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

Nature Medicine, Journal Year: 2021, Volume and Issue: 28(1), P. 201 - 211

Published: Nov. 15, 2021

Abstract Although critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate dynamics during Coronavirus Disease 2019 (COVID-19) ARDS, compared to ARDS from other pathogens, is unclear. Moreover, mechanisms underlying the beneficial effects dexamethasone severe COVID-19 remain elusive. Using single-cell RNA sequencing and plasma proteomics, we discovered that, bacterial was associated with expansion distinct neutrophil states characterized by interferon (IFN) prostaglandin signaling. Dexamethasone affected circulating neutrophils, altered IFN active downregulated interferon-stimulated genes activated IL-1R2 + neutrophils. expanded immunosuppressive immature neutrophils remodeled cellular interactions changing information receivers into providers. Male patients had higher proportions preferential steroid-induced expansion, potentially affecting outcomes. Our atlas (see ‘Data availability’ section) defines COVID-19-enriched molecular action develop targeted immunotherapies COVID-19.

Language: Английский

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Innate immunological pathways in COVID-19 pathogenesis

Science Immunology, Journal Year: 2022, Volume and Issue: 7(67)

Published: Jan. 7, 2022

Coronavirus disease 2019 (COVID-19) is a characterized by profound dysregulation of the innate immune system. This knowledge has emerged from large body single-cell omics studies patients with COVID-19, which have provided one most detailed cellular atlases human ever. However, we are only beginning to understand immunological pathways that govern host defense and immunopathology in COVID-19. In this review, discuss emerging understanding how SARS-CoV-2 host-derived molecules activate specific pattern recognition receptors elicit protective interferon responses pathological cytokine responses, particular focus on acute infection lung pathophysiology critical addition, these modulated virus-host interactions stress-sensing pathways. In-depth mechanisms will likely uncover molecular targets for treatment COVID-19 other viral infections. it reveal fine balance between beneficial versus causing responses.

Language: Английский

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The role of neutrophil extracellular traps in acute lung injury

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: July 29, 2022

Acute lung injury (ALI) is a heterogeneous inflammatory condition associated with high morbidity and mortality. Neutrophils play key role in the development of different forms ALI, release neutrophil extracellular traps (NETs) emerging as common pathogenic mechanism. NETs are essential controlling pathogens, their defective or increased degradation leads to higher risk infection. However, also contain several pro-inflammatory cytotoxic molecules than can exacerbate thromboinflammation tissue injury. To reduce NET-mediated damage inflammation, DNase frequently used preclinical models ALI due its capability digesting NET DNA scaffold. Moreover, recent advances biology led selective inhibitors, which appear experimental models. Here we provide an overview discussing existing gaps our knowledge novel therapeutic approaches modulate impact on

Language: Английский

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COVID-19 and cellular senescence

Nature reviews. Immunology, Journal Year: 2022, Volume and Issue: 23(4), P. 251 - 263

Published: Oct. 5, 2022

Language: Английский

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Immunosuppressive reprogramming of neutrophils by lung mesenchymal cells promotes breast cancer metastasis

Science Immunology, Journal Year: 2023, Volume and Issue: 8(80)

Published: Feb. 3, 2023

Neutrophils, the most abundant innate immune cells, function as crucial regulators of adaptive system in diverse pathological conditions, including metastatic cancer. However, it remains largely unknown whether their immunomodulatory functions are intrinsic or acquired within tissue environment. Here, using mouse models breast cancer lungs, we show that, although neutrophils isolated from bone marrow (BM) blood minimally immunosuppressive, lung-infiltrating robustly suppressive both T cells and natural killer (NK) cells. We found that this tissue-specific immunosuppressive capacity exists steady state is reinforced by tumor-associated inflammation. Acquisition potent immunosuppression activity was endowed lung-resident stroma, specifically CD140a + mesenchymal (MCs) via prostaglandin-endoperoxide synthase 2 (PTGS2), rate-limiting enzyme for prostaglandin E (PGE ) biosynthesis. MC-specific deletion Ptgs2 pharmacological inhibition PGE receptors reversed lung neutrophil–mediated mitigated metastasis vivo. These stroma–targeting strategies substantially improved therapeutic efficacy adoptive cell–based immunotherapy treating disease mice. Collectively, our results reveal immunoregulatory effects induced tissue-resident stroma targeting stromal factors represents an effective approach to boost immunity against disease.

Language: Английский

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Neutrophils in COVID-19: recent insights and advances

Virology Journal, Journal Year: 2023, Volume and Issue: 20(1)

Published: Aug. 2, 2023

Abstract Coronavirus disease 2019 (COVID-19) is an acute respiratory caused by severe syndrome coronavirus 2 (SARS-CoV-2), which can lead to distress (ARDS), multi-organ failure and death, posing significant threat human health. Studies have found that pathological mechanisms, such as cytokine storms uncontrolled innate immune system activation, release of damage-associated molecular patterns during tissue injury a high incidence thrombotic events, are associated with the function dysfunction neutrophils. Specifically, increased formation low-density neutrophils (LDNs) neutrophil extracellular traps (NETs) has been shown be closely linked severity poor prognosis in patients COVID-19. Our work focuses on understanding number, abnormal lung infiltration, elevated neutrophil-to-lymphocyte ratio pathogenesis We also explore involvement NETs LDNs progression thrombosis formation, along potential therapeutic strategies targeting formation.

