Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 28
Filter
1.
Front Immunol ; 12: 797390, 2021.
Article in English | MEDLINE | ID: covidwho-1686476

ABSTRACT

Phosphodiesterase 4 (PDE4) inhibitors are immunomodulatory drugs approved to treat diseases associated with chronic inflammatory conditions, such as COPD, psoriasis and atopic dermatitis. Tanimilast (international non-proprietary name of CHF6001) is a novel, potent and selective inhaled PDE4 inhibitor in advanced clinical development for the treatment of COPD. To begin testing its potential in limiting hyperinflammation and immune dysregulation associated to SARS-CoV-2 infection, we took advantage of an in vitro model of dendritic cell (DC) activation by SARS-CoV-2 genomic ssRNA (SCV2-RNA). In this context, Tanimilast decreased the release of pro-inflammatory cytokines (TNF-α and IL-6), chemokines (CCL3, CXCL9, and CXCL10) and of Th1-polarizing cytokines (IL-12, type I IFNs). In contrast to ß-methasone, a reference steroid anti-inflammatory drug, Tanimilast did not impair the acquisition of the maturation markers CD83, CD86 and MHC-II, nor that of the lymph node homing receptor CCR7. Consistent with this, Tanimilast did not reduce the capability of SCV2-RNA-stimulated DCs to activate CD4+ T cells but skewed their polarization towards a Th2 phenotype. Both Tanimilast and ß-methasone blocked the increase of MHC-I molecules in SCV2-RNA-activated DCs and restrained the proliferation and activation of cytotoxic CD8+ T cells. Our results indicate that Tanimilast can modulate the SCV2-RNA-induced pro-inflammatory and Th1-polarizing potential of DCs, crucial regulators of both the inflammatory and immune response. Given also the remarkable safety demonstrated by Tanimilast, up to now, in clinical studies, we propose this inhaled PDE4 inhibitor as a promising immunomodulatory drug in the scenario of COVID-19.


Subject(s)
COVID-19/immunology , Dendritic Cells , Phosphodiesterase 4 Inhibitors/pharmacology , RNA/pharmacology , SARS-CoV-2/physiology , Virus Activation/drug effects , CD8-Positive T-Lymphocytes/immunology , COVID-19/drug therapy , Cytokines/immunology , Dendritic Cells/immunology , Dendritic Cells/virology , Humans , Th1 Cells/immunology , Th2 Cells/immunology , Virus Activation/immunology
2.
Cells ; 10(12)2021 11 23.
Article in English | MEDLINE | ID: covidwho-1538383

ABSTRACT

Dendritic cells (DCs) are the most potent antigen-presenting cells, and their function is essential to configure adaptative immunity and avoid excessive inflammation. DCs are predicted to play a crucial role in the clinical evolution of the infection by the severe acute respiratory syndrome (SARS) coronavirus (CoV)-2. DCs interaction with the SARS-CoV-2 Spike protein, which mediates cell receptor binding and subsequent fusion of the viral particle with host cell, is a key step to induce effective immunity against this virus and in the S protein-based vaccination protocols. Here we evaluated human DCs in response to SARS-CoV-2 S protein, or to a fragment encompassing the receptor binding domain (RBD) challenge. Both proteins increased the expression of maturation markers, including MHC molecules and costimulatory receptors. DCs interaction with the SARS-CoV-2 S protein promotes activation of key signaling molecules involved in inflammation, including MAPK, AKT, STAT1, and NFκB, which correlates with the expression and secretion of distinctive proinflammatory cytokines. Differences in the expression of ACE2 along the differentiation of human monocytes to mature DCs and inter-donor were found. Our results show that SARS-CoV-2 S protein promotes inflammatory response and provides molecular links between individual variations and the degree of response against this virus.


Subject(s)
Dendritic Cells/pathology , Dendritic Cells/virology , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Cell Adhesion Molecules/metabolism , Cell Differentiation , Cytokines/biosynthesis , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Inflammation/pathology , Lectins, C-Type/metabolism , Protein Domains , Proto-Oncogene Proteins c-akt/metabolism , Receptors, Cell Surface/metabolism , STAT Transcription Factors/metabolism , Signal Transduction , Tissue Donors
3.
J Allergy Clin Immunol ; 149(3): 912-922, 2022 03.
Article in English | MEDLINE | ID: covidwho-1536619

