of multiple viruses through enhancing viral binding to host cells, uptake, and replication [ 49 – 53 ]. Hence, PANX-1 and probenecid (an FDA-approved PANX-1 inhibitor) have been recently suggested for further investigation in the efforts to develop a COVID-19 treatment [ 54 ]. Collectively, our signature correlations, consistent with a large body of literature, suggest a potential role for P2Y 2 R in the pathogenesis of SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 early infection signature identified potential key infection mechanisms and drug targets

Duche

Sayer

et al. 2021

BMC Genomics

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Background The ongoing COVID-19 outbreak has caused devastating mortality and posed a significant threat to public health worldwide. Despite the severity of this illness and 2.3 million worldwide deaths, the disease mechanism is mostly unknown. Previous studies that characterized differential gene expression due to SARS-CoV-2 infection lacked robust validation. Although vaccines are now available, effective treatment options are still out of reach. Results To characterize the transcriptional activity of SARS-CoV-2 infection, a gene signature consisting of 25 genes was generated using a publicly available RNA-Sequencing (RNA-Seq) dataset of cultured cells infected with SARS-CoV-2. The signature estimated infection level accurately in bronchoalveolar lavage fluid (BALF) cells and peripheral blood mononuclear cells (PBMCs) from healthy and infected patients (mean 0.001 vs. 0.958; P < 0.0001). These signature genes were investigated in their ability to distinguish the severity of SARS-CoV-2 infection in a single-cell RNA-Sequencing dataset. TNFAIP3, PPP1R15A, NFKBIA, and IFIT2 had shown bimodal gene expression in various immune cells from severely infected patients compared to healthy or moderate infection cases. Finally, this signature was assessed using the publicly available ConnectivityMap database to identify potential disease mechanisms and drug repurposing candidates. Pharmacological classes of tricyclic antidepressants, SRC-inhibitors, HDAC inhibitors, MEK inhibitors, and drugs such as atorvastatin, ibuprofen, and ketoconazole showed strong negative associations (connectivity score < − 90), highlighting the need for further evaluation of these candidates for their efficacy in treating SARS-CoV-2 infection. Conclusions Thus, using the 25-gene SARS-CoV-2 infection signature, the SARS-CoV-2 infection status was captured in BALF cells, PBMCs and postmortem lung biopsies. In addition, candidate SARS-CoV-2 therapies with known safety profiles were identified. The signature genes could potentially also be used to characterize the COVID-19 disease severity in patients’ expression profiles of BALF cells.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 early infection signature identified potential key infection mechanisms and drug targets

Duche

Sayer

et al. 2021

BMC Genomics

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“…Due to the fact that Panx1-channels also regulate host responses to viruses (Orellana et al, 2013;Malik and Eugenin, 2019) the impact of Panx1 in COVID19 patients displaying hyper-inflammation has recently been discussed (Swayne et al, 2020). For the patient recovery especially the early phase of innate immunity seems to be critical and immunosuppression could limit viral entry and disease progression.…”

Section: Panx1 In Leukocyte Recruitment During Acute Inflammationmentioning

confidence: 99%

“…For the patient recovery especially the early phase of innate immunity seems to be critical and immunosuppression could limit viral entry and disease progression. Therefore, targeting Panx1-channels could improve therapeutic approaches and might reduce SARS-CoV-2 infectivity and vascular inflammatory responses in COVID19 patients (Swayne et al, 2020).…”

Section: Panx1 In Leukocyte Recruitment During Acute Inflammationmentioning

confidence: 99%

The Role of Connexin 43 and Pannexin 1 During Acute Inflammation

Kameritsch

Pogoda

2020

Front. Physiol.

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During acute inflammation, the recruitment of leukocytes from the blood stream into the inflamed tissue is a well-described mechanism encompassing the interaction of endothelial cells with leukocytes allowing leukocytes to reach the site of tissue injury or infection where they can fulfill their function such as phagocytosis. This process requires a fine-tuned regulation of a plethora of signaling cascades, which are still incompletely understood. Here, connexin 43 (Cx43) and pannexin 1 (Panx1) are known to be pivotal for the correct communication of endothelial cells with leukocytes. Pharmacological as well as genetic approaches provide evidence that endothelial Cx43-hemichannels and Panx1-channels release signaling molecules including ATP and thereby regulate vessel function and permeability as well as the recruitment of leukocytes during acute inflammation. Furthermore, Cx43 hemichannels and Panx1-channels in leukocytes release signaling molecules and can mediate the activation and function of leukocytes in an autocrine manner. The focus of the present review is to summarize the current knowledge of the role of Cx43 and Panx1 in endothelial cells and leukocytes in the vasculature during acute inflammation and to discuss relevant molecular mechanisms regulating Cx43 and Panx1 function.

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“…Older and recent studies have documented that MSC transplantation and transdifferentiation ( Dilger et al, 2020 ) is dependent on gap junctional cell coupling and the intricate interplay and changes in expression levels of connexin family members. Pannexins might also be involved ( Swayne et al, 2020 ) and thus MSCs might modulate the inflammasome via gap junctional dependent mechanisms.…”

Section: Mesenchymal Stem Cellsmentioning

confidence: 99%

Is There an Effect of Fetal Mesenchymal Stem Cells in the Mother–Fetus Dyad in COVID-19 Pregnancies and Vertical Transmission?

Samara

Herlenius

2021

Front. Physiol.

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Because of the polysystemic nature of coronavirus disease 2019 (COVID-19), during the present pandemic, there have been serious concerns regarding pregnancy, vertical transmission, and intrapartum risk. The majority of pregnant patients with COVID-19 infection present with mild or asymptomatic course of the disease. Some cases were hospitalized, and few needed intensive care unit admission, or mechanical ventilation. There have also been scarce case reports where neonates required mechanical ventilation post COVID-19 pregnancies. Without approved therapies other than dexamethasone, advanced mesenchymal cell therapy is one immunomodulatory therapeutic approach that is currently explored and might hold great promise. We suggest that the circulating fetal stem cells might have an immune-protective effect to mothers and contribute to the often mild and even asymptomatic post-COVID-19 pregnancies. Thus, COVID-19 pregnancies come forth as a paradigm to be further and more comprehensively approached, to understand both the mechanism and action of circulating stem cells in immunoprotection and hypoxia in microcirculation.

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Consideration of Pannexin 1 channels in COVID-19 pathology and treatment

Cited by 25 publications

References 69 publications

SARS-CoV-2 early infection signature identified potential key infection mechanisms and drug targets

SARS-CoV-2 early infection signature identified potential key infection mechanisms and drug targets

The Role of Connexin 43 and Pannexin 1 During Acute Inflammation

Is There an Effect of Fetal Mesenchymal Stem Cells in the Mother–Fetus Dyad in COVID-19 Pregnancies and Vertical Transmission?

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