SARS-CoV-2 engages inflammasome and pyroptosis in human primary monocytes

Ferreira, André C.; Soares, Vinícius Cardoso; Azevedo-Quintanilha, Isaclaudia G. de; Dias, Suelen da Silva Gomes; Fintelman-Rodrigues, Natália; Sacramento, Carolina Q.; Mattos, Mayara; Freitas, Caroline de; Temerozo, Jairo R.; Teixeira, Lívia; Hottz, Eugênio D.; Barreto, Ester A.; Pão, Camila R. R.; Palhinha, Lohanna; Miranda, Milene Dias; Bou-Habib, Dumith Chequer; Bozza, Fernando A.; Bozza, Patrı́cia T.; Souza, Thiago Moreno L.

doi:10.1038/s41420-021-00428-w

Cited by 217 publications

(262 citation statements)

References 46 publications

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“…patients and non-classical monocytes might be among the first cells to undergo this lytic programmed cell death process, after inflammasome engagement (32).…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, there are reports of a reduction of this sub-population in viral infections and in inflammatory or auto-immune diseases, where the decrease in circulation was mainly attributed to tissue migration ( 29 – 31 ). Interestingly, inflammasome activation and pyroptotic cell death was described in circulating monocytes from severe COVID-19 patients and non-classical monocytes might be among the first cells to undergo this lytic programmed cell death process, after inflammasome engagement ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

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Severe COVID-19 Recovery Is Associated with Timely Acquisition of a Myeloid Cell Immune-Regulatory Phenotype

et al. 2021

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After more than one year since the COVID-19 outbreak, patients with severe disease still constitute the bottleneck of the pandemic management. Aberrant inflammatory responses, ranging from cytokine storm to immune-suppression, were described in COVID-19 and no treatment was demonstrated to change the prognosis significantly. Therefore, there is an urgent need for understanding the underlying pathogenic mechanisms to guide therapeutic interventions. This study was designed to assess myeloid cell activation and phenotype leading to recovery in patients surviving severe COVID-19. We evaluated longitudinally patients with COVID-19 related respiratory insufficiency, stratified according to the need of intensive care unit admission (ICU, n = 11, and No-ICU, n = 9), and age and sex matched healthy controls (HCs, n = 11), by flow cytometry and a wide array of serum inflammatory/immune-regulatory mediators. All patients featured systemic immune-regulatory myeloid cell phenotype as assessed by both unsupervised and supervised analysis of circulating monocyte and dendritic cell subsets. Specifically, we observed a reduction of CD14lowCD16+ monocytes, and reduced expression of CD80, CD86, and Slan. Moreover, mDCs, pDCs, and basophils were significantly reduced, in comparison to healthy subjects. Contemporaneously, both monocytes and DCs showed increased expression of CD163, CD204, CD206, and PD-L1 immune-regulatory markers. The expansion of M2-like monocytes was significantly higher at admission in patients featuring detectable SARS-CoV-2 plasma viral load and it was positively correlated with the levels of specific antibodies. In No-ICU patients, we observed a peak of the alterations at admission and a progressive regression to a phenotype similar to HCs at discharge. Interestingly, in ICU patients, the expression of immuno-suppressive markers progressively increased until discharge. Notably, an increase of M2-like HLA-DRhighPD-L1+ cells in CD14++CD16− monocytes and in dendritic cell subsets was observed at ICU discharge. Furthermore, IFN-γ and IL-12p40 showed a decline over time in ICU patients, while high values of IL1RA and IL-10 were maintained. In conclusion, these results support that timely acquisition of a myeloid cell immune-regulatory phenotype might contribute to recovery in severe systemic SARS-CoV-2 infection and suggest that therapeutic agents favoring an innate immune system regulatory shift may represent the best strategy to be implemented at this stage.

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“…patients and non-classical monocytes might be among the first cells to undergo this lytic programmed cell death process, after inflammasome engagement (32).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Severe COVID-19 Recovery Is Associated with Timely Acquisition of a Myeloid Cell Immune-Regulatory Phenotype

et al. 2021

View full text Add to dashboard Cite

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“…In the event that immune enhancement is observed in a given subgroup in response to viral exposure, such as individuals predisposed to autoimmune or inflammatory response, identification of therapeutic alternatives, and mitigation strategies for at-risk individuals may be beneficial. Such options may include the use of monoclonal antibodies, potentially with Fc-domain mutations to disrupt FcγR crosslinking ( 100 ); blockade of FcγR or PRR signaling via Syk or NF-κB pathways ( 45 , 79 ); downregulation of NLRP3 inflammasome activation ( 101 ); blockade of the terminal complement pathway ( 102 ); and saturation of FcγRs ( 55 , 103 ) or downregulation of the complement pathway receptor FCN1 ( 35 ) via therapeutic IVIG, possibly excluding afucosylated or activating fractions. Meanwhile, ongoing consideration and testing of pathway-informed, well-tolerated therapeutic candidates may be beneficial in active cases, including repurposed therapeutics targeting viral replication (e.g., remdesivir, ivermectin), leukocyte-mediated tissue damage (e.g., doxycycline, IFN-λ), and dysregulated inflammatory response (e.g., barcitinib, ruxolitinib, tocilizumab, dexamethasone) ( 104 ) in COVID-19.…”

Section: Discussion and Implications For Antibody-based Therapeuticsmentioning

confidence: 99%

Severe Clinical Worsening in COVID-19 and Potential Mechanisms of Immune-Enhanced Disease

Hussman

2021

Front. Med.