ABSTRACT

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is an acute, febrile, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated syndrome, often with cardiohemodynamic dysfunction. Insight into mechanism of disease is still incomplete. OBJECTIVE: Our objective was to analyze immunologic features of MIS-C patients compared to febrile controls (FC). METHODS: MIS-C patients were defined by narrow criteria, including having evidence of cardiohemodynamic involvement and no macrophage activation syndrome. Samples were collected from 8 completely treatment-naive patients with MIS-C (SARS-CoV-2 serology positive), 3 patients with unclassified MIS-C-like disease (serology negative), 14 FC, and 5 MIS-C recovery (RCV). Three healthy controls (HCs) were used for comparisons of normal range. Using spectral flow cytometry, we assessed 36 parameters in antigen-presenting cells (APCs) and 29 in T cells. We used biaxial analysis and uniform manifold approximation and projection (UMAP). RESULTS: Significant elevations in cytokines including CXCL9, M-CSF, and IL-27 were found in MIS-C compared to FC. Classic monocytes and type 2 dendritic cells (DCs) were downregulated (decreased CD86, HLA-DR) versus HCs; however, type 1 DCs (CD11c+CD141+CLEC9A+) were highly activated in MIS-C patients versus FC, expressing higher levels of CD86, CD275, and atypical conventional DC markers such as CD64, CD115, and CX3CR1. CD169 and CD38 were upregulated in multiple monocyte subtypes. CD56dim/CD57-/KLRGhi/CD161+/CD38- natural killer (NK) cells were a unique subset in MIS-C versus FC without macrophage activation syndrome. CONCLUSION: Orchestrated by complex cytokine signaling, type 1 DC activation and NK dysregulation are key features in the pathophysiology of MIS-C. NK cell findings may suggest a relationship with macrophage activation syndrome, while type 1 DC upregulation implies a role for antigen cross-presentation.


Subject(s)
COVID-19/complications , Dendritic Cells/immunology , Dendritic Cells/virology , SARS-CoV-2/immunology , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/virology , ADP-ribosyl Cyclase 1/blood , Adolescent , Antigens, Viral/immunology , COVID-19/immunology , COVID-19/virology , Case-Control Studies , Child , Child, Preschool , Cross-Priming , Cytokines/blood , Dendritic Cells/classification , Female , HLA-DR Antigens/blood , Humans , Immunophenotyping , Interferon-gamma/blood , Interleukins/blood , Killer Cells, Natural/immunology , Male , Membrane Glycoproteins/blood , Models, Immunological , Monocytes/immunology , Sialic Acid Binding Ig-like Lectin 1/blood , T-Lymphocytes/immunology , T-Lymphocytes/virology , Up-Regulation
5.
Clin Sci (Lond) ; 135(19): 2217-2242, 2021 10 14.
Article in English | MEDLINE | ID: covidwho-1462047

ABSTRACT

The ability of dendritic cells (DCs) to sense viral pathogens and orchestrate a proper immune response makes them one of the key players in antiviral immunity. Different DC subsets have complementing functions during viral infections, some specialize in antigen presentation and cross-presentation and others in the production of cytokines with antiviral activity, such as type I interferons. In this review, we summarize the latest updates concerning the role of DCs in viral infections, with particular focus on the complex interplay between DC subsets and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Despite being initiated by a vast array of immune receptors, DC-mediated antiviral responses often converge towards the same endpoint, that is the production of proinflammatory cytokines and the activation of an adaptive immune response. Nonetheless, the inherent migratory properties of DCs make them a double-edged sword and often viral recognition by DCs results in further viral dissemination. Here we illustrate these various aspects of the antiviral functions of DCs and also provide a brief overview of novel antiviral vaccination strategies based on DCs targeting.


Subject(s)
COVID-19/virology , Dendritic Cells/virology , Receptors, Pattern Recognition/immunology , SARS-CoV-2/pathogenicity , Virus Diseases/virology , Cytokines/immunology , Dendritic Cells/immunology , Humans , Virus Diseases/immunology
6.
EMBO J ; 40(20): e106765, 2021 10 18.
Article in English | MEDLINE | ID: covidwho-1436404

ABSTRACT

The current pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and outbreaks of new variants highlight the need for preventive treatments. Here, we identified heparan sulfate proteoglycans as attachment receptors for SARS-CoV-2. Notably, neutralizing antibodies against SARS-CoV-2 isolated from COVID-19 patients interfered with SARS-CoV-2 binding to heparan sulfate proteoglycans, which might be an additional mechanism of antibodies to neutralize infection. SARS-CoV-2 binding to and infection of epithelial cells was blocked by low molecular weight heparins (LMWH). Although dendritic cells (DCs) and mucosal Langerhans cells (LCs) were not infected by SARS-CoV-2, both DC subsets efficiently captured SARS-CoV-2 via heparan sulfate proteoglycans and transmitted the virus to ACE2-positive cells. Notably, human primary nasal cells were infected by SARS-CoV-2, and infection was blocked by pre-treatment with LMWH. These data strongly suggest that heparan sulfate proteoglycans are important attachment receptors facilitating infection and transmission, and support the use of LMWH as prophylaxis against SARS-CoV-2 infection.


