Longitudinal characterization of circulating neutrophils uncovers distinct phenotypes associated with disease severity in hospitalized COVID-19 patients

LaSalle, Thomas J.; Gonye, Anna L.K.; Freeman, Samuel S.; Kapłonek, Paulina; Gushterova, Irena; Kays, Kyle R.; Manakongtreecheep, Kasidet; Tantivit, Jessica; Rojas-López, Maricarmen; Russo, Brian C.; Sharma, Nihaarika; Thomas, Molly; Lavin-Parsons, Kendall M.; Lilly, Brendan M.; McKaig, Brenna; Charland, Nicole C.; Khanna, Hargun K.; Lodenstein, Carl L.; Margolin, Justin D.; Blaum, Emily M.; Lirofonis, Paola B.; Sonny, Abraham; Bhattacharyya, Roby P.; Parry, Blair A.; Goldberg, Marcia B.; Alter, Galit; Filbin, Michael R.; Villani, Alexandra Chloé; Hacohen, Nir; Sade-Feldman, Moshe

doi:10.1101/2021.10.04.463121

Cited by 5 publications

(3 citation statements)

References 89 publications

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“…Conversely, IRF8 suppresses neutrophil generation (34). Consistent with this finding, increased absolute neutrophil counts have been associated with severe but not mild COVID-19 (35). These data are consistent with the notion that in mild patients, viral infection may directly stimulate appropriate selected ISGs responses, including CXCL10, and activate IFNa production that bridges innate and adaptive immunity through skewing DC differentiation/activation, towards the priming and expansion of Th1 cells, i.e.…”

Section: Discussionsupporting

confidence: 80%

Antiviral innate immunity is diminished in the upper respiratory tract of severe COVID-19 patients

Ramos‐Benitez

Strich

Alehashemi

et al. 2022

Preprint

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Understanding early innate immune responses to coronavirus disease 2019 (COVID‐19) is crucial to developing targeted therapies to mitigate disease severity. Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection elicits interferon expression leading to transcription of IFN-stimulated genes (ISGs) to control viral replication and spread. SARS-CoV-2 infection also elicits NF-κB signaling which regulates inflammatory cytokine expression contributing to viral control and likely disease severity. Few studies have simultaneously characterized these two components of innate immunity to COVID-19. We designed a study to characterize the expression of interferon alpha-2 (IFNA2) and interferon beta-1 (IFNB1), both type-1 interferons (IFN-1), interferon-gamma (IFNG), a type-2 interferon (IFN-2), ISGs, and NF-κB response genes in the upper respiratory tract (URT) of patients with mild (outpatient) versus severe (hospitalized) COVID-19. Further, we characterized the weekly dynamics of these responses in the upper and lower respiratory tracts (LRTs) and blood of severe patients to evaluate for compartmental differences. We observed significantly increased ISG and NF-κB responses in the URT of mild compared with severe patients early during illness. This pattern was associated with increased IFNA2 and IFNG expression in the URT of mild patients, a trend toward increased IFNB1-expression and significantly increased STING/IRF3/cGAS expression in the URT of severe patients. Our by-week across-compartment analysis in severe patients revealed significantly higher ISG responses in the blood compared with the URT and LRT of these patients during the first week of illness, despite significantly lower expression of IFNA2, IFNB1, and IFNG in blood. NF-κB responses, however, were significantly elevated in the LRT compared with the URT and blood of severe patients during peak illness (week 2). Our data support that severe COVID-19 is associated with impaired interferon signaling in the URT during early illness and robust pro-inflammatory responses in the LRT during peak illness.

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Section: Discussionsupporting

confidence: 80%

Antiviral innate immunity is diminished in the upper respiratory tract of severe COVID-19 patients

Ramos‐Benitez

Strich

Alehashemi

et al. 2022

Preprint

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“…Third, in a recent study it was shown that dexamethasone treatment in COVID-19 patients affected circulating neutrophils, altered their IFN signaling and expanded immature neutrophils [87]. Similarly, increase in abnormal/immature neutrophils in the blood stream during severe COVID-19 has been observed by previous studies [20,22,27,53]. Whether the hyperinflammatory environment as well as dexamethasone treatment specifically effects the functional responses of these immature neutrophils against bacterial infection is largely unknown.…”

