Lower Respiratory Tract Myeloid Cells Harbor SARS-Cov-2 and Display an Inflammatory Phenotype

Bain, William; Peñaloza, Hernán F.; Ladinsky, Mark S.; Geest, Rick van der; Sullivan, Mara; Ross, Mark A.; Kitsios, Georgios D; Methé, Barbara A.; McVerry, Bryan J.; Morris, Alison; Watson, Alan M.; Watkins, Simon C.; Croix, Claudette M. St.; Stolz, Donna B.; Björkman, Pamela J.; Lee, Janet

doi:10.1016/j.chest.2020.10.083

Cited by 12 publications

(9 citation statements)

References 10 publications

(10 reference statements)

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“…Studies of Middle East Respiratory Syndrome (MERS) Coronavirus have demonstrated infection of monocyte-derived macrophages with subsequent secretion of inflammatory cytokines such as CXCL10 and CXCL8 (IL-8)39 . Conversely, SARS-COV abortively infects human macrophages, but triggers production of CXCL10 and CCL240,41 .Consistent with our findings of activated monocytes with induced expression of viral sensing and IFN response genes, an earlier study has shown that lower respiratory tract myeloid cells can harbor SARS-COV-2 and display an inflammatory phenotype42 .Furthermore, recent work demonstrated that infected monocytes in bronchoalveolar lavage samples from patients with COVID-19 participate in a positive feedback loop in which infected myeloid cells produce T cell chemoattractants, recruiting T cells into the lung43 . These T cells then secrete IFN-γ, contributing to release of inflammatory cytokines from alveolar macrophages, thereby promoting further T cell activation43 .…”

supporting

confidence: 91%

Bifurcated monocyte states are predictive of mortality in severe COVID-19

Cillo

Somasundaram

Shan

et al. 2021

Preprint

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Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection presents with varied clinical manifestations, ranging from mild symptoms to acute respiratory distress syndrome (ARDS) with high mortality. Despite extensive analyses, there remains an urgent need to delineate immune cell states that contribute to mortality in severe COVID-19. We performed high-dimensional cellular and molecular profiling of blood and respiratory samples from critically ill COVID-19 patients to define immune cell genomic states that are predictive of outcome in severe COVID-19 disease. Critically ill patients admitted to the intensive care unit (ICU) manifested increased frequencies of inflammatory monocytes and plasmablasts that were also associated with ARDS not due to COVID-19. Single-cell RNAseq (scRNAseq)-based deconvolution of genomic states of peripheral immune cells revealed distinct gene modules that were associated with COVID-19 outcome. Notably, monocytes exhibited bifurcated genomic states, with expression of a cytokine gene module exemplified by CCL4 (MIP-1β) associated with survival and an interferon signaling module associated with death. These gene modules were correlated with higher levels of MIP-1β and CXCL10 levels in plasma, respectively. Monocytes expressing genes reflective of these divergent modules were also detectable in endotracheal aspirates. Machine learning algorithms identified the distinctive monocyte modules as part of a multivariate peripheral immune system state that was predictive of COVID-19 mortality. Follow-up analysis of the monocyte modules on ICU day 5 was consistent with bifurcated states that correlated with distinct inflammatory cytokines. Our data suggests a pivotal role for monocytes and their specific inflammatory genomic states in contributing to mortality in life-threatening COVID-19 disease and may facilitate discovery of new diagnostics and therapeutics.

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supporting

confidence: 91%

Bifurcated monocyte states are predictive of mortality in severe COVID-19

Cillo

Somasundaram

Shan

et al. 2021

Preprint

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“…These findings are relevant as MP-TF positively correlates with leukocytes, D-dimer, inflammatory parameters, and is associated with an increased thrombotic risk, disease severity and mortality in SARS-CoV-2 [67,68]. With respect to cellular sources for TF, there is evidence for participation of neutrophils [21], platelet-monocyte aggregates and [28] macrophages [69] although transcripts for TF were not upregulated in monocytes in SARS-CoV-2 [38], in contrast with sepsis [17,51,70]. At last, our univariate analysis supports the view that coagulation dysregulation in COVID-19 infection has a multifactorial etiology.…”