Subject(s)
COVID-19/transmission , Heparan Sulfate Proteoglycans/metabolism , Heparin, Low-Molecular-Weight/pharmacology , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/metabolism , Antibodies, Neutralizing/pharmacology , COVID-19/drug therapy , Chlorocebus aethiops , Dendritic Cells/metabolism , Dendritic Cells/virology , Epithelial Cells/metabolism , Epithelial Cells/virology , Host-Pathogen Interactions , Humans , Mucous Membrane/cytology , Mucous Membrane/virology , SARS-CoV-2/metabolism , Syndecan-1/metabolism , Syndecan-4/metabolism , Vero Cells
7.
PLoS Pathog ; 17(9): e1009878, 2021 09.
Article in English | MEDLINE | ID: covidwho-1394563

ABSTRACT

SARS-CoV-2 fine-tunes the interferon (IFN)-induced antiviral responses, which play a key role in preventing coronavirus disease 2019 (COVID-19) progression. Indeed, critically ill patients show an impaired type I IFN response accompanied by elevated inflammatory cytokine and chemokine levels, responsible for cell and tissue damage and associated multi-organ failure. Here, the early interaction between SARS-CoV-2 and immune cells was investigated by interrogating an in vitro human peripheral blood mononuclear cell (PBMC)-based experimental model. We found that, even in absence of a productive viral replication, the virus mediates a vigorous TLR7/8-dependent production of both type I and III IFNs and inflammatory cytokines and chemokines, known to contribute to the cytokine storm observed in COVID-19. Interestingly, we observed how virus-induced type I IFN secreted by PBMC enhances anti-viral response in infected lung epithelial cells, thus, inhibiting viral replication. This type I IFN was released by plasmacytoid dendritic cells (pDC) via an ACE-2-indipendent but Neuropilin-1-dependent mechanism. Viral sensing regulates pDC phenotype by inducing cell surface expression of PD-L1 marker, a feature of type I IFN producing cells. Coherently to what observed in vitro, asymptomatic SARS-CoV-2 infected subjects displayed a similar pDC phenotype associated to a very high serum type I IFN level and induction of anti-viral IFN-stimulated genes in PBMC. Conversely, hospitalized patients with severe COVID-19 display very low frequency of circulating pDC with an inflammatory phenotype and high levels of chemokines and pro-inflammatory cytokines in serum. This study further shed light on the early events resulting from the interaction between SARS-CoV-2 and immune cells occurring in vitro and confirmed ex vivo. These observations can improve our understanding on the contribution of pDC/type I IFN axis in the regulation of the anti-viral state in asymptomatic and severe COVID-19 patients.


Subject(s)
COVID-19/immunology , Dendritic Cells/classification , Interferon Type I/metabolism , SARS-CoV-2/immunology , Adult , Aged, 80 and over , Asymptomatic Infections , Cell Line, Tumor , Dendritic Cells/immunology , Dendritic Cells/virology , Epithelial Cells/cytology , Female , Hospitalization , Humans , Interferon Type I/immunology , Lung/cytology , Male , Middle Aged , Neuropilin-1/metabolism , Phenotype , Severity of Illness Index , Toll-Like Receptor 7/metabolism
8.
Proc Natl Acad Sci U S A ; 118(22)2021 06 01.
Article in English | MEDLINE | ID: covidwho-1232098

ABSTRACT

Comprehensive and accurate comparisons of transcriptomic distributions of cells from samples taken from two different biological states, such as healthy versus diseased individuals, are an emerging challenge in single-cell RNA sequencing (scRNA-seq) analysis. Current methods for detecting differentially abundant (DA) subpopulations between samples rely heavily on initial clustering of all cells in both samples. Often, this clustering step is inadequate since the DA subpopulations may not align with a clear cluster structure, and important differences between the two biological states can be missed. Here, we introduce DA-seq, a targeted approach for identifying DA subpopulations not restricted to clusters. DA-seq is a multiscale method that quantifies a local DA measure for each cell, which is computed from its k nearest neighboring cells across a range of k values. Based on this measure, DA-seq delineates contiguous significant DA subpopulations in the transcriptomic space. We apply DA-seq to several scRNA-seq datasets and highlight its improved ability to detect differences between distinct phenotypes in severe versus mildly ill COVID-19 patients, melanomas subjected to immune checkpoint therapy comparing responders to nonresponders, embryonic development at two time points, and young versus aging brain tissue. DA-seq enabled us to detect differences between these phenotypes. Importantly, we find that DA-seq not only recovers the DA cell types as discovered in the original studies but also reveals additional DA subpopulations that were not described before. Analysis of these subpopulations yields biological insights that would otherwise be undetected using conventional computational approaches.


