Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 28
Filter
1.
Proc Natl Acad Sci U S A ; 119(1)2022 01 04.
Article in English | MEDLINE | ID: covidwho-1595265

ABSTRACT

Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) provokes a potentially fatal pneumonia with multiorgan failure, and high systemic inflammation. To gain mechanistic insight and ferret out the root of this immune dysregulation, we modeled, by in vitro coculture, the interactions between infected epithelial cells and immunocytes. A strong response was induced in monocytes and B cells, with a SARS-CoV-2-specific inflammatory gene cluster distinct from that seen in influenza A or Ebola virus-infected cocultures, and which reproduced deviations reported in blood or lung myeloid cells from COVID-19 patients. A substantial fraction of the effect could be reproduced after individual transfection of several SARS-CoV-2 proteins (Spike and some nonstructural proteins), mediated by soluble factors, but not via transcriptional induction. This response was greatly muted in monocytes from healthy children, perhaps a clue to the age dependency of COVID-19. These results suggest that the inflammatory malfunction in COVID-19 is rooted in the earliest perturbations that SARS-CoV-2 induces in epithelia.


Subject(s)
COVID-19/immunology , Epithelial Cells/immunology , Monocytes/immunology , SARS-CoV-2/pathogenicity , Adult , B-Lymphocytes/immunology , COVID-19/pathology , Child , Coculture Techniques , Ebolavirus/pathogenicity , Epithelial Cells/virology , Gene Expression Profiling , Humans , Inflammation , Influenza A virus/pathogenicity , Lung/immunology , Myeloid Cells/immunology , Species Specificity , Viral Proteins/immunology
2.
Front Immunol ; 12: 738093, 2021.
Article in English | MEDLINE | ID: covidwho-1518484

ABSTRACT

Disease caused by SARS-CoV-2 coronavirus (COVID-19) led to significant morbidity and mortality worldwide. A systemic hyper-inflammation characterizes severe COVID-19 disease, often associated with acute respiratory distress syndrome (ARDS). Blood biomarkers capable of risk stratification are of great importance in effective triage and critical care of severe COVID-19 patients. Flow cytometry and next-generation sequencing were done on peripheral blood cells and urokinase-type plasminogen activator receptor (suPAR), and cytokines were measured from and mass spectrometry-based proteomics was done on plasma samples from an Indian cohort of COVID-19 patients. Publicly available single-cell RNA sequencing data were analyzed for validation of primary data. Statistical analyses were performed to validate risk stratification. We report here higher plasma abundance of suPAR, expressed by an abnormally expanded myeloid cell population, in severe COVID-19 patients with ARDS. The plasma suPAR level was found to be linked to a characteristic plasma proteome, associated with coagulation disorders and complement activation. Receiver operator characteristic curve analysis to predict mortality identified a cutoff value of suPAR at 1,996.809 pg/ml (odds ratio: 2.9286, 95% confidence interval 1.0427-8.2257). Lower-than-cutoff suPAR levels were associated with a differential expression of the immune transcriptome as well as favorable clinical outcomes, in terms of both survival benefit (hazard ratio: 0.3615, 95% confidence interval 0.1433-0.912) and faster disease remission in our patient cohort. Thus, we identified suPAR as a key pathogenic circulating molecule linking systemic hyperinflammation to the hypercoagulable state and stratifying clinical outcomes in severe COVID-19 patients with ARDS.


Subject(s)
COVID-19/blood , Receptors, Urokinase Plasminogen Activator/blood , SARS-CoV-2 , Adult , Aged , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/immunology , Blood Proteins/analysis , COVID-19/immunology , Cytokines/blood , Humans , Inflammation/blood , Inflammation/immunology , Middle Aged , Myeloid Cells/immunology , Proteome/analysis , Randomized Controlled Trials as Topic , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/immunology , Severity of Illness Index , Young Adult
3.
Signal Transduct Target Ther ; 6(1): 372, 2021 10 27.
Article in English | MEDLINE | ID: covidwho-1493075

ABSTRACT

Varying differentiation of myeloid cells is common in tumors, inflammation, autoimmune diseases, and metabolic diseases. The release of cytokines from myeloid cells is an important driving factor that leads to severe COVID-19 cases and subsequent death. This review briefly summarizes the results of single-cell sequencing of peripheral blood, lung tissue, and cerebrospinal fluid of COVID-19 patients and describes the differentiation trajectory of myeloid cells in patients. Moreover, we describe the function and mechanism of abnormal differentiation of myeloid cells to promote disease progression. Targeting myeloid cell-derived cytokines or checkpoints is essential in developing a combined therapeutic strategy for patients with severe COVID-19.


