SARS-CoV-2 viroporin triggers the NLRP3 inflammatory pathway

Xu, Huanzhou; Chitre, Siddhi; Akinyemi, Ibukun A.; Loeb, Julia C.; Lednicky, John A.; McIntosh, Michael T.; Bhaduri‐McIntosh, Sumita

doi:10.1101/2020.10.27.357731

Cited by 30 publications

(35 citation statements)

References 36 publications

(32 reference statements)

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“…Since SARS-CoV-2 primes NLRP3 (Rodrigues et al 2021, Xu et al 2020), we anticipated an increase in mRNA levels coding for NLRP3 with SARS-CoV-2 infection. We observed a 2-fold increase in NLRP3 levels in buffy coat cells from 27 positive subjects compared to cells from 14 non-infected subjects (Figure 2a).…”

Section: Resultsmentioning

confidence: 99%

“…Notably, it has been observed that viral proteins of the SARS-CoV virus ORF3a, ORF8b and Viroporin 3a activate the NLRP3 inflammasome (Chen et al 2019, Shi et al 2019, Siu et al 2019). More recently, in vitro studies showed that also SARS-CoV-2 induces the NLRP3 inflammasome formation (Xu et al 2020). Presence of NLRP3 inflammasome aggregates has also been shown in the lungs of fatal COVID-19 pneumonia and in PBMCs and tissues of COVID-19 positive post-mortem patients upon autopsy (Rodrigues et al 2021, Toldo et al 2021).…”

Section: Introductionmentioning

confidence: 99%

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Targeting of the NLRP3 Inflammasome for early COVID-19

Marchetti

Mould

Tengesdal

et al. 2021

Preprint

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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-1β 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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting of the NLRP3 Inflammasome for early COVID-19

Marchetti

Mould

Tengesdal

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…Orf3a-activated IL-1β expression occurs via NF-kB pathway. These leads to disruption of the intracellular ion balance, promoting mitochondrial damage, and generating ROS, which act as co-activators of NLRP3 [ 46 ].…”

Section: Inflammasome Activation In Covid-19 Patientsmentioning

confidence: 99%

Inflammasome Activation-Induced Hypercoagulopathy: Impact on Cardiovascular Dysfunction Triggered in COVID-19 Patients

Gedefaw

Ullah

Leung

et al. 2021

Cells

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Coronavirus disease 2019 (COVID-19) is the most devastating infectious disease in the 21st century with more than 2 million lives lost in less than a year. The activation of inflammasome in the host infected by SARS-CoV-2 is highly related to cytokine storm and hypercoagulopathy, which significantly contribute to the poor prognosis of COVID-19 patients. Even though many studies have shown the host defense mechanism induced by inflammasome against various viral infections, mechanistic interactions leading to downstream cellular responses and pathogenesis in COVID-19 remain unclear. The SARS-CoV-2 infection has been associated with numerous cardiovascular disorders including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism. The inflammatory response triggered by the activation of NLRP3 inflammasome under certain cardiovascular conditions resulted in hyperinflammation or the modulation of angiotensin-converting enzyme 2 signaling pathways. Perturbations of several target cells and tissues have been described in inflammasome activation, including pneumocytes, macrophages, endothelial cells, and dendritic cells. The interplay between inflammasome activation and hypercoagulopathy in COVID-19 patients is an emerging area to be further addressed. Targeted therapeutics to suppress inflammasome activation may have a positive effect on the reduction of hyperinflammation-induced hypercoagulopathy and cardiovascular disorders occurring as COVID-19 complications.

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“…Viroporins are hydrophobic proteins that are considered virulence factors that are typically not essential for virus replication. However, some form pores that facilitate ion transport across cell membranes, ensuring virus release with the potential for coincident inflammasome activation ( 3 , 4 ). Nevertheless, we did not see clear evidence of decreased clinical virulence caused by SARS-CoV-2 UF-8.…”

Section: Announcementmentioning

confidence: 99%