Subject(s)
Aging/genetics , COVID-19/genetics , Cell Lineage/genetics , Melanoma/genetics , RNA, Small Cytoplasmic/genetics , Skin Neoplasms/genetics , Aging/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/virology , Brain/cytology , Brain/metabolism , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Cell Lineage/immunology , Cytokines/genetics , Cytokines/immunology , Datasets as Topic , Dendritic Cells/immunology , Dendritic Cells/virology , Gene Expression Profiling , Gene Expression Regulation , High-Throughput Nucleotide Sequencing , Humans , Melanoma/immunology , Melanoma/pathology , Monocytes/immunology , Monocytes/virology , Phenotype , RNA, Small Cytoplasmic/immunology , SARS-CoV-2/pathogenicity , Severity of Illness Index , Single-Cell Analysis/methods , Skin Neoplasms/immunology , Skin Neoplasms/pathology , T-Lymphocytes/immunology , T-Lymphocytes/virology , Transcriptome
9.
PLoS Pathog ; 17(4): e1009487, 2021 04.
Article in English | MEDLINE | ID: covidwho-1231264

ABSTRACT

Lipocalin 2 (LCN2) is a secreted glycoprotein with roles in multiple biological processes. It contributes to host defense by interference with bacterial iron uptake and exerts immunomodulatory functions in various diseases. Here, we aimed to characterize the function of LCN2 in lung macrophages and dendritic cells (DCs) using Lcn2-/- mice. Transcriptome analysis revealed strong LCN2-related effects in CD103+ DCs during homeostasis, with differential regulation of antigen processing and presentation and antiviral immunity pathways. We next validated the relevance of LCN2 in a mouse model of influenza infection, wherein LCN2 protected from excessive weight loss and improved survival. LCN2-deficiency was associated with enlarged mediastinal lymph nodes and increased lung T cell numbers, indicating a dysregulated immune response to influenza infection. Depletion of CD8+ T cells equalized weight loss between WT and Lcn2-/- mice, proving that LCN2 protects from excessive disease morbidity by dampening CD8+ T cell responses. In vivo T cell chimerism and in vitro T cell proliferation assays indicated that improved antigen processing by CD103+ DCs, rather than T cell intrinsic effects of LCN2, contribute to the exacerbated T cell response. Considering the antibacterial potential of LCN2 and that commensal microbes can modulate antiviral immune responses, we speculated that LCN2 might cause the observed influenza phenotype via the microbiome. Comparing the lung and gut microbiome of WT and Lcn2-/- mice by 16S rRNA gene sequencing, we observed profound effects of LCN2 on gut microbial composition. Interestingly, antibiotic treatment or co-housing of WT and Lcn2-/- mice prior to influenza infection equalized lung CD8+ T cell counts, suggesting that the LCN2-related effects are mediated by the microbiome. In summary, our results highlight a novel regulatory function of LCN2 in the modulation of antiviral immunity.


Subject(s)
Influenza, Human/immunology , Lipocalin-2/metabolism , Microbiota/immunology , Transcriptome , Animals , Antigen Presentation , CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Dendritic Cells/virology , Female , Gastrointestinal Microbiome , Homeostasis , Humans , Immunity , Influenza, Human/virology , Lipocalin-2/genetics , Lung/immunology , Lung/virology , Lymphocyte Activation , Macrophages/immunology , Male , Mice , Mice, Inbred C57BL , Specific Pathogen-Free Organisms
10.
J Immunol ; 206(8): 1691-1696, 2021 04 15.
Article in English | MEDLINE | ID: covidwho-1158408

ABSTRACT

Severe COVID-19 disease is associated with elevated inflammatory responses. One form of Aicardi-Goutières syndrome caused by inactivating mutations in ADAR results in reduced adenosine-to-inosine (A-to-I) editing of endogenous dsRNAs, induction of IFNs, IFN-stimulated genes, other inflammatory mediators, morbidity, and mortality. Alu elements, ∼10% of the human genome, are the most common A-to-I-editing sites. Using leukocyte whole-genome RNA-sequencing data, we found reduced A-to-I editing of Alu dsRNAs in patients with severe COVID-19 disease. Dendritic cells infected with COVID-19 also exhibit reduced A-to-I editing of Alu dsRNAs. Unedited Alu dsRNAs, but not edited Alu dsRNAs, are potent inducers of IRF and NF-κB transcriptional responses, IL6, IL8, and IFN-stimulated genes. Thus, decreased A-to-I editing that may lead to accumulation of unedited Alu dsRNAs and increased inflammatory responses is associated with severe COVID-19 disease.