Subject(s)
COVID-19/immunology , Cell Differentiation/immunology , Cellular Microenvironment/immunology , Myeloid Cells/immunology , SARS-CoV-2/immunology , Animals , COVID-19/therapy , Humans , Myeloid Cells/virology , Single-Cell Analysis
4.
Mol Syst Biol ; 17(10): e10387, 2021 10.
Article in English | MEDLINE | ID: covidwho-1478718

ABSTRACT

We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.


Subject(s)
COVID-19/immunology , Computational Biology/methods , Databases, Factual , SARS-CoV-2/immunology , Software , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/genetics , COVID-19/virology , Computer Graphics , Cytokines/genetics , Cytokines/immunology , Data Mining/statistics & numerical data , Gene Expression Regulation , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , Immunity, Cellular/drug effects , Immunity, Humoral/drug effects , Immunity, Innate/drug effects , Lymphocytes/drug effects , Lymphocytes/immunology , Lymphocytes/virology , Metabolic Networks and Pathways/genetics , Metabolic Networks and Pathways/immunology , Myeloid Cells/drug effects , Myeloid Cells/immunology , Myeloid Cells/virology , Protein Interaction Mapping , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Signal Transduction , Transcription Factors/genetics , Transcription Factors/immunology , Viral Proteins/genetics , Viral Proteins/immunology
5.
Immunity ; 54(4): 753-768.e5, 2021 04 13.
Article in English | MEDLINE | ID: covidwho-1385739

ABSTRACT

Viral infections induce a conserved host response distinct from bacterial infections. We hypothesized that the conserved response is associated with disease severity and is distinct between patients with different outcomes. To test this, we integrated 4,780 blood transcriptome profiles from patients aged 0 to 90 years infected with one of 16 viruses, including SARS-CoV-2, Ebola, chikungunya, and influenza, across 34 cohorts from 18 countries, and single-cell RNA sequencing profiles of 702,970 immune cells from 289 samples across three cohorts. Severe viral infection was associated with increased hematopoiesis, myelopoiesis, and myeloid-derived suppressor cells. We identified protective and detrimental gene modules that defined distinct trajectories associated with mild versus severe outcomes. The interferon response was decoupled from the protective host response in patients with severe outcomes. These findings were consistent, irrespective of age and virus, and provide insights to accelerate the development of diagnostics and host-directed therapies to improve global pandemic preparedness.


Subject(s)
Immunity/genetics , Virus Diseases/immunology , Antigen Presentation/genetics , Cohort Studies , Hematopoiesis/genetics , Humans , Interferons/blood , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Myeloid Cells/immunology , Myeloid Cells/pathology , Prognosis , Severity of Illness Index , Systems Biology , Transcriptome , Virus Diseases/blood , Virus Diseases/classification , Virus Diseases/genetics , Viruses/classification , Viruses/pathogenicity
6.
J Immunol ; 207(2): 720-734, 2021 07 15.
Article in English | MEDLINE | ID: covidwho-1311404

ABSTRACT

Most shared resource flow cytometry facilities do not permit analysis of radioactive samples. We are investigating low-dose molecular targeted radionuclide therapy (MTRT) as an immunomodulator in combination with in situ tumor vaccines and need to analyze radioactive samples from MTRT-treated mice using flow cytometry. Further, the sudden shutdown of core facilities in response to the COVID-19 pandemic has created an unprecedented work stoppage. In these and other research settings, a robust and reliable means of cryopreservation of immune samples is required. We evaluated different fixation and cryopreservation protocols of disaggregated tumor cells with the aim of identifying a protocol for subsequent flow cytometry of the thawed sample, which most accurately reflects the flow cytometric analysis of the tumor immune microenvironment of a freshly disaggregated and analyzed sample. Cohorts of C57BL/6 mice bearing B78 melanoma tumors were evaluated using dual lymphoid and myeloid immunophenotyping panels involving fixation and cryopreservation at three distinct points during the workflow. Results demonstrate that freezing samples after all staining and fixation are completed most accurately matches the results from noncryopreserved equivalent samples. We observed that cryopreservation of living, unfixed cells introduces a nonuniform alteration to PD1 expression. We confirm the utility of our cryopreservation protocol by comparing tumors treated with in situ tumor vaccines, analyzing both fresh and cryopreserved tumor samples with similar results. Last, we use this cryopreservation protocol with radioactive specimens to demonstrate potentially beneficial effector cell changes to the tumor immune microenvironment following administration of a novel MTRT in a dose- and time-dependent manner.


