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Front Immunol ; 12: 752612, 2021.
Article in English | MEDLINE | ID: covidwho-1456293


Background: Lymphopenia and the neutrophil/lymphocyte ratio may have prognostic value in COVID-19 severity. Objective: We investigated neutrophil subsets and functions in blood and bronchoalveolar lavage (BAL) of COVID-19 patients on the basis of patients' clinical characteristics. Methods: We used a multiparametric cytometry profiling based to mature and immature neutrophil markers in 146 critical or severe COVID-19 patients. Results: The Discovery study (38 patients, first pandemic wave) showed that 80% of Intensive Care Unit (ICU) patients develop strong myelemia with CD10-CD64+ immature neutrophils (ImNs). Cellular profiling revealed three distinct neutrophil subsets expressing either the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the interleukin-3 receptor alpha (CD123), or programmed death-ligand 1 (PD-L1) overrepresented in ICU patients compared to non-ICU patients. The proportion of LOX-1- or CD123-expressing ImNs is positively correlated with clinical severity, cytokine storm (IL-1ß, IL-6, IL-8, TNFα), acute respiratory distress syndrome (ARDS), and thrombosis. BALs of patients with ARDS were highly enriched in LOX-1-expressing ImN subsets and in antimicrobial neutrophil factors. A validation study (118 patients, second pandemic wave) confirmed and strengthened the association of the proportion of ImN subsets with disease severity, invasive ventilation, and death. Only high proportions of LOX-1-expressing ImNs remained strongly associated with a high risk of severe thrombosis independently of the plasma antimicrobial neutrophil factors, suggesting an independent association of ImN markers with their functions. Conclusion: LOX-1-expressing ImNs may help identifying COVID-19 patients at high risk of severity and thrombosis complications.

COVID-19/complications , Neutrophils/immunology , Scavenger Receptors, Class E/genetics , Thrombosis/etiology , Adult , Aged , B7-H1 Antigen/genetics , B7-H1 Antigen/immunology , Bronchoalveolar Lavage Fluid/immunology , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Critical Illness , Female , Humans , Interleukin-3 Receptor alpha Subunit/genetics , Interleukin-3 Receptor alpha Subunit/immunology , Interleukin-8/genetics , Interleukin-8/immunology , Male , Middle Aged , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/genetics , Respiratory Distress Syndrome/immunology , SARS-CoV-2/physiology , Scavenger Receptors, Class E/immunology , Thrombosis/genetics , Thrombosis/immunology
Cell Commun Signal ; 19(1): 76, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1318284


Hypoxia is a pathological condition common to many diseases, although multiple organ injuries induced by hypoxia are often overlooked. There is increasing evidence to suggest that the hypoxic environment may activate innate immune cells and suppress adaptive immunity, further stimulating inflammation and inhibiting immunosurveillance. We found that dysfunctional immune regulation may aggravate hypoxia-induced tissue damage and contribute to secondary injury. Among the diverse mechanisms of hypoxia-induced immune dysfunction identified to date, the role of programmed death-ligand 1 (PD-L1) has recently attracted much attention. Besides leading to tumour immune evasion, PD-L1 has also been found to participate in the progression of the immune dysfunction which mediates hypoxia-induced multiple organ injury. In this review, we aimed to summarise the role of immune dysfunction in hypoxia-induced multiple organ injury, the effects of hypoxia on the cellular expression of PD-L1, and the effects of upregulated PD-L1 expression on immune regulation. Furthermore, we summarise the latest information pertaining to the involvement, diagnostic value, and therapeutic potential of immunosuppression induced by PD-L1 in various types of hypoxia-related diseases, including cancers, ischemic stroke, acute kidney injury, and obstructive sleep apnoea. Video Abstract.