Subject(s)
Adenosine/genetics , Alu Elements/genetics , COVID-19/genetics , Inosine/genetics , RNA Editing/genetics , RNA, Double-Stranded/genetics , SARS-CoV-2 , Severity of Illness Index , Adenosine/metabolism , COVID-19/pathology , Dendritic Cells/metabolism , Dendritic Cells/virology , Genome, Human , Humans , Inosine/metabolism , Interferon Regulatory Factors/metabolism , NF-kappa B/metabolism , RNA-Seq , Signal Transduction/genetics
11.
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
12.
J Infect Dis ; 223(5): 785-795, 2021 03 03.
Article in English | MEDLINE | ID: covidwho-1117041

ABSTRACT

Studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients and experimentally infected animals indicate a critical role for augmented expression of proinflammatory chemokines and cytokines in severe disease. Here, we demonstrate that SARS-CoV-2 infection of human monocyte-derived macrophages (MDMs) and monocyte-derived dendritic cells was abortive, but induced the production of multiple antiviral and proinflammatory cytokines (interferon-α, interferon-ß, tumor necrosis factor, and interleukins 1ß, 6, and 10) and a chemokine (CXCL10). Despite the lack of efficient replication in MDMs, SARS-CoV-2 induced profound interferon-mediated cell death of host cells. Macrophage activation and death were not enhanced by exposure to low levels of convalescent plasma, suggesting that antibody-dependent enhancement of infection does not contribute to cell death. Together, these results indicate that infection of macrophages and dendritic cells potentially plays a major role in coronavirus disease 2019 pathogenesis, even in the absence of productive infection.


Subject(s)
COVID-19/therapy , Dendritic Cells/virology , Macrophages/virology , SARS-CoV-2/immunology , COVID-19/immunology , Cell Death , Chemokines/genetics , Chemokines/metabolism , Cytokines/genetics , Cytokines/metabolism , Dendritic Cells/immunology , Dendritic Cells/ultrastructure , Humans , Immunization, Passive , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/virology , Macrophages/immunology , Macrophages/ultrastructure , Microscopy, Electron, Transmission , RNA, Messenger/metabolism , RNA, Viral/metabolism
13.
Inflamm Res ; 70(4): 407-428, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1103389

ABSTRACT

BACKGROUND: The aim of this review is to explore whether patients with autoimmune diseases (AIDs) were at high risk of infection during the COVID-19 epidemic and how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic affected immune system. METHODS: A systematic literature search was performed using the foreign databases (NCBI, web of science, EBSCO, ELSEVIER ScienceDirect) and Chinese databases (WanFang, CNKI (China National Knowledge Infrastructure), VIP, CBM) to locate all relevant publications (up to January 10, 2021). The search strategies used Medical Search Headings (MeSH) headings and keywords for "COVID-19" or "SARS-CoV-2" or "coronavirus" and "autoimmune disease". RESULTS: This review evaluates the effect of SARS-CoV-2 on the immune system through ACE-2 receptor binding as the main pathway for cell attachment and invasion. It is speculated that SARS-COV-2 infection can activate lymphocytes and inflammatory response, which may play a role in the clinical onset of AIDs and also patients were treated with immunomodulatory drugs during COVID-19 outbreak. Preliminary studies suggested that the risk of developing severe forms of COVID-19 in patients with AIDs treated with immunomodulators or biologics might not increase. A large number of samples are needed for further verification, leading to an excessive immune response to external stimuli. CONCLUSION: The relationship between autoimmune diseases and SARS-CoV-2 infection is complex. During the COVID-19 epidemic, individualized interventions for AIDs should be provided such as Internet-based service.


