Dexamethasone modulates immature neutrophils and interferon programming in severe COVID-19

Sinha, Sarthak; Rosin, Nicole L.; Arora, Rohit; Labit, Elodie; Jaffer, Arzina; Cao, Leslie; Farias, Raquel; Nguyen, Antoinette; Almeida, Luiz G. N. de; Dufour, Antoine; Bromley, Amy; McDonald, Braedon; Gillrie, Mark R.; Fritzler, Marvin J.; Yipp, Bryan G.; Biernaskie, Jeff

doi:10.1038/s41591-021-01576-3

Cited by 181 publications

(177 citation statements)

References 82 publications

(108 reference statements)

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“…Second, our observations are limited to a single center study, hence further prospective multi-center studies with larger patient samples specifically looking at the correlation between elevated levels of certain cytokines as well as the potential beneficial role of corticosteroid treatment and the risk for developing bacterial superinfections are required to elaborate and verify the observations from our study. 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].…”

Section: Plos Pathogensmentioning

confidence: 58%

“…Even though corticosteroid treatment was widely used during previous viral pandemics, such as influenza [76][77][78], SARS-CoV [79,80] and MERS-CoV [81], its use remains controversial [82], since observational studies reported increased mortality and nosocomial infections during influenza [83,84], and delayed clearance of SARS-CoV and MERS-CoV [85,86]. So far, only a limited number of published studies on the mechanistic effects of corticosteroid therapy in COVID-19 is available [87]. However, a few studies reported improved clinical symptoms and oxygenation, reduced length of hospitalization and ICU stay as well as lower 28-day mortality among patients with invasive mechanical ventilation [6,32,40,[88][89][90].…”

Section: Plos Pathogensmentioning

confidence: 99%

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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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Section: Plos Pathogensmentioning

confidence: 58%

Section: Plos Pathogensmentioning

confidence: 99%

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

et al. 2022

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“…Increased pro-inflammatory cytokines [1][2][3][4] , deficient type I interferon (IFN) responses [5][6][7] , activation of inflammasomes 8 , neutrophils [9][10][11] , and monocytes/macrophages 1,2,[11][12][13][14] have all been associated with severe COVID-19. Coordinated activation of CD8 and CD4 T cells, T cell activation state, and antigen (Ag)-specificity have all been linked to favorable outcomes of SARS-CoV-2 infection [15][16][17][18][19][20] .…”

Section: Introductionmentioning

confidence: 99%

Mild SARS-CoV-2 infection in rhesus macaques is associated with viral control prior to antigen-specific T cell responses in tissues

Nelson

Namasivayam

Foreman

et al. 2022

Preprint

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SARS-CoV-2 primarily replicates in mucosal sites, and more information is needed about immune responses in infected tissues. We used rhesus macaques to model protective primary immune responses in tissues during mild COVID-19. Viral RNA levels were highest on days 1-2 post-infection and fell precipitously thereafter. 18F-fluorodeoxyglucose (FDG)-avid lung abnormalities and interferon (IFN)-activated myeloid cells in the bronchoalveolar lavage (BAL) were found on days ~3-4. Virus-specific effector CD8 and CD4 T cells were detectable in the BAL and lung tissue on days ~7-10, after viral RNA, lung inflammation, and IFN-activated myeloid cells had declined. Notably, SARS-CoV-2-specific T cells were not detectable in the nasal turbinates, salivary glands, and tonsils on day 10 post-infection. Thus, SARS-CoV-2 replication wanes in the lungs prior to T cell responses, and in the nasal and oral mucosa despite the apparent lack of Ag-specific T cells, suggesting that innate immunity efficiently restricts viral replication during mild COVID-19.

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“…Females, on the other hand, "had a considerably more tempered neutrophil interferon response, therefore dexamethasone had less impact." Dexamethasone showed different effects according to sex, which could have serious consequences for sex-dependent outcomes and treatment efficacy in severe COVID-19 symptoms [5].…”

Section: Main Bodymentioning

confidence: 99%

Dexamethasone is a gold weapon for immunomodulation in severe COVID-19 but has no effect on endocrine interleukin 6 and sex-linked response the problem – In silico study

Ahmed¹,

Kazzaz

2021

Preprint

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Nearly two years after the lethal pandemic of COVID-19, which is considered a joker virus that may bypasses many immune defenses in our bodies such as innate and adaptive immunity, with all types of cells, there are important markers at the long road for treatment, such as interleukin (Il-6), neutrophils, high ferritin, and high D dimer. Additionally, post COVID-19 or long COVID-19 effects include neuropsychiatric problems such as smell dysfunctions and hormonal dysfunctions. Therefore, this article will highlight the adrenal gland as a place where the immune and endocrine systems meet. Additionally, dexamethasone has no effect on Il-6 secreted from the adrenal cortex, which allows Il-6 to be produced during stress. We need a new classification of IL-6 at physiological and pathological aspects, as the stimulatory factors are different. Endocrine Il-6 is stimulated by ACTH, but immune Il-6 is stimulated by il-1β and angiotensin II. Of note, dexamethasone saves critically COVID-19 patients but has no effect on Il-6 of endocrine origin, either basal or stimulated. Therefore, the adrenal gland serves as a vital link between the endocrine and immunological systems the pathogenesis of COVID-19.The importance of synergistic actions of cytokines in HPA axis stimulation has been demonstrated by several studies. Viruses that induce early, innate NK cell-mediated anti-viral defenses, characterized by early proinflammatory cytokine production, cellular infiltration, and inflammation, tend to produce early glucocorticoid responses, thereby protecting the host from pro inflammatory cytokine-mediated pathology. Viral infections, in general, are physiologically stressful, as indicated by the concomitant activation of the HPA axis. That substances released from the adrenal gland could affect immune function was one of the initial indications that there are meaningful interactions between the neuroendocrine and immune systems In addition, Il-6 is the key sex-linked variation in immune responses. by molecular docking Binding interaction dexamethasone with interleukin6. It shows binding affinity was found -6.7 Kcal/mol

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Dexamethasone modulates immature neutrophils and interferon programming in severe COVID-19

Cited by 181 publications

References 82 publications

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

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

Mild SARS-CoV-2 infection in rhesus macaques is associated with viral control prior to antigen-specific T cell responses in tissues

Dexamethasone is a gold weapon for immunomodulation in severe COVID-19 but has no effect on endocrine interleukin 6 and sex-linked response the problem – In silico study

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