Inflammasome activation in COVID-19 patients

Rodrigues, Tamara Silva; Sa, Keyla Sg; Ishimoto, Adriene Y; Becerra, Amanda; Oliveira, Samuel; Almeida, Letícia de; Gonçalves, Augusto Velozo; Perucello, Debora B.; Castro, Ricardo Macedo Corrêa e; Veras, Flávio P.; Toller-Kawahisa, Juliana E; Nascimento, Daniele C.; Lima, Mikhael HF de; Silva, Camila Ms; Caetité, Diego B; Martins, Ronaldo B.; Castro, Ítalo A.; Pontelli, Marjorie Cornejo; Barros, Fábio Cury de; Amaral, Natália Brasil; Giannini, Marcela C; Bonjorno, Letícia Pastorelli; Lopes, M. Beatriz S.; Benatti, Maíra Nilson; Santana, Rodrigo de Carvalho; Vilar, Fernando Crivelenti; Auxiliadora‐Martins, Maria; Luppino‐Assad, Rodrigo; Almeida, Silvana; Oliveira, Fabíola Reis; Batah, Sabrina Setembre; Siyuan, Li; Cunha, Thiago Mattar; Alves-Filho, José C.; Cunha, Fernando Q.; Cunha, Larissa D.; Frantz, Fabiani Gai; Kohlsdorf, Tiana; Fabro, Alexandre Todorovic; Arruda, Eurico; Oliveira, Renê DR de; Louzada‐Júnior, Paulo; Zamboni, Dario S.

doi:10.1101/2020.08.05.20168872

Cited by 33 publications

(46 citation statements)

References 20 publications

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“… 118–121 IL-1β is downstream of the inflammasome and upstream of IL-6, and this entire pathway has now been implicated in the severity of COVID-19. 122 , 123 Accordingly, IL-1β and IL-6 have both been identified as potential therapeutic targets in severe COVID-19, with retrospective cohort studies suggesting that anakinra, an IL-1 receptor antagonist that blocks the function of IL-1α and IL-1β, may be efficacious. 124 , 125 Retrospective studies of IL-6 blockade have also suggested this to be an effective treatment for COVID-19, however a randomized clinical trial did not demonstrate a therapeutic benefit.…”

Section: Cardiovascular Comorbidity In Covid-19 and Potential Sex Difmentioning

confidence: 99%

Higher mortality of COVID-19 in males: sex differences in immune response and cardiovascular comorbidities

Bienvenu

Noonan

Wang

et al. 2020

Cardiovascular Research

272

194

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The high mortality rate of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is a critical concern of the Coronavirus Disease 2019 (COVID-19) pandemic. Strikingly, men account for the majority of COVID-19 deaths, with current figures ranging from 59–75% of total mortality. However, despite clear implications in relation to COVID-19 mortality, most research has not considered sex as a critical factor in data analysis. Here, we highlight fundamental biological differences that exist between males and females, and how these may make significant contributions to the male-biased COVID-19 mortality. We present preclinical evidence identifying the influence of biological sex on the expression and regulation of angiotensin-converting enzyme 2 (ACE2), which is the main receptor used by SARS-CoV-2 to enter cells. However, we note that there is a lack of reports showing that sexual dimorphism of ACE2 expression exists and is of functional relevance in humans. In contrast, there is strong evidence, especially in the context of viral infections, that sexual dimorphism plays a central role in the genetic and hormonal regulation of immune responses, both of the innate as well as the adaptive immune system. We review evidence supporting that ineffective anti-SARS-CoV-2 responses, coupled with a predisposition for inappropriate hyperinflammatory responses, could provide a biological explanation for the male bias in COVID-19 mortality. A prominent finding in COVID-19 is the increased risk of death with pre-existing cardiovascular comorbidities such as hypertension, obesity and age. We contextualise how important features of sexual dimorphism and inflammation in COVID-19 may exhibit a reciprocal relationship with comorbidities, and explain their increased mortality risk. Ultimately, we demonstrate that biological sex is a fundamental variable of critical relevance to our mechanistic understanding of SARS-CoV-2 infection and the pursuit of effective COVID-19 preventative and therapeutic strategies.