Subject(s)
Autoimmune Diseases/complications , Autoimmune Diseases/epidemiology , COVID-19/complications , COVID-19/epidemiology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Angiotensin-Converting Enzyme 2/metabolism , Arthritis, Rheumatoid/immunology , Autoimmune Diseases/immunology , Azetidines/therapeutic use , COVID-19/drug therapy , COVID-19/therapy , Dendritic Cells/virology , Humans , Immune System , Immunity, Innate , Immunization, Passive/trends , Inflammatory Bowel Diseases/immunology , Killer Cells, Natural/virology , Lupus Erythematosus, Systemic/immunology , Monocytes/virology , Multiple Sclerosis/immunology , Purines/therapeutic use , Pyrazoles/therapeutic use , Sulfonamides/therapeutic use
14.
Platelets ; 32(3): 325-330, 2021 Apr 03.
Article in English | MEDLINE | ID: covidwho-1092288

ABSTRACT

Platelets play an essential role in maintaining vascular integrity after injury. In addition, platelets contribute to the immune response to pathogens. For instance, they express receptors that mediate binding of viruses, and toll-like receptors that activate the cell in response to pathogen-associated molecular patterns. Platelets can be beneficial and/or detrimental during viral infections. They reduce blood-borne viruses by engulfing the free virus and presenting the virus to neutrophils. However, platelets can also enhance inflammation and tissue injury during viral infections. Here, we discuss the roles of platelets in viral infection.


Subject(s)
Blood Platelets/immunology , COVID-19/immunology , Host-Pathogen Interactions/immunology , Neutrophils/immunology , Receptors, Virus/immunology , Viral Proteins/immunology , Viruses/immunology , Animals , Blood Platelets/pathology , Blood Platelets/virology , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Cell Communication/genetics , Cell Communication/immunology , Dendritic Cells/immunology , Dendritic Cells/pathology , Dendritic Cells/virology , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Humans , Immunity, Innate , Lymphocytes/immunology , Lymphocytes/pathology , Lymphocytes/virology , Neutrophils/pathology , Neutrophils/virology , Platelet Activation/immunology , Protein Binding , Receptors, Virus/genetics , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology , Viral Proteins/genetics , Viruses/pathogenicity
15.
J Exp Med ; 218(4)2021 04 05.
Article in English | MEDLINE | ID: covidwho-1061104

ABSTRACT

Several studies have analyzed antiviral immune pathways in late-stage severe COVID-19. However, the initial steps of SARS-CoV-2 antiviral immunity are poorly understood. Here we have isolated primary SARS-CoV-2 viral strains and studied their interaction with human plasmacytoid predendritic cells (pDCs), a key player in antiviral immunity. We show that pDCs are not productively infected by SARS-CoV-2. However, they efficiently diversified into activated P1-, P2-, and P3-pDC effector subsets in response to viral stimulation. They expressed CD80, CD86, CCR7, and OX40 ligand at levels similar to influenza virus-induced activation. They rapidly produced high levels of interferon-α, interferon-λ1, IL-6, IP-10, and IL-8. All major aspects of SARS-CoV-2-induced pDC activation were inhibited by hydroxychloroquine. Mechanistically, SARS-CoV-2-induced pDC activation critically depended on IRAK4 and UNC93B1, as established using pDC from genetically deficient patients. Overall, our data indicate that human pDC are efficiently activated by SARS-CoV-2 particles and may thus contribute to type I IFN-dependent immunity against SARS-CoV-2 infection.


Subject(s)
COVID-19/immunology , COVID-19/metabolism , Cell Plasticity/immunology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Interleukin-1 Receptor-Associated Kinases/metabolism , Membrane Transport Proteins/metabolism , SARS-CoV-2/immunology , Biomarkers , COVID-19/drug therapy , COVID-19/virology , Cytokines/metabolism , Dendritic Cells/virology , Host-Pathogen Interactions/immunology , Humans , Hydroxychloroquine/pharmacology , Hydroxychloroquine/therapeutic use , Immunomodulation , Immunophenotyping , Inflammation Mediators/metabolism , Interferon Type I/metabolism , Interferons/metabolism
16.
Med Hypotheses ; 145: 110335, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-837968

ABSTRACT

The COVID-19 positive cases are increasing at an alarming rate across the world. On the contrary, the morbidity and mortality are showing decreasing trend as time progresses. The most intriguing part is the rise in asymptomatic Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) positive cases in the population, which made us speculate some kind of gradual development of immunity in the population. To date, no attention has been given to the accumulation of killed/inactivated/degenerated SARS-CoV-2 associated molecular particle patterns (SAMPPs). In this paper, we introduced the concept of SAMMPs and its existence on inanimate objects is quite conceivable due to the size of SARS-CoV-2 and exuberant shedding of the virus in respiratory secretions. SAMPPs can come into the contact with mucosal surfaces and thereof associated antigen-presenting dendritic cells. Thus, we hypothesized the existence of SAMPPs mediated the development of immunity against SARS-CoV-2 infection, which has caused an increase in the incidence rate of asymptomatic cases and a decrease in mortality rate. To understand the existence of SAMPPs associated natural immunity against SARS-CoV-2, future population based serological testing are recommended to investigate serum antibody levels against various molecular particles associated with SAMPPs.