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Infection by the novel SARS-CoV-2 coronavirus produces a range of outcomes, with the majority of cases producing mild or asymptomatic effects, and a smaller subset progressing to critical or fatal COVID-19 disease featuring severe acute respiratory distress. Although the mechanisms driving severe disease progression remain unknown, it is possible that the abrupt clinical deterioration observed in patients with critical disease corresponds to a discrete underlying expansion of viral tropism, from infection of cells comprising respiratory linings and alveolar epithelia to direct infection and activation of inflammatory monocytes and macrophages. Dysregulated immune responses could then contribute to disease severity. This article discusses the potential role of monocyte/macrophage (Mo/Mϕ) infection by SARS-CoV-2 in mediating the immune response in severe COVID-19. Additional mechanisms of immune-enhanced disease, comprising maladaptive immune responses that may aggravate rather than alleviate severity, are also discussed. Severe acute clinical worsening in COVID-19 patients may be influenced by the emergence of antibodies that participate in hyperinflammatory monocyte response, release of neutrophil extracellular traps (NETs), thrombosis, platelet apoptosis, viral entry into Fc gamma receptor (FcγR)-expressing immune cells, and induction of autoantibodies with cross-reactivity against host proteins. While the potential roles of Mo/Mϕ infection and immune-enhanced pathology in COVID-19 are consistent with a broad range of clinical and laboratory findings, their prominence remains tentative pending further validation. In the interim, these proposed mechanisms present immediate avenues of inquiry that may help to evaluate the safety of candidate vaccines and antibody-based therapeutics, and to support consideration of pathway-informed, well-tolerated therapeutic candidates targeting the dysregulated immune response.

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“…There is emerging evidence for the role of pyroptosis in promoting inflammation and immunity in viral infections, including influenza [ 55 ] and, recently, also COVID-19 [ 56 , 57 ]. Mechanistically, most information was collected from studies on the influenza virus, a long-recognized potent activator of the NLRP3 inflammasome.…”

Section: Regulated Cell Death In Host Defense Against Respiratory Virusesmentioning

confidence: 99%

Role of DAMPs in respiratory virus-induced acute respiratory distress syndrome—with a preliminary reference to SARS-CoV-2 pneumonia

Land

2021

Genes Immun

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When surveying the current literature on COVID-19, the “cytokine storm” is considered to be pathogenetically involved in its severe outcomes such as acute respiratory distress syndrome, systemic inflammatory response syndrome, and eventually multiple organ failure. In this review, the similar role of DAMPs is addressed, that is, of those molecules, which operate upstream of the inflammatory pathway by activating those cells, which ultimately release the cytokines. Given the still limited reports on their role in COVID-19, the emerging topic is extended to respiratory viral infections with focus on influenza. At first, a brief introduction is given on the function of various classes of activating DAMPs and counterbalancing suppressing DAMPs (SAMPs) in initiating controlled inflammation-promoting and inflammation-resolving defense responses upon infectious and sterile insults. It is stressed that the excessive emission of DAMPs upon severe injury uncovers their fateful property in triggering dysregulated life-threatening hyperinflammatory responses. Such a scenario may happen when the viral load is too high, for example, in the respiratory tract, “forcing” many virus-infected host cells to decide to commit “suicidal” regulated cell death (e.g., necroptosis, pyroptosis) associated with release of large amounts of DAMPs: an important topic of this review. Ironically, although the aim of this “suicidal” cell death is to save and restore organismal homeostasis, the intrinsic release of excessive amounts of DAMPs leads to those dysregulated hyperinflammatory responses—as typically involved in the pathogenesis of acute respiratory distress syndrome and systemic inflammatory response syndrome in respiratory viral infections. Consequently, as briefly outlined in this review, these molecules can be considered valuable diagnostic and prognostic biomarkers to monitor and evaluate the course of the viral disorder, in particular, to grasp the eventual transition precociously from a controlled defense response as observed in mild/moderate cases to a dysregulated life-threatening hyperinflammatory response as seen, for example, in severe/fatal COVID-19. Moreover, the pathogenetic involvement of these molecules qualifies them as relevant future therapeutic targets to prevent severe/ fatal outcomes. Finally, a theory is presented proposing that the superimposition of coronavirus-induced DAMPs with non-virus-induced DAMPs from other origins such as air pollution or high age may contribute to severe and fatal courses of coronavirus pneumonia.

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SARS-CoV-2 engages inflammasome and pyroptosis in human primary monocytes

Cited by 217 publications

References 46 publications

Severe COVID-19 Recovery Is Associated with Timely Acquisition of a Myeloid Cell Immune-Regulatory Phenotype

Severe COVID-19 Recovery Is Associated with Timely Acquisition of a Myeloid Cell Immune-Regulatory Phenotype

Severe Clinical Worsening in COVID-19 and Potential Mechanisms of Immune-Enhanced Disease

Role of DAMPs in respiratory virus-induced acute respiratory distress syndrome—with a preliminary reference to SARS-CoV-2 pneumonia

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