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2.
J Steroid Biochem Mol Biol ; 213: 105957, 2021 10.
Article in English | MEDLINE | ID: covidwho-1561628

ABSTRACT

This review examines the beneficial effects of ultraviolet radiation on systemic autoimmune diseases, including multiple sclerosis and type I diabetes, where the epidemiological evidence for the vitamin D-independent effects of sunlight is most apparent. Ultraviolet radiation, in addition to its role in the synthesis of vitamin D, stimulates anti-inflammatory pathways, alters the composition of dendritic cells, T cells, and T regulatory cells, and induces nitric oxide synthase and heme oxygenase metabolic pathways, which may directly or indirectly mitigate disease progression and susceptibility. Recent work has also explored how the immune-modulating functions of ultraviolet radiation affect type II diabetes, cancer, and the current global pandemic caused by SARS-CoV-2. These diseases are particularly important amidst global changes in lifestyle that result in unhealthy eating, increased sedentary habits, and alcohol and tobacco consumption. Compelling epidemiological data shows increased ultraviolet radiation associated with reduced rates of certain cancers, such as colorectal cancer, breast cancer, non-Hodgkins lymphoma, and ultraviolet radiation exposure correlated with susceptibility and mortality rates of COVID-19. Therefore, understanding the effects of ultraviolet radiation on both vitamin D-dependent and -independent pathways is necessary to understand how they influence the course of many human diseases.


Subject(s)
COVID-19/prevention & control , Diabetes Mellitus, Type 1/prevention & control , Diabetes Mellitus, Type 2/prevention & control , Multiple Sclerosis/prevention & control , Neoplasms/prevention & control , Sunlight , Vitamin D/metabolism , Alcohol Drinking/adverse effects , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Dendritic Cells/immunology , Dendritic Cells/radiation effects , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 2/immunology , Diabetes Mellitus, Type 2/pathology , Disease Progression , Disease Susceptibility , Heme Oxygenase (Decyclizing)/genetics , Heme Oxygenase (Decyclizing)/immunology , Humans , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Neoplasms/immunology , Neoplasms/pathology , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/immunology , SARS-CoV-2/pathogenicity , SARS-CoV-2/radiation effects , Sedentary Behavior , T-Lymphocytes/immunology , T-Lymphocytes/radiation effects , Vitamin D/immunology
3.
Front Immunol ; 12: 697622, 2021.
Article in English | MEDLINE | ID: covidwho-1518482

ABSTRACT

Objectives: The longitudinal and systematic evaluation of immunity in coronavirus disease 2019 (COVID-19) patients is rarely reported. Methods: Parameters involved in innate, adaptive, and humoral immunity were continuously monitored in COVID-19 patients from onset of illness until 45 days after symptom onset. Results: This study enrolled 27 mild, 47 severe, and 46 deceased COVID-19 patients. Generally, deceased patients demonstrated a gradual increase of neutrophils and IL-6 but a decrease of lymphocytes and platelets after the onset of illness. Specifically, sustained low numbers of CD8+ T cells, NK cells, and dendritic cells were noted in deceased patients, while these cells gradually restored in mild and severe patients. Furthermore, deceased patients displayed a rapid increase of HLA-DR expression on CD4+ T cells in the early phase, but with a low level of overall CD45RO and HLA-DR expressions on CD4+ and CD8+ T cells, respectively. Notably, in the early phase, deceased patients showed a lower level of plasma cells and antigen-specific IgG, but higher expansion of CD16+CD14+ proinflammatory monocytes and HLA-DR-CD14+ monocytic-myeloid-derived suppressor cells (M-MDSCs) than mild or severe patients. Among these immunological parameters, M-MDSCs showed the best performance in predicting COVID-19 mortality, when using a cutoff value of ≥10%. Cluster analysis found a typical immunological pattern in deceased patients on day 9 after onset, which was characterized as the increase of inflammatory markers (M-MDSCs, neutrophils, CD16+CD14+ monocytes, and IL-6) but a decrease of host immunity markers. Conclusions: This study systemically characterizes the kinetics of immunity of COVID-19, highlighting the importance of immunity in patient prognosis.