Adaptive Immunity/genetics , B7-H1 Antigen/immunology , Inflammation/immunology , Tumor Hypoxia/genetics , Acute Kidney Injury/genetics , Acute Kidney Injury/immunology , Adaptive Immunity/immunology , B7-H1 Antigen/genetics , Humans , Immunity, Innate/genetics , Inflammation/genetics , Ischemic Stroke/genetics , Ischemic Stroke/immunology , Monitoring, Immunologic , Neoplasms/genetics , Neoplasms/immunology , Sleep Apnea, Obstructive/genetics , Sleep Apnea, Obstructive/immunology , Tumor Hypoxia/immunology
Cell Immunol ; 364: 104347, 2021 06.
Article in English | MEDLINE | ID: covidwho-1157177


Myeloid-derived suppressor cells (MDSC) are important immune-regulatory cells but their identification remains difficult. Here, we provide a critical view on selected surface markers, transcriptional and translational pathways commonly used to identify MDSC by specific, their developmental origin and new possibilities by transcriptional or proteomic profiling. Discrimination of MDSC from their non-suppressive counterparts is a prerequisite for the development of successful therapies. Understanding the switch mechanisms that direct granulocytic and monocytic development into a pro-inflammatory or anti-inflammatory direction will be crucial for therapeutic strategies. Manipulation of these myeloid checkpoints are exploited by tumors and pathogens, such as M. tuberculosis (Mtb), HIV or SARS-CoV-2, that induce MDSC for immune evasion. Thus, specific markers for MDSC identification may reveal also novel molecular candidates for therapeutic intervention at the level of MDSC.

Biomarkers/metabolism , Gene Expression Profiling/methods , Myeloid-Derived Suppressor Cells/immunology , Proteomics/methods , Signal Transduction/immunology , Animals , B7-H1 Antigen/genetics , B7-H1 Antigen/immunology , B7-H1 Antigen/metabolism , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , Cells, Cultured , Humans , Mice , Myeloid-Derived Suppressor Cells/metabolism , Neoplasms/genetics , Neoplasms/immunology , Neoplasms/metabolism , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/immunology , Programmed Cell Death 1 Receptor/metabolism , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Signal Transduction/genetics , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism
Cells ; 9(10)2020 09 29.
Article in English | MEDLINE | ID: covidwho-982845


COVID-19, caused by SARS-CoV-2 virus, emerged as a pandemic disease posing a severe threat to global health. To date, sporadic studies have demonstrated that innate immune mechanisms, specifically neutrophilia, NETosis, and neutrophil-associated cytokine responses, are involved in COVID-19 pathogenesis; however, our understanding of the exact nature of this aspect of host-pathogen interaction is limited. Here, we present a detailed dissection of the features and functional profiles of neutrophils, dendritic cells, and monocytes in COVID-19. We portray the crucial role of neutrophils as drivers of hyperinflammation associated with COVID-19 disease via the shift towards their immature forms, enhanced degranulation, cytokine production, and augmented interferon responses. We demonstrate the impaired functionality of COVID-19 dendritic cells and monocytes, particularly their low expression of maturation markers, increased PD-L1 levels, and their inability to upregulate phenotype upon stimulation. In summary, our work highlights important data that prompt further research, as therapeutic targeting of neutrophils and their associated products may hold the potential to reduce the severity of COVID-19.

Coronavirus Infections/blood , Dendritic Cells/immunology , Monocytes/immunology , Neutrophils/immunology , Pneumonia, Viral/blood , Adult , Aged , Aged, 80 and over , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , COVID-19 , Cells, Cultured , Coronavirus Infections/immunology , Cytokines/genetics , Cytokines/metabolism , Female , Humans , Immunity, Innate , Immunophenotyping , Male , Middle Aged , Pandemics , Pneumonia, Viral/immunology
Cell Mol Immunol ; 17(9): 995-997, 2020 09.
Article in English | MEDLINE | ID: covidwho-625131

Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Molecular Targeted Therapy/methods , Pneumonia, Viral/immunology , Pneumonia/immunology , Severe Acute Respiratory Syndrome/immunology , Antiviral Agents/therapeutic use , Apyrase/antagonists & inhibitors , Apyrase/genetics , Apyrase/immunology , B-Lymphocytes/immunology , B-Lymphocytes/pathology , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/genetics , B7-H1 Antigen/immunology , Betacoronavirus/immunology , COVID-19 , Case-Control Studies , Coronavirus Infections/drug therapy , Coronavirus Infections/genetics , Coronavirus Infections/virology , Gene Expression/drug effects , Humans , Immunologic Factors/therapeutic use , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , NK Cell Lectin-Like Receptor Subfamily C/antagonists & inhibitors , NK Cell Lectin-Like Receptor Subfamily C/genetics , NK Cell Lectin-Like Receptor Subfamily C/immunology , Pandemics , Pneumonia/drug therapy , Pneumonia/genetics , Pneumonia/virology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/genetics , Pneumonia, Viral/virology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/virology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/pathology