Subject(s)
Cryopreservation/methods , Flow Cytometry/methods , Leukocytes, Mononuclear/immunology , Melanoma, Experimental/pathology , Myeloid Cells/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Immunophenotyping/methods , Mice , Mice, Inbred C57BL , Natural Killer T-Cells/immunology , Pandemics , Signal Transduction/immunology , Tumor Microenvironment/immunology
7.
Methods Mol Biol ; 2099: 195-204, 2020.
Article in English | MEDLINE | ID: covidwho-1292553

ABSTRACT

Innate immune cells play a vital role in mounting an effective host response to a variety of pathogen challenges. Myeloid cells such as neutrophils and monocyte-macrophages are major innate leukocytes that orchestrate protective immunity to viral lung infections. However, a dysregulated cytokine response can promote excessive infiltration and robust pro-inflammatory activity of neutrophils and monocyte-macrophages, leading to fatal disease. Following virus infection, the beneficial or deleterious role of infiltrating neutrophils and monocyte-macrophages is determined largely by their ability to secrete inflammatory cytokines and chemokines. A majority of studies use the total number of infiltrating cells and their activation status as measures to demonstrate their role during an infection. Consequently, the ability of neutrophils and Inflammatory Monocyte Macrophages (IMMs) to secrete inflammatory cytokines and chemokines, and its correlation with the disease severity, is not well defined. In this chapter, we report useful markers to identify lung infiltrating innate immune cells and define their activation status. We also describe a simple method to measure intracellular cytokine production to evaluate the inflammatory activity of neutrophils and IMMs in a mouse model of human coronavirus infection.


Subject(s)
Chemokines/immunology , Coronavirus Infections/immunology , Cytokines/immunology , Inflammation/immunology , Middle East Respiratory Syndrome Coronavirus/immunology , Myeloid Cells/immunology , SARS Virus/immunology , Animals , Coronavirus Infections/virology , Disease Models, Animal , Humans , Immunity, Innate , Leukocytes/immunology , Lung/immunology , Macrophages/immunology , Mice , Mice, Inbred BALB C , Monocytes/immunology , Neutrophils/immunology
8.
Commun Biol ; 4(1): 631, 2021 05 27.
Article in English | MEDLINE | ID: covidwho-1283664

ABSTRACT

IL22 is an important cytokine involved in the intestinal defense mechanisms against microbiome. By using ileum-derived organoids, we show that the expression of anti-microbial peptides (AMPs) and anti-viral peptides (AVPs) can be induced by IL22. In addition, we identified a bacterial and a viral route, both leading to IL22 production by T cells, but via different pathways. Bacterial products, such as LPS, induce enterocyte-secreted SAA1, which triggers the secretion of IL6 in fibroblasts, and subsequently IL22 in T cells. This IL22 induction can then be enhanced by macrophage-derived TNFα in two ways: by enhancing the responsiveness of T cells to IL6 and by increasing the expression of IL6 by fibroblasts. Viral infections of intestinal cells induce IFNß1 and subsequently IL7. IFNß1 can induce the expression of IL6 in fibroblasts and the combined activity of IL6 and IL7 can then induce IL22 expression in T cells. We also show that IL22 reduces the expression of viral entry receptors (e.g. ACE2, TMPRSS2, DPP4, CD46 and TNFRSF14), increases the expression of anti-viral proteins (e.g. RSAD2, AOS, ISG20 and Mx1) and, consequently, reduces the viral infection of neighboring cells. Overall, our data indicates that IL22 contributes to the innate responses against both bacteria and viruses.