Language: Английский

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Aging, inflammaging and immunosenescence as risk factors of severe COVID-19

Immunity & Ageing, Journal Year: 2022, Volume and Issue: 19(1)

Published: Nov. 11, 2022

Abstract Coronavirus disease 2019 (COVID-19) is a respiratory infectious caused by the novel severe acute syndrome coronavirus 2 (SARS-CoV-2). COVID-19 characterized having heterogeneous course, ranging from asymptomatic and mild symptoms to more critical cases. In most cases severity of related host factors, especially deregulation immune response in patients. Even if indiscriminately affects individuals different age group, ethnicity economic status; disproportional mortality occur elderly individuals. This point out that aging one risk factor for unfavourable clinical outcomes among The biology complex process; Aging can alter structure function cells, tissues, organs resulting impaired stress. Alongside with other systems, system also affected process. Immunosenescence an associated change overall immunological challenges elderly. Similarly, apart normal inflammatory process, low grade, sterile, chronic inflammation which termed as inflammaging. We hypothesized inflammaging immunosenescence could play important role SARS-CoV-2 pathogenesis poor recovery review summarizes changes how these part outcome add understanding targeted immunotherapy

Language: Английский

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Autoantibodies in COVID‐19 correlate with antiviral humoral responses and distinct immune signatures

Allergy, Journal Year: 2022, Volume and Issue: 77(8), P. 2415 - 2430

Published: April 1, 2022

Several autoimmune features occur during coronavirus disease 2019 (COVID-19), with possible implications for course, immunity, and pathology. In this study, we longitudinally screened clinically relevant systemic autoantibodies to assess their prevalence, temporal trajectory, association comorbidities, severity of COVID-19.We performed highly sensitive indirect immunofluorescence assays detect antinuclear antibodies (ANA) antineutrophil cytoplasmic (ANCA), along serum proteomics virome-wide serological profiling in a multicentric cohort 175 COVID-19 patients followed up 1 year after infection, eleven vaccinated individuals, 41 unexposed controls.Compared healthy controls, similar prevalence patterns ANA were present acute recovery. However, the paired analysis revealed subgroup transient presence certain COVID-19. Furthermore, severe exhibited high ANCA disease. These quantitatively associated higher SARS-CoV-2-specific antibody titers thus linking autoantibody production increased antigen-specific humoral responses. Notably, qualitative breadth cross-reactive other coronaviruses was comparable ANA-positive ANA-negative individuals autoantibody-positive patients, multiparametric characterization demonstrated an inflammatory signature alterations B-cell compartment recovery.Highly SARS-CoV-2 while correlated antiviral immune responses signatures.

Language: Английский

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

Cell Reports Medicine, Journal Year: 2022, Volume and Issue: 3(10), P. 100779 - 100779

Published: Sept. 26, 2022

Mechanisms of neutrophil involvement in severe coronavirus disease 2019 (COVID-19) remain incompletely understood. Here, we collect longitudinal blood samples from 306 hospitalized COVID-19+ patients and 86 controls perform bulk RNA sequencing enriched neutrophils, plasma proteomics, high-throughput antibody profiling to investigate relationships between states severity. We identify dynamic switches six distinct subtypes. At days 3 7 post-hospitalization, with display a granulocytic myeloid-derived suppressor cell-like gene expression signature, while resolving show progenitor-like signature. Humoral responses are identified as potential drivers effector functions, elevated acute respiratory syndrome 2 (SARS-CoV-2)-specific immunoglobulin G1 (IgG1)-to-IgA1 ratios who survived. In vitro experiments confirm that patient-derived IgG antibodies induce phagocytosis healthy donor IgA predominantly cell death. Overall, our study demonstrates dysregulated myelopoietic response COVID-19 role for IgA-dominant contributing mortality.

Language: Английский

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Programmed cell death: the pathways to severe COVID-19?

Biochemical Journal, Journal Year: 2022, Volume and Issue: 479(5), P. 609 - 628

Published: March 4, 2022

Two years after the emergence of SARS-CoV-2, our understanding COVID-19 disease pathogenesis is still incomplete. Despite unprecedented global collaborative scientific efforts and rapid vaccine development, an uneven roll-out novel variants concern such as omicron underscore critical importance identifying mechanisms that contribute to this disease. Overt inflammation cell death have been proposed be central drivers severe pathology in patients their pathways molecular components therefore present promising targets for host-directed therapeutics. In review, we summarize current knowledge on role impact diverse programmed (PCD) We dissect complex connection inflammatory signaling at cellular level identify a number questions remain addressed. provide rationale targeting potential treatment overview therapeutics could potentially enter clinical trials near future.

Language: Английский

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