Pannexin-1 channel opening is critical for COVID-19 pathogenesis

Luu, Ross H.; Valdebenito, Silvana; Scemes, Eliana; Cibelli, Antonio; Spray, David C.; Rovegno, Maximiliano; Tichauer, Juan E.; Cottignies-Calamarte, Andréa; Rosenberg, Arielle R.; Capron, Calude; Belouzard, Sandrine; Dubuisson, Jean; Annane, Djillali; Grandmaison, Geoffroy Lorin de la; Cramer–Bordé, Elisabeth; Bomsel, Morgane; Eugenín, Eliseo A.

doi:10.1016/j.isci.2021.103478

Cited by 29 publications

(38 citation statements)

References 195 publications

(201 reference statements)

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“…It should be noted that PxHC not only share many molecular and physiological characteristics with CxHC, but also contribute to the pathogenesis of inflammatory diseases. For instance, PxHC promote inflammasome activation, viral replication and infection (e.g., HIV and SARS-CoV-2) [ 166 , 167 , 168 ]. A combined blockade of CxHC and PxHC may prove to be more effective in the treatment of some inflammatory diseases than targeting either type of hemichannels.…”

Section: Discussionmentioning

confidence: 99%

The Role of Connexin Hemichannels in Inflammatory Diseases

Peng

Wang

et al. 2022

Biology

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The connexin protein family consists of approximately 20 members, and is well recognized as the structural unit of the gap junction channels that perforate the plasma membranes of coupled cells and, thereby, mediate intercellular communication. Gap junctions are assembled by two preexisting hemichannels on the membranes of apposing cells. Non-junctional connexin hemichannels (CxHC) provide a conduit between the cell interior and the extracellular milieu, and are believed to be in a protectively closed state under physiological conditions. The development and characterization of the peptide mimetics of the amino acid sequences of connexins have resulted in the development of a panel of blockers with a higher selectivity for CxHC, which have become important tools for defining the role of CxHC in various biological processes. It is increasingly clear that CxHC can be induced to open by pathogen-associated molecular patterns. The opening of CxHC facilitates the release of damage-associated molecular patterns, a class of endogenous molecules that are critical for the pathogenesis of inflammatory diseases. The blockade of CxHC leads to attenuated inflammation, reduced tissue injury and improved organ function in human and animal models of about thirty inflammatory diseases and disorders. These findings demonstrate that CxHC may contribute to the intensification of inflammation, and serve as a common target in the treatments of various inflammatory diseases. In this review, we provide an update on the progress in the understanding of CxHC, with a focus on the role of these channels in inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

The Role of Connexin Hemichannels in Inflammatory Diseases

Peng

Wang

et al. 2022

Biology

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“…Probenecid can modulate the expression of ACE2 [ 65 ], and targets the pannexin-1 gene, PANX1 [ 66 ]. PANX1 is an ATP release channel that facilitates the communication between T cells to inhibit the severity of airway inflammation [ 67 , 68 ]. PANX1 limits airway inflammation driven by type-2 CD4+ T-cell inflammatory responses, and probenecid is an inhibitor of PANX1 [ 69 ] that mediates the activation of caspase-1 and release of IL-1β induced by P2X7 receptor activation [ 70 ].…”

Section: Probenecid and Inflammationmentioning

confidence: 99%

Repurposing Probenecid to Inhibit SARS-CoV-2, Influenza Virus, and Respiratory Syncytial Virus (RSV) Replication

Tripp

Martin²

2022

Viruses

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Viral replication and transmissibility are the principal causes of endemic and pandemic disease threats. There remains a need for broad-spectrum antiviral agents. The most common respiratory viruses are endemic agents such as coronaviruses, respiratory syncytial viruses, and influenza viruses. Although vaccines are available for SARS-CoV-2 and some influenza viruses, there is a paucity of effective antiviral drugs, while for RSV there is no vaccine available, and therapeutic treatments are very limited. We have previously shown that probenecid is safe and effective in limiting influenza A virus replication and SARS-CoV-2 replication, along with strong evidence showing inhibition of RSV replication in vitro and in vivo. This review article will describe the antiviral activity profile of probenecid against these three viruses.