Subject(s)
Interleukins/biosynthesis , Interleukins/metabolism , Animals , Anti-Bacterial Agents/metabolism , Antiviral Agents/metabolism , Cell Culture Techniques , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Enterocytes/immunology , Enterocytes/metabolism , Female , Fibroblasts/immunology , Fibroblasts/metabolism , Interleukins/immunology , Intestinal Mucosa/metabolism , Intestines/physiology , Mice , Mice, Inbred C57BL , Myeloid Cells/immunology , Myeloid Cells/metabolism , Organoids/metabolism , Pore Forming Cytotoxic Proteins/genetics , Pore Forming Cytotoxic Proteins/metabolism
9.
Immunity ; 54(6): 1304-1319.e9, 2021 06 08.
Article in English | MEDLINE | ID: covidwho-1246001

ABSTRACT

Despite mounting evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) engagement with immune cells, most express little, if any, of the canonical receptor of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2). Here, using a myeloid cell receptor-focused ectopic expression screen, we identified several C-type lectins (DC-SIGN, L-SIGN, LSECtin, ASGR1, and CLEC10A) and Tweety family member 2 (TTYH2) as glycan-dependent binding partners of the SARS-CoV-2 spike. Except for TTYH2, these molecules primarily interacted with spike via regions outside of the receptor-binding domain. Single-cell RNA sequencing analysis of pulmonary cells from individuals with coronavirus disease 2019 (COVID-19) indicated predominant expression of these molecules on myeloid cells. Although these receptors do not support active replication of SARS-CoV-2, their engagement with the virus induced robust proinflammatory responses in myeloid cells that correlated with COVID-19 severity. We also generated a bispecific anti-spike nanobody that not only blocked ACE2-mediated infection but also the myeloid receptor-mediated proinflammatory responses. Our findings suggest that SARS-CoV-2-myeloid receptor interactions promote immune hyperactivation, which represents potential targets for COVID-19 therapy.


Subject(s)
COVID-19/metabolism , COVID-19/virology , Host-Pathogen Interactions , Lectins, C-Type/metabolism , Membrane Proteins/metabolism , Myeloid Cells/immunology , Myeloid Cells/metabolism , Neoplasm Proteins/metabolism , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/metabolism , Binding Sites , COVID-19/genetics , Cell Line , Cytokines , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Inflammation Mediators/metabolism , Lectins, C-Type/chemistry , Membrane Proteins/chemistry , Models, Molecular , Neoplasm Proteins/chemistry , Protein Binding , Protein Conformation , Single-Domain Antibodies/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship
10.
Immunity ; 54(5): 1083-1095.e7, 2021 05 11.
Article in English | MEDLINE | ID: covidwho-1179682

ABSTRACT

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV-2 infection. We profiled MIS-C, adult COVID-19, and healthy pediatric and adult individuals using single-cell RNA sequencing, flow cytometry, antigen receptor repertoire analysis, and unbiased serum proteomics, which collectively identified a signature in MIS-C patients that correlated with disease severity. Despite having no evidence of active infection, MIS-C patients had elevated S100A-family alarmins and decreased antigen presentation signatures, indicative of myeloid dysfunction. MIS-C patients showed elevated expression of cytotoxicity genes in NK and CD8+ T cells and expansion of specific IgG-expressing plasmablasts. Clinically severe MIS-C patients displayed skewed memory T cell TCR repertoires and autoimmunity characterized by endothelium-reactive IgG. The alarmin, cytotoxicity, TCR repertoire, and plasmablast signatures we defined have potential for application in the clinic to better diagnose and potentially predict disease severity early in the course of MIS-C.


Subject(s)
COVID-19/immunology , COVID-19/pathology , SARS-CoV-2/immunology , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/pathology , Adolescent , Alarmins/immunology , Autoantibodies/immunology , CD8-Positive T-Lymphocytes/immunology , Child , Child, Preschool , Cytotoxicity, Immunologic/genetics , Endothelium/immunology , Endothelium/pathology , Humans , Killer Cells, Natural/immunology , Myeloid Cells/immunology , Plasma Cells/immunology , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Severity of Illness Index
11.
FASEB J ; 35(5): e21577, 2021 05.
Article in English | MEDLINE | ID: covidwho-1172658

ABSTRACT

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is an emerging respiratory pathogen that has rapidly spread in human populations. Severe forms of infection associate cytokine release syndrome and acute lung injury due to hyperinflammatory responses even though virus clearance is achieved. Key components of inflammation include immune cell recruitment in infected tissues, a step which is under the control of endothelial cells. Here, we review endothelial cell responses in inflammation and infection due to SARS-CoV-2 together with phenotypic and functional alterations of monocytes, T and B lymphocytes with which they interact. We surmise that endothelial cells function as an integrative and active platform for the various cells recruited, where fine tuning of immune responses takes place and which provides opportunities for therapeutic intervention.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , COVID-19/pathology , Endothelial Cells/pathology , Myeloid Cells/immunology , Animals , B-Lymphocytes/cytology , B-Lymphocytes/immunology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Cytokines/immunology , Humans , Immunologic Memory , Myeloid Cells/cytology , T-Lymphocytes/cytology , T-Lymphocytes/immunology
12.
Front Immunol ; 12: 627548, 2021.
Article in English | MEDLINE | ID: covidwho-1156119

