Blocking viral replication, the downstream IFN response or inflammasome activation in vivo during the chronic phase of the disease attenuates many aspects of the overactive immune inflammatory response (especially the inflammatory macrophage response) and disease.Ī, Schematic of therapy: SARS-CoV-2-infected MISTRG6-hACE2 mice were treated with dexamethasone (Dex) and remdesivir (RDV) at 7, 8 and 9 d.p.i., and with anti-IFNAR2 antibodies at 7 and 11 d.p.i., and analysed at 14 or 28 d.p.i. Replicating SARS-CoV-2 in these human macrophages activates inflammasomes and initiates an inflammatory cascade with a unique transcriptome, results in pyroptosis, and contributes to the downstream type-I IFN response. Here we show that human lung macrophages are infected by SARS-CoV-2. High levels of IL-1β, IL-18 and lactate dehydrogenase (LDH) are correlated with COVID-19 severity in patients, suggesting a role for inflammasome activation and pyroptosis in pathology 5, 6, 7, 14, 15, 16, 17, 18, 29. This chronicity is recapitulated in SARS-CoV-2-infected MISTRG6-hACE2 humanized mice 19. Thus, inflammasomes oppose host infection by SARS-CoV-2 through the production of inflammatory cytokines and suicide by pyroptosis to prevent a productive viral cycle.Īcute SARS-CoV-2 infection resolves in most patients but becomes chronic and sometimes deadly in about 10–20% of patients 1, 2, 3, 4, 5, 6, 7, 14, 15, 16, 20, 24, 25, 26, 27.
Notably, this blockade of inflammasome activation leads to the release of infectious virus by the infected macrophages. Inflammasome activation and the accompanying inflammatory response are necessary for lung inflammation, as inhibition of the NLRP3 inflammasome pathway reverses chronic lung pathology. In response to infection mediated by CD16 and ACE2 receptors, human macrophages activate inflammasomes, release interleukin 1 (IL-1) and IL-18, and undergo pyroptosis, thereby contributing to the hyperinflammatory state of the lungs.
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Here we show that SARS-CoV-2 infection and replication in lung-resident human macrophages is a critical driver of disease. Blocking either viral replication with remdesivir 21, 22, 23 or the downstream IFN-stimulated cascade with anti-IFNAR2 antibodies in vivo in the chronic stages of disease attenuates the overactive immune inflammatory response, especially inflammatory macrophages. Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA and a sustained interferon (IFN) response, all of which are recapitulated and required for pathology in the SARS-CoV-2-infected MISTRG6-hACE2 humanized mouse model of COVID-19, which has a human immune system 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. Nature volume 606, pages 585–593 ( 2022) Cite this article Inflammasome activation in infected macrophages drives COVID-19 pathology
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