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“…In addition, Panx1 channel-mediated ATP release leads to an upregulation of Panx1 phosphorylation and of vascular cell adhesion molecule 1 and is, therefore, involved in the activation and migration of leukocytes [ 17 ]. Due to their contribution to inflammation and the link to viral infectious diseases, such as human immunodeficiency virus (HIV) infections and hepatitis C, it seems likely to assume that Panx1 channels can also play a role in COVID-19 [ 18 , 19 , 20 , 21 ]. Recently, it was found that the SARS-CoV-2 spike protein, a fusion protein essential in the induction of the infection, triggers prolonged Panx1 channel opening [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…Due to their contribution to inflammation and the link to viral infectious diseases, such as human immunodeficiency virus (HIV) infections and hepatitis C, it seems likely to assume that Panx1 channels can also play a role in COVID-19 [ 18 , 19 , 20 , 21 ]. Recently, it was found that the SARS-CoV-2 spike protein, a fusion protein essential in the induction of the infection, triggers prolonged Panx1 channel opening [ 18 ]. Furthermore, Panx1 mRNA and protein expression levels were shown to be elevated in samples of patients with a SARS-CoV2 infection, indicating a role of Panx1 channel opening in COVID-19 and suggesting Panx1 channels as potential drug targets [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, it was found that the SARS-CoV-2 spike protein, a fusion protein essential in the induction of the infection, triggers prolonged Panx1 channel opening [ 18 ]. Furthermore, Panx1 mRNA and protein expression levels were shown to be elevated in samples of patients with a SARS-CoV2 infection, indicating a role of Panx1 channel opening in COVID-19 and suggesting Panx1 channels as potential drug targets [ 18 ]. Several drugs have been proposed for the treatment of COVID-19 due to their antiviral and/or anti-inflammatory effects, including hydroxychloroquine, chloroquine, azithromycin, dexamethasone, ribavirin, remdesivir, favipiravir, lopinavir and the combination of the latter with ritonavir ( Table 1 ) [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Effects of Drugs Formerly Suggested for COVID-19 Repurposing on Pannexin1 Channels

Caufriez

Tabernilla

Campenhout

et al. 2022

IJMS

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Although many efforts have been made to elucidate the pathogenesis of COVID-19, the underlying mechanisms are yet to be fully uncovered. However, it is known that a dysfunctional immune response and the accompanying uncontrollable inflammation lead to troublesome outcomes in COVID-19 patients. Pannexin1 channels are put forward as interesting drug targets for the treatment of COVID-19 due to their key role in inflammation and their link to other viral infections. In the present study, we selected a panel of drugs previously tested in clinical trials as potential candidates for the treatment of COVID-19 early on in the pandemic, including hydroxychloroquine, chloroquine, azithromycin, dexamethasone, ribavirin, remdesivir, favipiravir, lopinavir, and ritonavir. The effect of the drugs on pannexin1 channels was assessed at a functional level by means of measurement of extracellular ATP release. Immunoblot analysis and real-time quantitative reversetranscription polymerase chain reaction analysis were used to study the potential of the drugs to alter pannexin1 protein and mRNA expression levels, respectively. Favipiravir, hydroxychloroquine, lopinavir, and the combination of lopinavir with ritonavir were found to inhibit pannexin1 channel activity without affecting pannexin1 protein or mRNA levels. Thusthree new inhibitors of pannexin1 channels were identified that, though currently not being used anymore for the treatment of COVID-19 patients, could be potential drug candidates for other pannexin1-related diseases.

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Pannexin-1 channel opening is critical for COVID-19 pathogenesis

Cited by 29 publications

References 195 publications

The Role of Connexin Hemichannels in Inflammatory Diseases

The Role of Connexin Hemichannels in Inflammatory Diseases

Repurposing Probenecid to Inhibit SARS-CoV-2, Influenza Virus, and Respiratory Syncytial Virus (RSV) Replication

Effects of Drugs Formerly Suggested for COVID-19 Repurposing on Pannexin1 Channels

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