A rationale for targeting the P2X7 receptor in Coronavirus disease 19
Francesco Di Virgilio 1, Yong Tang 2, Alba Clara Sarti 1, Marco Rossato 3
Br J Pharmacol. 2020 Nov;177(21):4990-4994. doi: 10.1111/bph.15138. Epub 2020 Jul 26.
Severe pneumonia which shares several of the features of acute respiratory distress syndrome (ARDS) is the main cause of morbidity and mortality in Coronavirus disease 19 (Covid-19) for which there is no effective treatment, so far. ARDS is caused and sustained by an uncontrolled inflammatory activation characterized by a massive release of cytokines (cytokine storm), diffuse lung oedema, inflammatory cell infiltration, and disseminated coagulation. Macrophage and T lymphocyte dysfunction plays a central role in this syndrome. In several experimental in vitro and in vivo models, many of these pathophysiological changes are triggered by stimulation of the P2X7 receptor. We hypothesize that this receptor might be an ideal candidate to target in Covid-19-associated severe pneumonia. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit
The potential involvement of P2X7 receptor in COVID‐19 pathogenesis: a new therapeutic target?
Paulo A F Pacheco and Robson X Faria
Scand J Immunol. 2020 Aug 14 : e12960.
The pathogenesis of the Coronavirus disease 2019 (COVID‐19) remains under investigation. However, growing evidence suggests the establishment of a hyperinflammatory response, characterized by sustained production of cytokines, such as IL‐1β. The release and maturation of this cytokine is dependent on the activation of a catalytic multiprotein complex, known as “inflammasome”. The most investigated is the NLRP3 inflammasome, which can be activated by various stimuli, such as the recognition of extracellular ATP by the P2X7 receptor. Based on published literature, it is shown evidence that supports the idea that the P2X7R/NLRP3 axis may be involved in the immune dysregulation caused by the SARS‐CoV‐2 infection.
Activation of P2X7 Receptor by ATP Plays an Important Role in Regulating Inflammatory Responses during Acute Viral Infection
Benjamin H. Lee, 1 , 3 David M. Hwang, 2 , 4 Nades Palaniyar, 1 , 4 Sergio Grinstein, 1 , 5 Dana J. Philpott, 6 and Jim Hu 1 , 4 , *
David M. Ojcius, Editor
PLoS One. 2012; 7(4): e35812.
Acute viral infection causes damages to the host due to uncontrolled viral replication but even replication deficient viral vectors can induce systemic inflammatory responses. Indeed, overactive host innate immune responses to viral vectors have led to devastating consequences. Macrophages are important innate immune cells that recognize viruses and induce inflammatory responses at the early stage of infection. However, tissue resident macrophages are not easily activated by the mere presence of virus suggesting that their activation requires additional signals from other cells in the tissue in order to trigger inflammatory responses. Previously, we have shown that the cross-talk between epithelial cells and macrophages generates synergistic inflammatory responses during adenoviral vector infection. Here, we investigated whether ATP is involved in the activation of macrophages to induce inflammatory responses during an acute adenoviral infection. Using a macrophage-epithelial cell co-culture system we demonstrated that ATP signaling through P2X7 receptor (P2X7R) is required for induction of inflammatory mediators. We also showed that ATP-P2X7R signaling regulates inflammasome activation as inhibition or deficiency of P2X7R as well as caspase-1 significantly reduced IL-1β secretion. Furthermore, we found that intranasal administration of replication deficient adenoviral vectors in mice caused a high mortality in wild-type mice with symptoms of acute respiratory distress syndrome but the mice deficient in P2X7R or caspase-1 showed increased survival. In addition, wild-type mice treated with apyrase or inhibitors of P2X7R or caspase-1 showed higher rates of survival. The improved survival in the P2X7R deficient mice correlated with diminished levels of IL-1β and IL-6 and reduced neutrophil infiltration in the early phase of infection. These results indicate that ATP, released during viral infection, is an important inflammatory regulator that activates the inflammasome pathway and regulates inflammatory responses.