Section: Discussionmentioning

confidence: 87%

Upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in SARS-CoV-2 infection

et al. 2021

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Background: SARS-CoV-2 infection is associated with thrombotic and microvascular complications. The cause of coagulopathy in the disease is incompletely understood. Methods: A single-center cross-sectional study including 66 adult COVID-19 patients (40 moderate, 26 severe disease), and 9 controls, performed between 04/2020 and 10/2020. Markers of coagulation, endothelial cell function [angiopoietin-1,-2, P-selectin, von Willebrand Factor Antigen (WF:Ag), von Willebrand Factor Ristocetin Cofactor, ADAMTS13, thrombomodulin, soluble Endothelial cell Protein C Receptor (sEPCR), Tissue Factor Pathway Inhibitor], neutrophil activation (elastase, citrullinated histones) and fibrinolysis (tissue-type plasminogen activator, plasminogen activator inhibitor-1) were evaluated using ELISA. Tissue Factor (TF) was estimated by antithrombin-FVIIa complex (AT/FVIIa) and microparticles-TF (MP-TF). We correlated each marker and determined its association with severity. Expression of pulmonary TF, thrombomodulin and EPCR was determined by immunohistochemistry in 9 autopsies. Findings: Comorbidities were frequent in both groups, with older age associated with severe disease. All patients were on prophylactic anticoagulants. Three patients (4.5%) developed pulmonary embolism. Mortality was 7.5%. Patients presented with mild alterations in the coagulogram (compensated state). Biomarkers of endothelial cell, neutrophil activation and fibrinolysis were elevated in severe vs moderate disease; AT/ FVIIa and MP-TF levels were higher in severe patients. Logistic regression revealed an association of Ddimers, angiopoietin-1, vWF:Ag, thrombomodulin, white blood cells, absolute neutrophil count (ANC) and hemoglobin levels with severity, with ANC and vWF:Ag identified as independent factors. Notably, postmortem specimens demonstrated epithelial expression of TF in the lung of fatal COVID-19 cases with loss of thrombomodulin staining, implying in a shift towards a procoagulant state. Interpretation: Coagulation dysregulation has multifactorial etiology in SARS-Cov-2 infection. Upregulation of pulmonary TF with loss of thrombomodulin emerge as a potential link to immunothrombosis, and therapeutic targets in the disease.

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“…Earlier studies have highlighted the paramount role of myeloid antigen-presenting cells (APCs), such as macrophages and dendritic cells (DCs), in mediating an antiviral inflammatory response, which is exacerbated in severe COVID-19 cases (Bain et al, 2021;Merad and Martin, 2020). A critical role of lung macrophages in inducing the inflammation associated with the pathologic sequelae of SARS-CoV-2 infection has been confirmed also in nonhuman primates (NHP) (Hoang et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Siglec-1 on dendritic cells mediates SARS-CoV-2 trans-infection of target cells while on macrophages triggers proinflammatory responses

Perez-Zsolt

Basagoiti

Rodó

et al. 2021

Preprint

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COVID-19 pandemic is not yet under control by vaccination, and effective antivirals are critical for preparedness. Here we report that macrophages and dendritic cells, key antigen presenting myeloid cells (APCs), are largely resistant to SARS-CoV-2 infection. APCs effectively captured viruses within cellular compartments that lead to antigen degradation. Macrophages sense SARS-CoV-2 and released higher levels of cytokines, including those related to cytokine storm in severe COVID-19. The sialic acid-binding Ig-like lectin 1 (Siglec-1/CD169) present on APCs, which interacts with sialylated gangliosides on membranes of retroviruses or filoviruses, also binds SARS-CoV-2 via GM1. Blockage of Siglec-1 receptors by monoclonal antibodies reduces SARS-CoV-2 uptake and transfer to susceptible target cells. APCs expressing Siglec-1 and carrying SARS-CoV-2 are found in pulmonary tissues of non-human primates. Single cell analysis reveals the in vivo induction of cytokines in those macrophages. Targeting Siglec-1 could offer cross-protection against SARS-CoV-2 and other enveloped viruses that exploit APCs for viral dissemination, including those yet to come in future outbreaks.

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Lower Respiratory Tract Myeloid Cells Harbor SARS-Cov-2 and Display an Inflammatory Phenotype

Cited by 12 publications

References 10 publications

Bifurcated monocyte states are predictive of mortality in severe COVID-19

Bifurcated monocyte states are predictive of mortality in severe COVID-19

Upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in SARS-CoV-2 infection

Siglec-1 on dendritic cells mediates SARS-CoV-2 trans-infection of target cells while on macrophages triggers proinflammatory responses

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