ABSTRACT

Background: Emerging evidence argues that monocytes, circulating innate immune cells, are principal players in COVID-19 pneumonia. The study aimed to investigate the role of soluble (s)CD163 and sCD14 plasmatic levels in predicting disease severity and characterize peripheral blood monocytes and dendritic cells (DCs), in patients with COVID-19 pneumonia (COVID-19 subjects). Methods: On admission, in COVID-19 subjects sCD163 and sCD14 plasmatic levels, and peripheral blood monocyte and DC subsets were compared to healthy donors (HDs). According to clinical outcome, COVID-19 subjects were divided into ARDS and non-ARDS groups. Results: Compared to HDs, COVID-19 subjects showed higher sCD163 (p<0.0001) and sCD14 (p<0.0001) plasmatic levels. We observed higher sCD163 plasmatic levels in the ARDS group compared to the non-ARDS one (p=0.002). The cut-off for sCD163 plasmatic level greater than 2032 ng/ml was predictive of disease severity (AUC: 0.6786, p=0.0022; sensitivity 56.7% [CI: 44.1-68.4] specificity 73.8% [CI: 58.9-84.7]). Positive correlation between plasmatic levels of sCD163, LDH and IL-6 and between plasmatic levels of sCD14, D-dimer and ferritin were found. Compared to HDs, COVID-19 subjects showed lower percentages of non-classical (p=0.0012) and intermediate monocytes (p=0.0447), slanDCs (p<0.0001), myeloid DCs (mDCs, p<0.0001), and plasmacytoid DCs (pDCs, p=0.0014). Compared to the non-ARDS group, the ARDS group showed lower percentages of non-classical monocytes (p=0.0006), mDCs (p=0.0346), and pDCs (p=0.0492). Conclusions: The increase in sCD163 and sCD14 plasmatic levels, observed on hospital admission in COVID-19 subjects, especially in those who developed ARDS, and the correlations of these monocyte/macrophage activation markers with typical inflammatory markers of COVID-19 pneumonia, underline their potential use to assess the risk of progression of the disease. In an early stage of the disease, the assessment of sCD163 plasmatic levels could have clinical utility in predicting the severity of COVID-19 pneumonia.


Subject(s)
Antigens, CD/blood , Antigens, Differentiation, Myelomonocytic/blood , COVID-19/immunology , Dendritic Cells/immunology , Lipopolysaccharide Receptors/blood , Monocytes/immunology , Myeloid Cells/immunology , Receptors, Cell Surface/blood , SARS-CoV-2/immunology , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/blood , COVID-19/diagnosis , COVID-19/virology , Case-Control Studies , Dendritic Cells/metabolism , Dendritic Cells/virology , Disease Progression , Female , Host-Pathogen Interactions , Humans , Immunity, Innate , Male , Middle Aged , Monocytes/metabolism , Monocytes/virology , Myeloid Cells/metabolism , Myeloid Cells/virology , Patient Admission , Phenotype , Severity of Illness Index , Up-Regulation
13.
Immunity ; 54(4): 797-814.e6, 2021 04 13.
Article in English | MEDLINE | ID: covidwho-1149231

ABSTRACT

Immune response dynamics in coronavirus disease 2019 (COVID-19) and their severe manifestations have largely been studied in circulation. Here, we examined the relationship between immune processes in the respiratory tract and circulation through longitudinal phenotypic, transcriptomic, and cytokine profiling of paired airway and blood samples from patients with severe COVID-19 relative to heathy controls. In COVID-19 airways, T cells exhibited activated, tissue-resident, and protective profiles; higher T cell frequencies correlated with survival and younger age. Myeloid cells in COVID-19 airways featured hyperinflammatory signatures, and higher frequencies of these cells correlated with mortality and older age. In COVID-19 blood, aberrant CD163+ monocytes predominated over conventional monocytes, and were found in corresponding airway samples and in damaged alveoli. High levels of myeloid chemoattractants in airways suggest recruitment of these cells through a CCL2-CCR2 chemokine axis. Our findings provide insights into immune processes driving COVID-19 lung pathology with therapeutic implications for targeting inflammation in the respiratory tract.