Section: Plos Pathogensmentioning

confidence: 82%

Hyperinflammatory environment drives dysfunctional myeloid cell effector response to bacterial challenge in COVID-19

et al. 2022

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COVID-19 displays diverse disease severities and symptoms including acute systemic inflammation and hypercytokinemia, with subsequent dysregulation of immune cells. Bacterial superinfections in COVID-19 can further complicate the disease course and are associated with increased mortality. However, there is limited understanding of how SARS-CoV-2 pathogenesis and hypercytokinemia impede the innate immune function against bacterial superinfections. We assessed the influence of COVID-19 plasma hypercytokinemia on the functional responses of myeloid immune cells upon bacterial challenges from acute-phase COVID-19 patients and their corresponding recovery (rec)-phase. We show that a severe hypercytokinemia status in COVID-19 patients correlates with the development of bacterial superinfections. Neutrophils and monocytes derived from COVID-19 patients in their acute-phase showed an impaired intracellular microbicidal capacity upon bacterial challenges. The impaired microbicidal capacity was reflected by abrogated MPO and reduced NETs production in neutrophils along with reduced ROS production in both neutrophils and monocytes. Moreover, we observed a distinct pattern of cell surface receptor expression on both neutrophils and monocytes, in line with suppressed autocrine and paracrine cytokine signaling. This phenotype was characterized by a high expression of CD66b, CXCR4 and low expression of CXCR1, CXCR2 and CD15 in neutrophils and low expression of HLA-DR, CD86 and high expression of CD163 and CD11b in monocytes. Furthermore, the impaired antibacterial effector function was mediated by synergistic effect of the cytokines TNF-α, IFN-γ and IL-4. COVID-19 patients receiving dexamethasone showed a significant reduction of overall inflammatory markers in the plasma as well as exhibited an enhanced immune response towards bacterial challenge ex vivo. Finally, broad anti-inflammatory treatment was associated with a reduction in CRP, IL-6 levels as well as length of ICU and hospital stay in critically ill COVID-19 patients. Our data provides insights into the transient functional dysregulation of myeloid immune cells against subsequent bacterial infections in COVID-19 patients and describe a beneficial role for the use of dexamethasone in these patients.

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“…Altered myeloid cell expression states, including the accumulation of cells with hallmarks of myeloid-derived suppressor cells (MDSC), are consistent features in the blood of COVID-19 patients, and serve as a hallmark of severity [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] . Monocytes and granulocytes associated with increased COVID-19 severity exhibit low expression of HLA-DR, and high expression of hallmark MDSC genes such as S100A12 (EN-RAGE), and can impair T cell activation via contactdependent (i.e., PD-L1) and soluble mechanisms, including IL-10, TGF-β, arginase 1, IDOdependent tryptophan metabolism, and reactive oxygen and nitrogen species (reviewed in [19][20][21][22] ).…”

Section: Introductionmentioning

confidence: 99%

A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling

Hackney¹,

Shivram²,

Heiden³

et al. 2022

Preprint

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Altered myeloid inflammation and lymphopenia are hallmarks of severe infections, including with SARS-CoV-2. Here, we identified a gene program, defined by correlation with EN-RAGE (S100A12) gene expression, which was up-regulated in airway and blood myeloid cells from COVID-19 patients. The EN-RAGE program was expressed in 7 cohorts and observed in patients with both COVID-19 and acute respiratory distress syndrome (ARDS) from other causes. This program was associated with greater clinical severity and predicted future mechanical ventilation and death. EN-RAGE+ myeloid cells express features consistent with suppressor cell functionality, with low HLA-DR and high PD-L1 surface expression and higher expression of T cell-suppressive genes. Sustained EN-RAGE signature expression in airway and blood myeloid cells correlated with clinical severity and increasing expression of T cell exhaustion markers, such as PD-1. IL-6 treatment of monocytes in vitro upregulated many of the severity-associated genes in the EN-RAGE gene program, along with potential mediators of T cell suppression, such as IL-10. Blockade of IL-6 signaling by tocilizumab in a placebo-controlled clinical trial led to a rapid normalization of ENRAGE and T cell gene expression. This identifies IL-6 as a key driver of myeloid dysregulation associated with worse clinical outcomes in COVID-19 patients and provides insights into shared pathophysiological mechanisms in non-COVID-19 ARDS.

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Longitudinal characterization of circulating neutrophils uncovers distinct phenotypes associated with disease severity in hospitalized COVID-19 patients

Cited by 5 publications

References 89 publications

Antiviral innate immunity is diminished in the upper respiratory tract of severe COVID-19 patients

Antiviral innate immunity is diminished in the upper respiratory tract of severe COVID-19 patients

Hyperinflammatory environment drives dysfunctional myeloid cell effector response to bacterial challenge in COVID-19

A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling

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