Subject(s)
COVID-19 Serological Testing/methods , COVID-19 Vaccines , COVID-19/prevention & control , Pathogen-Associated Molecular Pattern Molecules/immunology , Antiviral Agents/therapeutic use , Asymptomatic Infections , COVID-19/immunology , Dendritic Cells/virology , Humans , Immune System , Models, Theoretical , Vaccines, DNA
17.
Prostaglandins Leukot Essent Fatty Acids ; 161: 102177, 2020 10.
Article in English | MEDLINE | ID: covidwho-796199

ABSTRACT

As the infected cases of COVID-19 reach more than 20 million with more than 778,000 deaths globally, an increase in psychiatric disorders including anxiety and depression has been reported. Scientists globally have been searching for novel therapies and vaccines to fight against COVID-19. Improving innate immunity has been suggested to block progression of COVID-19 at early stages, while omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been shown to have immunomodulation effects. Moreover, n-3 PUFAs have also been shown to improve mood disorders, thus, future research is warranted to test if n-3 PUFAs may have the potential to improve our immunity to counteract both physical and mental impact of COVID-19.


Subject(s)
Anxiety/prevention & control , Coronavirus Infections/prevention & control , Depression/prevention & control , Dietary Supplements , Fatty Acids, Omega-3/administration & dosage , Immunologic Factors/administration & dosage , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Anxiety/immunology , Anxiety/metabolism , Anxiety/virology , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Cytokines/biosynthesis , Cytokines/immunology , Dendritic Cells/drug effects , Dendritic Cells/immunology , Dendritic Cells/virology , Depression/immunology , Depression/metabolism , Depression/virology , Epithelial Cells/drug effects , Epithelial Cells/immunology , Epithelial Cells/virology , Fatty Acids, Omega-3/immunology , Fatty Acids, Omega-3/metabolism , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate/drug effects , Immunologic Factors/immunology , Immunologic Factors/metabolism , Lymphocytes/drug effects , Lymphocytes/immunology , Lymphocytes/virology , Macrophages/drug effects , Macrophages/immunology , Macrophages/virology , Pneumonia, Viral/immunology , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , SARS-CoV-2
18.
Cells ; 9(9)2020 09 08.
Article in English | MEDLINE | ID: covidwho-760893

ABSTRACT

The ongoing pandemic due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has so far infected about 2.42 × 107 (as at 27 August 2020) subjects with more than 820,000 deaths. It is the third zoonotic coronavirus-dependent outbreak in the last twenty years and represents a major infective threat for public health worldwide. A main aspect of the infection, in analogy to other viral infections, is the so-called "cytokine storm", an inappropriate molecular response to virus spread which plays major roles in tissue and organ damage. Immunological therapies, including vaccines and humanized monoclonal antibodies, have been proposed as major strategies for prevention and treatment of the disease. Accordingly, a detailed mechanistic knowledge of the molecular events with which the virus infects cells and induces an immunological response appears necessary. In this review, we will report details of the initial process of SARS-CoV-2 cellular entry with major emphasis on the maturation of the spike protein. Then, a particular focus will be devoted to describe the possible mechanisms by which dendritic cells, a major cellular component of innate and adaptive immune responses, may play a role in the spread of the virus in the human body and in the clinical evolution of the disease.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/virology , Dendritic Cells/virology , Pneumonia, Viral/virology , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Humans , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/metabolism , Pyroptosis , Renin-Angiotensin System , SARS-CoV-2 , Virus Internalization
19.
Vaccine ; 38(42): 6487-6499, 2020 09 29.
Article in English | MEDLINE | ID: covidwho-720733