Subject(s)
COVID-19/immunology , Lung/immunology , Myeloid Cells/immunology , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , COVID-19/blood , COVID-19/mortality , COVID-19/pathology , Cytokines/immunology , Cytokines/metabolism , Humans , Inflammation , Longitudinal Studies , Lung/pathology , Macrophages/immunology , Macrophages/pathology , Middle Aged , Monocytes/immunology , Monocytes/pathology , Myeloid Cells/pathology , SARS-CoV-2 , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Transcriptome , Young Adult
14.
Cells ; 9(9)2020 09 16.
Article in English | MEDLINE | ID: covidwho-1148288

ABSTRACT

Vaccine design traditionally focuses on inducing adaptive immune responses against a sole target pathogen. Considering that many microbes evade innate immune mechanisms to initiate infection, and in light of the discovery of epigenetically mediated innate immune training, the paradigm of vaccine design has the potential to change. The Bacillus Calmette-Guérin (BCG) vaccine induces some level of protection against Mycobacterium tuberculosis (Mtb) while stimulating trained immunity that correlates with lower mortality and increased protection against unrelated pathogens. This review will explore BCG-induced trained immunity, including the required pathways to establish this phenotype. Additionally, potential methods to improve or expand BCG trained immunity effects through alternative vaccine delivery and formulation methods will be discussed. Finally, advances in new anti-Mtb vaccines, other antimicrobial uses for BCG, and "innate memory-based vaccines" will be examined.


Subject(s)
Adaptive Immunity/drug effects , BCG Vaccine/administration & dosage , COVID-19/prevention & control , Epigenesis, Genetic/drug effects , Myeloid Cells/drug effects , SARS-CoV-2/pathogenicity , Tuberculosis, Pulmonary/prevention & control , Acetylmuramyl-Alanyl-Isoglutamine/immunology , Acetylmuramyl-Alanyl-Isoglutamine/metabolism , COVID-19/immunology , COVID-19/virology , Cross Protection , Epigenesis, Genetic/immunology , Histones/genetics , Histones/immunology , Humans , Mycobacterium tuberculosis , Myeloid Cells/immunology , Myeloid Cells/pathology , Nod2 Signaling Adaptor Protein/genetics , Nod2 Signaling Adaptor Protein/immunology , Pathogen-Associated Molecular Pattern Molecules/immunology , Pathogen-Associated Molecular Pattern Molecules/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/immunology , Signal Transduction , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/immunology , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/microbiology
15.
Nat Commun ; 12(1): 1428, 2021 03 05.
Article in English | MEDLINE | ID: covidwho-1118806

ABSTRACT

Since the beginning of the SARS-CoV-2 pandemic, COVID-19 appeared as a unique disease with unconventional tissue and systemic immune features. Here we show a COVID-19 immune signature associated with severity by integrating single-cell RNA-seq analysis from blood samples and broncho-alveolar lavage fluids with clinical, immunological and functional ex vivo data. This signature is characterized by lung accumulation of naïve lymphoid cells associated with a systemic expansion and activation of myeloid cells. Myeloid-driven immune suppression is a hallmark of COVID-19 evolution, highlighting arginase-1 expression with immune regulatory features of monocytes. Monocyte-dependent and neutrophil-dependent immune suppression loss is associated with fatal clinical outcome in severe patients. Additionally, our analysis shows a lung CXCR6+ effector memory T cell subset is associated with better prognosis in patients with severe COVID-19. In summary, COVID-19-induced myeloid dysregulation and lymphoid impairment establish a condition of 'immune silence' in patients with critical COVID-19.


