NLRP3, the inflammasome and COVID-19 infection.

Severe coronavirus disease 2019 (COVID-19) is characterized by respiratory failure, shock, or multiorgan dysfunction, often accompanied by systemic hyperinflammation and dysregulated cytokine release. These features are linked to the intense and rapid stimulation of the innate immune response. The NLRP3 inflammasome is a central player in inflammatory macrophage activation which via caspase-1 activation leads to the release of the mature forms of the pro-inflammatory cytokines IL-1ß and IL-18, and via cleavage of Gasdermin D pyroptosis, an inflammatory form of cell death. Here we discuss the role of NLRP3 activation in COVID-19 and clinical trials currently underway to target NLRP3 to treat severe COVID-19.

Ironing Out Vaccine Efficacy.

Iron deficiency has been linked to impaired humoral immunity to vaccines. In this issue of Med, Frost et al. demonstrate the importance of serum iron levels for lymphocyte function during vaccination and infection, pointing to iron supplementation as a strategy to boost vaccine efficacy, including against COVID19.1.

Immunothrombosis and the molecular control of tissue factor by pyroptosis: prospects for new anticoagulants.

The interplay between innate immunity and coagulation after infection or injury, termed immunothrombosis, is the primary cause of disseminated intravascular coagulation (DIC), a condition that occurs in sepsis. Thrombosis associated with DIC is the leading cause of death worldwide. Interest in immunothrombosis has grown because of COVID-19, the respiratory disease caused by SARS-CoV-2, which has been termed a syndrome of dysregulated immunothrombosis. As the relatively new field of immunothrombosis expands at a rapid pace, the focus of academic and pharmacological research has shifted from generating treatments targeted at the traditional 'waterfall' model of coagulation to therapies better directed towards immune components that drive coagulopathies. Immunothrombosis can be initiated in macrophages by cleavage of the non-canonical inflammasome which contains caspase-11. This leads to release of tissue factor (TF), a membrane glycoprotein receptor that forms a high-affinity complex with coagulation factor VII/VIIa to proteolytically activate factors IX to IXa and X to Xa, generating thrombin and leading to fibrin formation and platelet activation. The mechanism involves the post-translational activation of TF, termed decryption, and release of decrypted TF via caspase-11-mediated pyroptosis. During aberrant immunothrombosis, decryption of TF leads to thromboinflammation, sepsis, and DIC. Therefore, developing therapies to target pyroptosis have emerged as an attractive concept to counteract dysregulated immunothrombosis. In this review, we detail the three mechanisms of TF control: concurrent induction of TF, caspase-11, and NLRP3 (signal 1); TF decryption, which increases its procoagulant activity (signal 2); and accelerated release of TF into the intravascular space via pyroptosis (signal 3). In this way, decryption of TF is analogous to the two signals of NLRP3 inflammasome activation, whereby induction of pro-IL-1ß and NLRP3 (signal 1) is followed by activation of NLRP3 (signal 2). We describe in detail TF decryption, which involves pathogen-induced alterations in the composition of the plasma membrane and modification of key cysteines on TF, particularly at the location of the critical, allosterically regulated disulfide bond of TF in its 219-residue extracellular domain. In addition, we speculate towards the importance of identifying new therapeutics to block immunothrombotic triggering of TF, which can involve inhibition of pyroptosis to limit TF release, or the direct targeting of TF decryption using cysteine-modifying therapeutics.

Can NLRP3 inhibitors improve on dexamethasone for the treatment of COVID-19?

Dexamethasone, a corticosteroid, has been approved for use in the treatment of severe COVID-19, which is characterised by hyperinflammation and associated lung damage. However, dexamethasone shows no clinical benefit in the treatment of less severe disease, and prolonged treatment may lead to immunosuppression and an increased risk of opportunistic infections. Hence there is a need for more specific anti-inflammatory therapies which also prevent severe disease. The NLRP3 inflammasome is an intracellular signalling complex which is responsible for the cleavage and release of the cytokines IL-1ß and IL-18 and has also been shown to be inhibited by dexamethasone. NLRP3 inflammasome activation is strongly correlated with COVID-19 severity and part of dexamethasone's clinical effect in COVID-19 may be via NLRP3 inhibition. Specific NLRP3 inhibitors are currently undergoing clinical trials for the treatment of COVID-19. In this review, we evaluate the evidence supporting the use of dexamethasone and speculate on the potential use of NLRP3 inhibitors to treat COVID-19 as a more specific approach that may not have the liabilities of dexamethasone.

Targeting immunometabolism to treat COVID-19.

The COVID-19 crisis has emphasised the need for antiviral therapies to combat current and future viral zoonoses. Recent studies have shown that immune cells such as macrophages are the main contributors to the inflammatory response seen in the later inflammatory phase of COVID-19. Immune cells in the context of a viral infection such as SARS-CoV-2 undergo metabolic reprogramming to elicit these pro-inflammatory effector functions. The evidence of metabolic reprogramming in COVID-19 offers opportunities for metabolites with immunomodulatory properties to be investigated as potential therapies to combat this hyper-inflammatory response. Recent research indicates that the metabolite itaconate, previously known to be broadly antibacterial, may have both antiviral and immunomodulatory potential. Furthermore, low itaconate levels have shown to correlate with COVID-19 disease severity, potentially implicating its importance in the disease. The antiviral potential of itaconate has encouraged researchers to synthesise itaconate derivatives for antiviral screening, with some encouraging results. This review summarises the antiviral and immunomodulatory potential of immunometabolic modulators including metformin, peroxisome proliferator-activated receptor agonists and TEPP-46 as well as itaconate, and its derivatives and their potential use as broad spectrum anti-viral agents.