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Section: Cardiovascular Comorbidity In Covid-19 and Potential Sex Difmentioning

confidence: 99%

Higher mortality of COVID-19 in males: sex differences in immune response and cardiovascular comorbidities

Bienvenu

Noonan

Wang

et al. 2020

Cardiovascular Research

272

194

View full text Add to dashboard Cite

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“…complement activation and extrusion of neutrophil extracellular traps are implicated [41,[56][57][58].…”

Section: Infection Of Epithelial-endothelial Co-cultures Elicits An Imentioning

confidence: 99%

“…In addition to upregulating inflammatory adhesion molecules, we analysed whether endothelial cells can be source of proinflammatory cytokines during SARS-CoV-2 infection. As IL-6 and CXCL10 are elevated in patients with severe COVID-19[41], we analysed whether endothelial cells released these pro-inflammatory cytokines upon SARS-CoV-2 infection. While endothelial cells released modest levels of CXCL10 72h…”

mentioning

confidence: 99%

Endothelial cells elicit a pro-inflammatory response to SARS-CoV-2 without productive viral infection

Schimmel

Chew

Stocks

et al. 2021

Preprint

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Thrombotic and microvascular complications are frequently seen in deceased COVID-19 patients, suggesting that vascular pathology is a major driver of severe disease. However, whether this is caused by direct viral infection of the endothelium or inflammation-induced endothelial activation remains highly contentious. What role the endothelium plays in viral amplification and inflammation thus remains a key unresolved question in the pathogenesis of SARS-CoV-2. Here, we use patient autopsy samples, primary human endothelial cells and an in vitro model of the pulmonary epithelial-endothelial cell barrier to show that primary human endothelial cells express the SARS-CoV-2 receptor ACE2 and the protease TMPRSS2, albeit at low levels. Accordingly, when present in a sufficiently high concentration, SARS-CoV-2 can enter primary human endothelial cells from either the apical or basolateral surface. Whilst inducing an inflammatory response, this is not a productive infection. We further demonstrate that in a co-culture model of the pulmonary epithelial-endothelial barrier, endothelial cells are not infected with SARS-CoV-2. They do however, sense and respond to an infection in the adjacent epithelial cells, resulting in the induction of a pro-inflammatory response. Taken together, these data suggest that in vivo, endothelial cells are unlikely to be infected with SARSCoV-2 and that infection is only likely to occur if the adjacent pulmonary epithelium is denuded (basolateral infection) or a high viral load is present in the blood (apical infection). In such a scenario, whilst SARS-CoV-2 infection of the endothelium can occur, it does not contribute to viral amplification. However, endothelial cells are still likely to play a key role in SARS-CoV-2 pathogenesis by sensing and mounting a pro-inflammatory response to SARS-CoV-2.

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“…They have also been linked to asthma and allergic inflammation [ 24 , 25 , 26 , 27 ]. And inflammasomes are mediators of certain acute inflammatory conditions, such as gout and the respiratory distress syndrome associated with the late stage of certain viral lung infections, including COVID-19 [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. Hence, feasible measures that could prevent inflammasome activation–most particularly, safe nutraceutical measures–might be of considerable value in preventive and therapeutic medicine.…”

Section: Mechanisms Involved In the Priming And Activation Of Inflmentioning

confidence: 99%

Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond

et al. 2020

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Inflammasomes are intracellular protein complexes that form in response to a variety of stress signals and that serve to catalyze the proteolytic conversion of pro-interleukin-1β and pro-interleukin-18 to active interleukin-1β and interleukin-18, central mediators of the inflammatory response; inflammasomes can also promote a type of cell death known as pyroptosis. The NLRP3 inflammasome has received the most study and plays an important pathogenic role in a vast range of pathologies associated with inflammation—including atherosclerosis, myocardial infarction, the complications of diabetes, neurological and autoimmune disorders, dry macular degeneration, gout, and the cytokine storm phase of COVID-19. A consideration of the molecular biology underlying inflammasome priming and activation enables the prediction that a range of nutraceuticals may have clinical potential for suppressing inflammasome activity—antioxidants including phycocyanobilin, phase 2 inducers, melatonin, and N-acetylcysteine, the AMPK activator berberine, glucosamine, zinc, and various nutraceuticals that support generation of hydrogen sulfide. Complex nutraceuticals or functional foods featuring a number of these agents may find utility in the prevention and control of a wide range of medical disorders.

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Inflammasome activation in COVID-19 patients

Cited by 33 publications

References 20 publications

Higher mortality of COVID-19 in males: sex differences in immune response and cardiovascular comorbidities

Higher mortality of COVID-19 in males: sex differences in immune response and cardiovascular comorbidities

Endothelial cells elicit a pro-inflammatory response to SARS-CoV-2 without productive viral infection

Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond

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