key: cord-0755286-3ubithu4
authors: Marchetti, Carlo; Mould, Kara; Tengesdal, Isak W.; Janssen, William J; Dinarello, Charles A.
title: Targeting of the NLRP3 Inflammasome for early COVID-19
date: 2021-02-24
journal: bioRxiv
DOI: 10.1101/2021.02.24.432734
sha: 4ee9a74da55c7d95bf4cda8f4acc29a9372fc2c5
doc_id: 755286
cord_uid: 3ubithu4

Following entry and replication of Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) into ACE2 expressing cells, the infected cells undergo lysis releasing more virus but also cell contents. In the lung, constitutive cytokines such as IL-1α are released together with other cell contents. A cascade of inflammatory cytokines ensues, including chemokines and IL-1β, triggering both local as well as systemic inflammation. This cascade of inflammatory cytokines in patients with COVID-19 is termed “Cytokine Release Syndrome” (CRS), and is associated with poor outcomes and death. Many studies reveal that blocking IL-1 activities in COVID-19 patients reduces disease severity and deaths. Here we report highly significant circulating levels of IL-1β, IL-1 Receptor antagonist, IL-6, TNFα, IL-10 and soluble urokinase plasminogen activator receptor in COVID-19 patients with mild or no symptoms. We also report that in circulating myeloid cells from the same patients, there is increased expression of the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) early in the infection. We observed increased NLRP3 gene expression in myeloid cells correlated with IL-1β gene expression and also with elevated circulating IL-1β levels. We conclude that early in SARS-CoV-2 infection, NLRP3 activation takes place and initiates the CRS. Thus, NLRP3 is a target to reduce the organ damage of inflammatory cytokines of the CRS.

Emerging from these reports is the concept that targeting of IL-1 result in improved outcomes, 46 including deaths. For example, high doses of anakinra reduces deaths as well as number of days 47 in the hospital (Cauchois et al. 2020, Cavalli et al. 2020, Huet et al. 2020 ). Anakinra has also been 48 administered in less severe hospitalized patients and resulted in similar reduction in disease 49 (Kyriazopoulou et al. 2020 ). Since anakinra blocks the IL-1 Receptor, the efficacy of anakinra may 50 be due to reducing IL-1a or IL-1b. Other studies report that specifically targeting IL-1b with the 51 neutralizing monoclonal antibody canakinumab also reduces outcomes. 52 The intracellular processing of IL-1β into its biologically active form is largely governed 53 by cytosolic macromolecular complexes termed inflammasomes (Franchi et al. 2009 As shown in Figure 1a influenza or sepsis. The use of anakinra or canakinumab in COVID-19 disease is associated with 118 recovery and survival. However, it is possible to reduce the detrimental properties of IL-1b and its 119 downstream cytokines by first preventing the processing and release of active IL-1b. The present 120 data provide a rationale to treat patients infected with SARS-CoV-2 early in the course of the 121 disease using a specific NLRP3 inhibitor in order to arrest the progression of IL-1b-mediated CRS. 122

Such a treatment offers an opportunity to reduce hospitalization and the need for supplemental 123 oxygen, particularly in subjects with high risk co-morbidities. 

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