ABSTRACT

The many carbohydrate chains on Covid-19 coronavirus SARS-CoV-2 and its S-protein form a glycan-shield that masks antigenic peptides and decreases uptake of inactivated virus or S-protein vaccines by APC. Studies on inactivated influenza virus and recombinant gp120 of HIV vaccines indicate that glycoengineering of glycan-shields to present α-gal epitopes (Galα1-3Galß1-4GlcNAc-R) enables harnessing of the natural anti-Gal antibody for amplifying vaccine efficacy, as evaluated in mice producing anti-Gal. The α-gal epitope is the ligand for the natural anti-Gal antibody which constitutes ~1% of immunoglobulins in humans. Upon administration of vaccines presenting α-gal epitopes, anti-Gal binds to these epitopes at the vaccination site and forms immune complexes with the vaccines. These immune complexes are targeted for extensive uptake by APC as a result of binding of the Fc portion of immunocomplexed anti-Gal to Fc receptors on APC. This anti-Gal mediated effective uptake of vaccines by APC results in 10-200-fold higher anti-viral immune response and in 8-fold higher survival rate following challenge with a lethal dose of live influenza virus, than same vaccines lacking α-gal epitopes. It is suggested that glycoengineering of carbohydrate chains on the glycan-shield of inactivated SARS-CoV-2 or on S-protein vaccines, for presenting α-gal epitopes, will have similar amplifying effects on vaccine efficacy. α-Gal epitope synthesis on coronavirus vaccines can be achieved with recombinant α1,3galactosyltransferase, replication of the virus in cells with high α1,3galactosyltransferase activity as a result of stable transfection of cells with several copies of the α1,3galactosyltransferase gene (GGTA1), or by transduction of host cells with replication defective adenovirus containing this gene. In addition, recombinant S-protein presenting multiple α-gal epitopes on the glycan-shield may be produced in glycoengineered yeast or bacteria expression systems containing the corresponding glycosyltransferases. Prospective Covid-19 vaccines presenting α-gal epitopes may provide better protection than vaccines lacking this epitope because of increased uptake by APC.


Subject(s)
Antigens, Viral/genetics , Betacoronavirus/drug effects , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Spike Glycoprotein, Coronavirus/genetics , Trisaccharides/immunology , Viral Vaccines/immunology , Animals , Antibodies, Viral/biosynthesis , Antigens, Viral/immunology , Antigens, Viral/metabolism , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/genetics , Coronavirus Infections/immunology , Coronavirus Infections/virology , Dendritic Cells/drug effects , Dendritic Cells/immunology , Dendritic Cells/virology , Genetic Engineering , HIV Core Protein p24/chemistry , HIV Core Protein p24/genetics , HIV Core Protein p24/immunology , HIV Envelope Protein gp120/chemistry , HIV Envelope Protein gp120/genetics , HIV Envelope Protein gp120/immunology , Humans , Immunogenicity, Vaccine , Macrophages/drug effects , Macrophages/immunology , Macrophages/virology , Mice , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Trisaccharides/chemistry , Viral Vaccines/administration & dosage , Viral Vaccines/biosynthesis , Viral Vaccines/genetics
20.
J Infect Dis ; 222(5): 734-745, 2020 08 04.
Article in English | MEDLINE | ID: covidwho-711823

ABSTRACT

Clinical manifestations of coronavirus disease 2019 (COVID-19) vary from asymptomatic virus shedding, nonspecific pharyngitis, to pneumonia with silent hypoxia and respiratory failure. Dendritic cells and macrophages are sentinel cells for innate and adaptive immunity that affect the pathogenesis of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). The interplay between SARS-CoV-2 and these cell types remains unknown. We investigated infection and host responses of monocyte-derived dendritic cells (moDCs) and macrophages (MDMs) infected by SARS-CoV-2. MoDCs and MDMs were permissive to SARS-CoV-2 infection and protein expression but did not support productive virus replication. Importantly, SARS-CoV-2 launched an attenuated interferon response in both cell types and triggered significant proinflammatory cytokine/chemokine expression in MDMs but not moDCs. Investigations suggested that this attenuated immune response to SARS-CoV-2 in moDCs was associated with viral antagonism of STAT1 phosphorylation. These findings may explain the mild and insidious course of COVID-19 until late deterioration.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/immunology , Dendritic Cells/immunology , Interferons/immunology , Monocytes/immunology , Pneumonia, Viral/immunology , STAT1 Transcription Factor/antagonists & inhibitors , Adaptive Immunity , Animals , Betacoronavirus/immunology , Betacoronavirus/isolation & purification , Betacoronavirus/metabolism , COVID-19 , Chemokines/metabolism , Chlorocebus aethiops , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Cytokines/metabolism , Dendritic Cells/metabolism , Dendritic Cells/virology , Humans , Macrophages/immunology , Macrophages/virology , Monocytes/virology , Pandemics , Phosphorylation , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , SARS-CoV-2 , STAT1 Transcription Factor/immunology , STAT1 Transcription Factor/metabolism , Vero Cells , Virus Replication/physiology , Virus Shedding
SELECTION OF CITATIONS
SEARCH DETAIL