Subject(s)
COVID-19/immunology , SARS-CoV-2/immunology , Aged , Aged, 80 and over , CD8-Positive T-Lymphocytes/immunology , COVID-19/blood , Case-Control Studies , Cytokines/immunology , Female , Humans , Male , Middle Aged , Monocytes/immunology , Myeloid Cells/immunology , Neutrophils/immunology , T-Lymphocytes/immunology
16.
Front Immunol ; 11: 595950, 2020.
Article in English | MEDLINE | ID: covidwho-1110296

ABSTRACT

In recent years, the success of immunotherapy targeting immunoregulatory receptors (immune checkpoints) in cancer have generated enthusiastic support to target these receptors in a wide range of other immune related diseases. While the overwhelming focus has been on blockade of these inhibitory pathways to augment immunity, agonistic triggering via these receptors offers the promise of dampening pathogenic inflammatory responses. V-domain Ig suppressor of T cell activation (VISTA) has emerged as an immunoregulatory receptor with constitutive expression on both the T cell and myeloid compartments, and whose agonistic targeting has proven a unique avenue relative to other checkpoint pathways to suppress pathologies mediated by the innate arm of the immune system. VISTA agonistic targeting profoundly changes the phenotype of human monocytes towards an anti-inflammatory cell state, as highlighted by striking suppression of the canonical markers CD14 and Fcγr3a (CD16), and the almost complete suppression of both the interferon I (IFN-I) and antigen presentation pathways. The insights from these very recent studies highlight the impact of VISTA agonistic targeting of myeloid cells, and its potential therapeutic implications in the settings of hyperinflammatory responses such as cytokine storms, driven by dysregulated immune responses to viral infections (with a focus on COVID-19) and autoimmune diseases. Collectively, these findings suggest that the VISTA pathway plays a conserved, non-redundant role in myeloid cell function.


Subject(s)
B7 Antigens/agonists , COVID-19/pathology , Cytokine Release Syndrome/prevention & control , Myeloid Cells/immunology , Animals , Antigen Presentation/immunology , B7 Antigens/antagonists & inhibitors , B7 Antigens/immunology , CD4-Positive T-Lymphocytes/immunology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , GPI-Linked Proteins/antagonists & inhibitors , Humans , Immunotherapy , Interferon Type I/antagonists & inhibitors , Lipopolysaccharide Receptors/antagonists & inhibitors , Lymphocyte Activation/immunology , Mice , Receptors, IgG/antagonists & inhibitors , SARS-CoV-2/immunology
17.
Int Immunol ; 33(4): 241-247, 2021 03 31.
Article in English | MEDLINE | ID: covidwho-1066348

ABSTRACT

An expanded myeloid cell compartment is a hallmark of severe coronavirus disease 2019 (COVID-19). However, data regarding myeloid cell expansion have been collected in Europe, where the mortality rate by COVID-19 is greater than those in other regions including Japan. Thus, characteristics of COVID-19-induced myeloid cell subsets remain largely unknown in the regions with low mortality rates. Here, we analyzed cellular dynamics of myeloid-derived suppressor cell (MDSC) subsets and examined whether any of them correlate with disease severity and prognosis, using blood samples from Japanese COVID-19 patients. We observed that polymorphonuclear (PMN)-MDSCs, but not other MDSC subsets, transiently expanded in severe cases but not in mild or moderate cases. Contrary to previous studies in Europe, this subset selectively expanded in survivors of severe cases and subsided before discharge, but such transient expansion was not observed in non-survivors in Japanese cohort. Analysis of plasma cytokine/chemokine levels revealed positive correlation of PMN-MDSC frequencies with IL-8 levels, indicating the involvement of IL-8 on recruitment of PMN-MDSCs to peripheral blood following the onset of severe COVID-19. Our data indicate that transient expansion of the PMN-MDSC subset results in improved clinical outcome. Thus, this myeloid cell subset may be a predictor of prognosis in cases of severe COVID-19 in Japan.


Subject(s)
COVID-19/pathology , Interleukin-8/blood , Myeloid-Derived Suppressor Cells/immunology , Neutrophils/immunology , SARS-CoV-2/immunology , Humans , Interleukin-8/immunology , Japan , Leukocyte Count , Myeloid Cells/immunology , Neutrophil Activation/immunology
18.
Nat Rev Immunol ; 21(8): 485-498, 2021 08.
Article in English | MEDLINE | ID: covidwho-1060053

ABSTRACT

Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes with potent immunosuppressive activity. They are implicated in the regulation of immune responses in many pathological conditions and are closely associated with poor clinical outcomes in cancer. Recent studies have indicated key distinctions between MDSCs and classical neutrophils and monocytes, and, in this Review, we discuss new data on the major genomic and metabolic characteristics of MDSCs. We explain how these characteristics shape MDSC function and could facilitate therapeutic targeting of these cells, particularly in cancer and in autoimmune diseases. Additionally, we briefly discuss emerging data on MDSC involvement in pregnancy, neonatal biology and COVID-19.


