Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure

Giamarellos‐Bourboulis, Evangelos J.; Netea, Mihai G.; Rovina, Nikoletta; Akinosoglou, Karolina; Antoniadou, Anastasia; Antonakos, Nikolaos; Damoraki, Georgia; Gkavogianni, Theologia; Adami, Maria Evangelia; Κatsaounou, Paraskevi; Ntaganou, Maria; Kyriakopoulou, Magdalini; Dimοpoulos, George; Koutsodimitropoulos, Ioannis; Velissaris, Dimitrios; Koufargyris, Panagiotis; Karageorgos, Athanasios D.; Katrini, Konstantina; Lekakis, Vasileios; Lupşe, Mihaela; Kotsaki, Antigone; Renieris, Georgios; Theodoulou, Danai; Panou, Vasiliki; Koukaki, Evangelia; Koulouris, Nikolaos; Gogos, Charalambos; Koutsoukou, Antonia

doi:10.1016/j.chom.2020.04.009

Cited by 1,958 publications

(2,301 citation statements)

References 14 publications

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“…There were also minimal associations between changes in CD4 T cell populations and clinical parameters, with the exception of EM2, which was positively correlated with D-dimer ( Figure S3I). Together, these data highlight T cell activation in COVID-19 patients similar to what has been observed in other acute infections or vaccinations (36,38,39), but also identify patients with high, low, or essentially no T cell response based on KI67 + or CD38 + HLA-DR + compared to control subjects.…”

Section: Sars-cov2 Infection Is Associated With Heterogeneous Cd4 T Csupporting

confidence: 76%

Deep immune profiling of COVID-19 patients reveals patient heterogeneity and distinct immunotypes with implications for therapeutic interventions

Mathew

Giles

Baxter

et al. 2020

Preprint

141

168

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COVID-19 has become a global pandemic. Immune dysregulation has been implicated, but immune responses remain poorly understood. We analyzed 71 COVID-19 patients compared to recovered and healthy subjects using high dimensional cytometry. Integrated analysis of ~200 immune and >30 clinical features revealed activation of T cell and B cell subsets, but only in some patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses could reach >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable to uninfected subjects. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change.These analyses identified three "immunotypes" associated with poor clinical trajectories versus improving health. These immunotypes may have implications for therapeutics and vaccines.

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Section: Sars-cov2 Infection Is Associated With Heterogeneous Cd4 T Csupporting

confidence: 76%

Deep immune profiling of COVID-19 patients reveals patient heterogeneity and distinct immunotypes with implications for therapeutic interventions

Mathew

Giles

Baxter

et al. 2020

Preprint

141

168

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“…Structure-function correlative analysis followed by comparative alignment of IRF3 and NLRP12 homologs across relevant mammalian orders reveal the potential explanatory power of our findings. The cleavage of IRF3 could explain the enigmatically blunted type-I IFN response that have been noted in early studies of SARS-CoV-2 infections [31,32], while the NSP5 mediated cleavage of NLRP12 might explain the hyperinflammatory response linked to severe COVID-19 disease [33,34]. Indeed, the lack or presence of cognate cleavage motifs in IRF3 and NLRP12 homologs presents interesting correlations with the presentation of disease in animal models; our results will enable the development of more effective animal models for severe COVID-19.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts

