Dataset Information

Discovery of drugs to treat cytokine storm-induced cardiac dysfunction

ABSTRACT: SARS-CoV2 infection leads to cardiac injury and dysfunction in 20-30% of hospitalized patients and higher rates of mortality in patients with pre-existing cardiovascular disease. Inflammatory factors released as part of the 'cytokine storm' are thought to play a critical role in cardiac dysfunction in severe COVID-19 patients. Here we use human cardiac organoid technology combined with high sensitivity phosphoproteomics and single nuclei RNA sequencing to identify inflammatory targets inducing cardiac dysfunction. This new pipeline allowed rapid progress and identification of putative therapeutics. We identify a novel interferon-gamma driven BRD4 (bromodomain protein 4)-fibrosis/iNOS axis as a key intracellular mediator of inflammation-induced cardiac dysfunction. This axis is therapeutically targetable using BRD4 inhibitors, which promoted full recovery of function in human cardiac organoids and prevented severe inflammation and death in a cytokine-storm mouse model. The BRD inhibitor INCB054329 was the most efficacious, and is a prime candidate for drug repurposing to attenuate cardiac dysfunction and improve COVID-19 mortality in humans.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart

DISEASE(S): Covid-19

SUBMITTER: Sean Humphrey

LAB HEAD: Sean Humphrey

PROVIDER: PXD020994 | Pride | 2022-02-21

REPOSITORIES: Pride

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Publications

BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection.

Mills Richard J RJ Humphrey Sean J SJ Fortuna Patrick R J PRJ Lor Mary M Foster Simon R SR Quaife-Ryan Gregory A GA Johnston Rebecca L RL Dumenil Troy T Bishop Cameron C Rudraraju Rajeev R Rawle Daniel J DJ Le Thuy T Zhao Wei W Lee Leo L Mackenzie-Kludas Charley C Mehdiabadi Neda R NR Halliday Christopher C Gilham Dean D Fu Li L Nicholls Stephen J SJ Johansson Jan J Sweeney Michael M Wong Norman C W NCW Kulikowski Ewelina E Sokolowski Kamil A KA Tse Brian W C BWC Devilée Lynn L Voges Holly K HK Reynolds Liam T LT Krumeich Sophie S Mathieson Ellen E Abu-Bonsrah Dad D Karavendzas Kathy K Griffen Brendan B Titmarsh Drew D Elliott David A DA McMahon James J Suhrbier Andreas A Subbarao Kanta K Porrello Enzo R ER Smyth Mark J MJ Engwerda Christian R CR MacDonald Kelli P A KPA Bald Tobias T James David E DE Hudson James E JE

Cell 20210316 8

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1β, and poly(I:C), induced d ...[more]

PMID: 33811809

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Project description:COVID-19 has rapidly circulated around the globe and caused significant morbidity and mortality. The disease is characterized by excessive production of pro-inflammatory cytokines and acute lung damage and patient mortality. Although initial cytokine cascades may be beneficial to the host for clearing the virus, enhanced production of pro-inflammatory cytokines and increasing levels in the systemic circulation, referred to as cytokine storm, can promote tissue damage by inducing inflammatory cell death in both infected and bystander cells. Of the multiple inflammatory cytokines produced by innate immune cells during SARS-CoV-2 infection, we found that the combination of TNF-α and IFN-γ specifically induced cell death characterized by GSDME¬–mediated pyroptosis, caspase-8–mediated apoptosis, and MLKL–mediated necroptosis. Cells deficient in both RIPK3 and caspase-8 or RIPK3 and FADD were resistant to this cell death. However, deletion of pyroptosis, apoptosis, or necroptosis individually was not sufficient to protect against cell death. Mechanistically, the STAT1/IRF1 axis activated by TNF-α and IFN-γ co-treatment induced iNOS for the production of nitric oxide. Pharmacological and genetic deletion of this pathway inhibited pyroptosis, apoptosis, and necroptosis in macrophages. Moreover, inhibition of inflammatory cell death protected mice from TNF-α and IFN-γ–induced lethal cytokine shock that mirrors the pathological symptoms of COVID-19. To determine the physiological relevance of protection, we neutralized both TNF-α and IFN-γ in multiple disease models associated with cytokine storm and found that this treatment provided substantial protection against not only SARS-CoV-2 infection, but also sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock models. Collectively, our findings reveal that blocking the COVID-19 cytokine-mediated inflammatory cell death signaling pathway identified in this study may benefit patients with COVID-19 or other cytokine storm-driven syndromes by limiting inflammation and tissue damage. Additionally, these results open new avenues for the treatment of other infectious and autoinflammatory diseases and cancer where TNF-α and IFN-γ synergism play key pathological roles.

Dataset Information

Discovery of drugs to treat cytokine storm-induced cardiac dysfunction

Publications

BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection.

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