Subject(s)
Cytokines/immunology , Monocytes/immunology , Myeloid Cells/immunology , Myeloid-Derived Suppressor Cells/immunology , Neutrophils/immunology , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , Cytokines/metabolism , Humans , Monocytes/metabolism , Myeloid Cells/metabolism , Myeloid-Derived Suppressor Cells/metabolism , Neoplasms/immunology , Neoplasms/metabolism , Neutrophils/metabolism , SARS-CoV-2/immunology , SARS-CoV-2/physiology
19.
Nat Microbiol ; 6(1): 73-86, 2021 01.
Article in English | MEDLINE | ID: covidwho-989838

ABSTRACT

Non-human primate models will expedite therapeutics and vaccines for coronavirus disease 2019 (COVID-19) to clinical trials. Here, we compare acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in young and old rhesus macaques, baboons and old marmosets. Macaques had clinical signs of viral infection, mild to moderate pneumonitis and extra-pulmonary pathologies, and both age groups recovered in two weeks. Baboons had prolonged viral RNA shedding and substantially more lung inflammation compared with macaques. Inflammation in bronchoalveolar lavage was increased in old versus young baboons. Using techniques including computed tomography imaging, immunophenotyping, and alveolar/peripheral cytokine response and immunohistochemical analyses, we delineated cellular immune responses to SARS-CoV-2 infection in macaque and baboon lungs, including innate and adaptive immune cells and a prominent type-I interferon response. Macaques developed T-cell memory phenotypes/responses and bystander cytokine production. Old macaques had lower titres of SARS-CoV-2-specific IgG antibody levels compared with young macaques. Acute respiratory distress in macaques and baboons recapitulates the progression of COVID-19 in humans, making them suitable as models to test vaccines and therapies.


Subject(s)
COVID-19/veterinary , Callithrix/immunology , Lung/immunology , Macaca mulatta/immunology , Monkey Diseases/virology , Papio/immunology , SARS-CoV-2/immunology , Adaptive Immunity , Animals , Antibodies, Viral/immunology , Bronchoalveolar Lavage , Bronchoalveolar Lavage Fluid , COVID-19/diagnostic imaging , COVID-19/immunology , COVID-19/pathology , Female , Humans , Immunity, Cellular/immunology , Immunoglobulin G/immunology , Inflammation/pathology , Lung/virology , Male , Monkey Diseases/immunology , Myeloid Cells/immunology , Viral Load , Virus Shedding
20.
Front Immunol ; 11: 2145, 2020.
Article in English | MEDLINE | ID: covidwho-776206

ABSTRACT

SARS-CoV-2 infection has recently been declared a pandemic. Some patients showing severe symptoms exhibit drastic inflammation and airway damage. In this study, we re-analyzed published scRNA-seq data of COVID-19 patient bronchoalveolar lavage fluid to further classify and compare immunological features according to the patient's disease severity. Patients with severe symptoms showed DNA damage and apoptotic features of epithelial cells. Our results suggested that epithelial damage was associated with neutrophil infiltration. Myeloid cells of severe patients showed higher expression of proinflammatory cytokines and chemokines such as CXCL8. As a result, neutrophils were abundant in lungs of patients from the severe group. Furthermore, recruited neutrophils highly expressed genes related to neutrophil extracellular traps. Neutrophil-mediated inflammation was regulated by glucocorticoid receptor expression and activity. Based on these results, we suggest that severe COVID-19 symptoms may be determined by differential expression of glucocorticoid receptors and neutrophils.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Interleukin-8/genetics , Neutrophils/immunology , Pneumonia, Viral/immunology , Receptors, Glucocorticoid/genetics , Severity of Illness Index , Transcriptome , Adult , Aged , Bronchoalveolar Lavage Fluid/immunology , COVID-19 , Coronavirus Infections/virology , Epithelial Cells/pathology , Extracellular Traps/immunology , Female , Gene Expression Profiling/methods , Humans , Inflammation/immunology , Interleukin-8/metabolism , Male , Middle Aged , Myeloid Cells/immunology , Neutrophil Infiltration/immunology , Pandemics , Pneumonia, Viral/virology , RNA-Seq , Receptors, Glucocorticoid/metabolism , SARS-CoV-2 , Single-Cell Analysis/methods
SELECTION OF CITATIONS
SEARCH DETAIL
...