Moustaqil

Ollivier

Chiu

et al. 2020

Preprint

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The genome of SARS-CoV-2 (SARS2) encodes for two viral proteases (NSP3/ papain-like protease and NSP5/ 3C-like protease or major protease) that are responsible for cleaving viral polyproteins for successful replication. NSP3 and NSP5 of SARS-CoV (SARS1) are known interferon antagonists. Here, we examined whether the protease function of SARS2 NSP3 and NSP5 target proteins involved in the host innate immune response. We designed a fluorescent based cleavage assay to rapidly screen the protease activity of NSP3 and NSP5 on a library of 71 human innate immune proteins (HIIPs), covering most pathways involved in human innate immunity. By expressing each of these HIIPs with a genetically encoded fluorophore in a cell-free system and titrating in the recombinant protease domain of NSP3 or NSP5, we could readily detect cleavage of cognate HIIPs on SDS-page gels. We identified 3 proteins that were specifically and selectively cleaved by NSP3 or NSP5: IRF-3, and NLRP12 and TAB1, respectively. Direct cleavage of IRF3 by NSP3 could explain the blunted Type-I IFN response seen during SARS-CoV-2 infections while NSP5 mediated cleavage of NLRP12 and TAB1 point to a molecular mechanism for enhanced production of IL-6 and inflammatory response observed in COVID-19 patients. Surprisingly, both NLRP12 and TAB1 have each two distinct cleavage sites. We demonstrate that in mice, the second cleavage site of NLRP12 is absent. We pushed this comparative alignment of IRF-3 and NLRP12 homologs and show that the lack or presence of cognate cleavage motifs in IRF-3 and NLRP12 could contribute to the presentation of disease in cats and tigers, for example. Our findings provide an explanatory framework for in-depth studies into the pathophysiology of COVID-19 and should facilitate the search or development of more effective animal models for severe COVID-19. Finally, we discovered that one particular species of bats, David's Myotis, possesses the five cleavage sites found in humans for NLRP12, TAB1 and IRF3. These bats are endemic from the Hubei province in China and we discuss its potential role as reservoir for the evolution of SARS1 and SASR2.

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“…However, it is unknown whether specific subsets of innate and adaptive immune cells could be differentially contributing to a dysregulated immune response underlying the development of ARDS in COVID- 19. The most recent studies indicate that immune exhaustion of effector T lymphocytes and altered humoral responses (7)(8)(9), combined with alterations in myeloid cells like monocytes (10,11) might be related to increased inflammation and contribute to disease progression in SARS-CoV-2 infected patients. Dendritic cells (DC) are a heterogeneous lineage of antigen presenting cells (APC), which includes different subsets of CD123 hi plasmacytoid DCs (pDC) and conventional (cDC) CD1c + and CD141 + DCs.…”

Section: Introductionmentioning

confidence: 99%

Differential Redistribution of Activated Monocyte and Dendritic Cell Subsets to the Lung Associates with Severity of COVID-19

Sánchez‐Cerrillo¹,

Landete

Aldave

et al. 2020

Preprint

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The SARS-CoV-2 is responsible for the pandemic COVID-19 in infected individuals, who can either exhibit mild symptoms or progress towards a life-threatening acute respiratory distress syndrome (ARDS). It is known that exacerbated inflammation and dysregulated immune responses involving T and myeloid cells occur in COVID-19 patients with severe clinical progression. However, the differential contribution of specific subsets of dendritic cells and monocytes to ARDS is still poorly understood. In addition, the role of CD8 + T cells present in the lung of COVID-19 patients and relevant for viral control has not been characterized. With the aim to improve the knowledge in this area, we developed a cross-sectional study, in which we have studied the frequencies and activation profiles of dendritic cells and monocytes present in the blood of COVID-19 patients with different clinical severity in comparison with healthy control individuals. Furthermore, these subpopulations and their association with antiviral effector CD8 + T cell subsets were also characterized in lung infiltrates from critical COVID-19 patients.Collectively, our results suggest that inflammatory transitional and non-classical monocytes preferentially migrate from blood to lungs in patients with severe COVID-19. CD1c + conventional dendritic cells also followed this pattern, whereas CD141 + conventional and CD123 hi plasmacytoid dendritic cells were depleted from blood but were absent in the lungs. Thus, this study increases the knowledge on the pathogenesis of COVID-19 disease and could be useful for the design of therapeutic strategies to fight SARS-CoV-2 infection.

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Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure

Cited by 1,958 publications

References 14 publications

Deep immune profiling of COVID-19 patients reveals patient heterogeneity and distinct immunotypes with implications for therapeutic interventions

Deep immune profiling of COVID-19 patients reveals patient heterogeneity and distinct immunotypes with implications for therapeutic interventions

SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts

Differential Redistribution of Activated Monocyte and Dendritic Cell Subsets to the Lung Associates with Severity of COVID-19

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