Repurposing drugs targeting the P2X7 receptor to limit hyperinflammation and disease during influenza virus infection

Abstract

Background and PurposeSevere influenza A virus (IAV) infections are associated with damaging hyperinflammation that can be fatal. There is an urgent need to identify new therapeutic agents to treat severe and pathogenic IAV infections. Repurposing of drugs with an existing and studied pharmacokinetic and safety profile is a highly attractive potential strategy. We have previously demonstrated that the NLRP3 inflammasome plays time‐dependent roles during severe IAV infection with early protective responses and later dysregulation leading to excessive inflammation, contributing to disease severity.Experimental ApproachWe tested two existing drugs, probenecid and AZ11645373, to target P2X7 receptor signalling and dampen NLRP3 inflammasome responses during severe IAV infection. In vitro, the drugs were assessed for their ability to limit NLRP3 inflammasome‐dependent IL‐1β secretion in macrophage cultures. In vivo, their effects were assessed on hyperinflammation and disease during severe IAV infection in C57BL/6 mice.Key ResultsTreatment of macrophages with probenecid or AZ11645373 in vitro diminished NLRP3 inflammasome‐dependent IL‐1β secretion. Intranasal therapeutic treatment of mice displaying severe influenza disease with probenecid or AZ11645373 reduced pro‐inflammatory cytokine production, cellular infiltrates in the lung, and provided protection against disease. Importantly, these drugs could be administered at either early or late stage of disease and provide therapeutic efficacy.Conclusions and ImplicationsOur study demonstrates that the anti‐inflammatory drugs probenecid and AZ11645373, which have documented pharmacokinetics and safety profiles in humans, are effective at dampening hyperinflammation and severe influenza disease providing potentially new therapeutic strategies for treating severe or pathogenic IAV infections.

Die Another Way: Interplay between Influenza A Virus, Inflammation and Cell Death

“…These results suggest a biphasic role for NLRP3 inflammasomes in severe IAV infection. Interestingly, the drugs probenecid and AZ11645373, which target the P2X7 receptor upstream of NLRP3 activation ( Figure 1B) in a less potent manner, also provided protection against HKx31 and PR8 infection when treatment was commenced prior to or following the development of severe disease [41], and thus potentially reduced the risk of adverse effects from potent NLRP3 inhibitor drugs. Collectively, TLR and NLRs may play a balancing act of mediating protective versus detrimental inflammation during severe IAV disease.…”

P2 Purinergic Signaling in the Distal Lung in Health and Disease

“…Therefore, if P2X 7 receptor is critically involved in the induction of detrimental hyperinflammation, inhibition of the receptor might be of therapeutic potential to limit tissue damage, whereas P2X 7 -signaling is protective by limiting virus replication. Interestingly, pharmacological inhibition of P2X 7 receptor ameliorated influenza A pneumonia in mice after inoculation of a lethal dose of virus particles and drug application as early as day 1 post infection [ 199 ]. P2X 7 receptor has also been related to pulmonary tuberculosis [ 77 ].…”

Low level laser therapy as a modality to attenuate cytokine storm at multiple levels, enhance recovery, and reduce the use of ventilators in COVID-19

“…Multiple signaling pathways are activated during an immune response and cytokine storm. The P2X purinoceptor 7 (P2X7r) is major factor involved in activation of the cytokine storm and lung pathology in response to viruses [24,25], infection, inflammation, hypoxia, or trauma [26]. P2X7r is an adenosine triphosphate (ATP) gated, nonselective cation channel, allowing Ca 2+ and Na + influx and K + efflux.…”