IL‐18 and infections: Is there a role for targeted therapies?

Vecchiè, Alessandra; Bonaventura, Aldo; Toldo, Stefano; Dagna, Lorenzo; Dinarello, Charles A.; Abbate, Antonio

doi:10.1002/jcp.30008

Cited by 104 publications

(87 citation statements)

References 156 publications

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“…The finding of the NLRP3 inflammasome in critical COVID-19 lung disease, however, adds to the literature as it is the first report to this point. In addition, it opens to the possibility that treatments directed against the NLRP3 inflammasome or derived cytokines, such as IL-1β and IL-18, may affect the lung pathology in COVID-19 [9][10][11][12]. NLRP3 inflammasome inhibitors are also under development and being explored for the treatment of COVID-19 (NCT04540120).…”

Section: Discussionmentioning

confidence: 99%

Inflammasome formation in the lungs of patients with fatal COVID-19

et al. 2020

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Objective The orf8b protein of the coronavirus SARS-CoV, analogous to SARS-CoV-2, triggers the NLRP3 inflammasome in macrophages in vitro. Deregulated inflammasome-mediated release of interleukin-1 family cytokines is important in hyper-inflammatory syndromes, like happens in SARS-CoV-2-mediated cytokine release syndrome. We propose that an intense inflammasome formation characterizes the lungs of patients with fatal COVID-19 disease due to pneumonia and acute respiratory distress syndrome (ARDS). Methods Samples from four patients with confirmed COVID-19 pneumonia who had been hospitalized at the Hospital of the University of Trieste (Italy) and died of ARDS and four lung samples from a historical repository from subjects who had died of cardiopulmonary arrest and had not been placed on mechanical ventilation and without evidence of pulmonary infection at postmortem examination were collected. Pathology samples had been fixed in formalin 10% at time of collection and subsequently embedded in paraffin. We conducted staining for ASC (Apoptosis-associated Speck-like protein containing a Caspase recruitment domain), NLRP3 (NACHT, LRR, and PYD domains-containing protein 3), and cleaved caspase-1. Results Intense expression of the inflammasome was detected, mainly in leukocytes, within the lungs of all patients with fatal COVID-19 in the areas of lung injury. The number of ASC inflammasome specks per high power fields was significantly higher in the lungs of patients with fatal COVID-19 as compared with the lungs of control subjects (52 ± 22 vs 6 ± 3, P = 0.0064). Conclusions These findings identify the presence of NLRP3 inflammasome aggregates in the lungs of fatal COVID-19 pneumonia thus providing the potential molecular link between viral infection and cytokine release syndrome.

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Section: Discussionmentioning

confidence: 99%

Inflammasome formation in the lungs of patients with fatal COVID-19

et al. 2020

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“…In severe cases, inflammation can spread to become a systemic response and activate a CNS-sympathetically-driven "fight-or-flight" stress response, and if not controlled, can escalate into widespread immune, cardiovascular and metabolic dysfunction, multiple organ failure and death. inflammatory response via caspase-1 activation and IL-1b and IL-18 maturation, and is critical for host defenses against bacterial, fungal, viral infections and trauma (105,106).…”

Section: ) Innate Pattern Recognition Receptors: Initial Sensing Of Dmentioning

confidence: 99%

Living in a Hostile World: Inflammation, New Drug Development, and Coronavirus

et al. 2021

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We present a brief history of the immune response and show that Metchnikoff’s theory of inflammation and phagocytotic defense was largely ignored in the 20th century. For decades, the immune response was believed to be triggered centrally, until Lafferty and Cunningham proposed the initiating signal came from the tissues. This shift opened the way for Janeway’s pattern recognition receptor theory, and Matzinger’s danger model. All models failed to appreciate that without inflammation, there can be no immune response. The situation changed in the 1990s when cytokine biology was rapidly advancing, and the immune system’s role expanded from host defense, to the maintenance of host health. An inflammatory environment, produced by immune cells themselves, was now recognized as mandatory for their attack, removal and repair functions after an infection or injury. We explore the cellular programs of the immune response, and the role played by cytokines and other mediators to tailor the right response, at the right time. Normally, the immune response is robust, self-limiting and restorative. However, when the antigen load or trauma exceeds the body’s internal tolerances, as witnessed in some COVID-19 patients, excessive inflammation can lead to increased sympathetic outflows, cardiac dysfunction, coagulopathy, endothelial and metabolic dysfunction, multiple organ failure and death. Currently, there are few drug therapies to reduce excessive inflammation and immune dysfunction. We have been developing an intravenous (IV) fluid therapy comprising adenosine, lidocaine and Mg2+ (ALM) that confers a survival advantage by preventing excessive inflammation initiated by sepsis, endotoxemia and sterile trauma. The multi-pronged protection appears to be unique and may provide a tool to examine the intersection points in the immune response to infection or injury, and possible ways to prevent secondary tissue damage, such as that reported in patients with COVID-19.

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“…Interestingly, IL6, IL10, and IL18 are secreted by ATII epithelial cells, the primary targets for SARS-CoV-2 infection (53). The latter of these cytokines, IL18, has further been suggested to be at the "eye of the cytokine storm", acting synergistically with various other primary cytokines in a proinflammatory manner to modulate the expression of secondary cytokines, such as IFN (72)(73)(74). Moreover, overproduction of IL18 has been linked to a predisposition for macrophage activation syndrome, resulting in an overactive immune response, as well as Kawasaki disease and systemic lupus erythematosus, autoimmune diseases which present symptoms similar to those seen in critically ill paediatric COVID-19 patients (75,76).…”

Section: The S2m Element Of Sars-cov-2 Interacts With Cellular Mirna-mentioning

confidence: 99%

SARS-CoV-2 highly conserved s2m element dimerizes via a kissing complex and interacts with host miRNA-1307-3p

Imperatore

Cunningham

Pellegrene

et al. 2020

Preprint

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The ongoing COVID-19 pandemic highlights the necessity for a more fundamental understanding of the coronavirus life cycle. The causative agent of the disease, SARS-CoV-2, is being studied extensively from a structural standpoint in order to gain insight into key molecular mechanisms required for its survival. Contained within the untranslated regions of the SARS-CoV-2 genome are various conserved stem-loop elements that are believed to function in RNA replication, viral protein translation, and discontinuous transcription. While the majority of these regions are variable in sequence, a 41-nucleotide s2m element within the 3’ UTR is highly conserved among coronaviruses and three other viral families. In this study, we demonstrate that the s2m element of SARS-CoV-2 dimerizes by forming an intermediate homodimeric kissing complex structure that is subsequently converted to a thermodynamically stable duplex conformation. This process is aided by the viral nucleocapsid protein, potentially indicating a role in mediating genome dimerization. Furthermore, we demonstrate that the s2m element interacts with multiple copies of host cellular miRNA-1307-3p. Taken together, our results highlight the potential significance of the dimer structures formed by the s2m element in key biological processes and implicate the motif as a possible therapeutic drug target for COVID-19 and other coronavirus-related diseases.

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IL‐18 and infections: Is there a role for targeted therapies?

Cited by 104 publications

References 156 publications

Inflammasome formation in the lungs of patients with fatal COVID-19

Inflammasome formation in the lungs of patients with fatal COVID-19

Living in a Hostile World: Inflammation, New Drug Development, and Coronavirus

SARS-CoV-2 highly conserved s2m element dimerizes via a kissing complex and interacts with host miRNA-1307-3p

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