Subject(s)
COVID-19/immunology , SARS-CoV-2 , Adaptive Immunity , Aged , Aged, 80 and over , Antibodies, Viral/blood , B-Lymphocytes/immunology , COVID-19/blood , COVID-19/classification , COVID-19/physiopathology , Cytokines/blood , Dendritic Cells/immunology , Female , Humans , Immunity, Innate , Immunoglobulin G/blood , Killer Cells, Natural/immunology , Lymphocyte Count , Male , Middle Aged , SARS-CoV-2/immunology , Severity of Illness Index , T-Lymphocytes/immunology
4.
Elife ; 102021 04 27.
Article in English | MEDLINE | ID: covidwho-1513055

ABSTRACT

Dendritic cells (DCs) regulate processes ranging from antitumor and antiviral immunity to host-microbe communication at mucosal surfaces. It remains difficult, however, to genetically manipulate human DCs, limiting our ability to probe how DCs elicit specific immune responses. Here, we develop a CRISPR-Cas9 genome editing method for human monocyte-derived DCs (moDCs) that mediates knockouts with a median efficiency of >94% across >300 genes. Using this method, we perform genetic screens in moDCs, identifying mechanisms by which DCs tune responses to lipopolysaccharides from the human microbiome. In addition, we reveal donor-specific responses to lipopolysaccharides, underscoring the importance of assessing immune phenotypes in donor-derived cells, and identify candidate genes that control this specificity, highlighting the potential of our method to pinpoint determinants of inter-individual variation in immunity. Our work sets the stage for a systematic dissection of the immune signaling at the host-microbiome interface and for targeted engineering of DCs for neoantigen vaccination.


Subject(s)
CRISPR-Associated Protein 9/genetics , CRISPR-Cas Systems , Clustered Regularly Interspaced Short Palindromic Repeats , Dendritic Cells/immunology , Gene Editing , Genomics , Immunity, Innate/genetics , Bacteroides thetaiotaomicron/immunology , CRISPR-Associated Protein 9/metabolism , Cells, Cultured , Cytokines/genetics , Cytokines/metabolism , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Gene Expression Regulation , Humans , Immunity, Innate/drug effects , Lipopolysaccharides/pharmacology , Phenotype , Signal Transduction , Toll-Like Receptor 4/agonists , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism
5.
Front Immunol ; 12: 739757, 2021.
Article in English | MEDLINE | ID: covidwho-1505515

ABSTRACT

Coronavirus disease 2019 (COVID-19) exhibits a sex bias with males showing signs of more severe disease and hospitalizations compared with females. The mechanisms are not clear but differential immune responses, particularly the initial innate immune response, between sexes may be playing a role. The early innate immune responses to SARS-CoV-2 have not been studied because of the gap in timing between the patient becoming infected, showing symptoms, and getting the treatment. The primary objective of the present study was to compare the response of dendritic cells (DCs) and monocytes from males and females to SARS-CoV-2, 24 h after infection. To investigate this, peripheral blood mononuclear cells (PBMCs) from healthy young individuals were stimulated in vitro with the virus. Our results indicate that PBMCs from females upregulated the expression of HLA-DR and CD86 on pDCs and mDCs after stimulation with the virus, while the activation of these cells was not significant in males. Monocytes from females also displayed increased activation than males. In addition, females secreted significantly higher levels of IFN-α and IL-29 compared with males at 24 h. However, the situation was reversed at 1 week post stimulation and males displayed high levels of IFN-α production compared with females. Further investigations revealed that the secretion of CXCL-10, a chemokine associated with lung complications, was higher in males than females at 24 h. The PBMCs from females also displayed increased induction of CTLs. Altogether, our results suggest that decreased activation of pDCs, mDCs, and monocytes and the delayed and prolonged IFN-α secretion along with increased CXCL-10 secretion may be responsible for the increased morbidity and mortality of males to COVID-19.


Subject(s)
COVID-19/immunology , Dendritic Cells/immunology , Leukocytes, Mononuclear/immunology , SARS-CoV-2/physiology , Adaptive Immunity , Adult , Chemokine CXCL1/metabolism , Female , HLA-DR Antigens/metabolism , Healthy Volunteers , Humans , Immunity, Innate , Interferon-gamma/metabolism , Male , Middle Aged , Sex Characteristics , Up-Regulation , Young Adult
6.
Proc Natl Acad Sci U S A ; 118(39)2021 09 28.
Article in English | MEDLINE | ID: covidwho-1493337

ABSTRACT

The COVID-19 pandemic highlights the importance of efficient and safe vaccine development. Vaccine adjuvants are essential to boost and tailor the immune response to the corresponding pathogen. To allow for an educated selection, we assessed the effect of different adjuvants on human monocyte-derived dendritic cells (DCs) and their ability to polarize innate and adaptive immune responses. In contrast to commonly used adjuvants, such as aluminum hydroxide, Toll-like receptor (TLR) agonists induced robust phenotypic and functional DC maturation. In a DC-lymphocyte coculture system, we investigated the ensuing immune reactions. While monophosphoryl lipid A synthetic, a TLR4 ligand, induced checkpoint inhibitors indicative for immune exhaustion, the TLR7/8 agonist Resiquimod (R848) induced prominent type-1 interferon and interleukin 6 responses and robust CTL, B-cell, and NK-cell proliferation, which is particularly suited for antiviral immune responses. The recently licensed COVID-19 vaccines, BNT162b and mRNA-1273, are both based on single-stranded RNA. Indeed, we could confirm that the cytokine profile induced by lipid-complexed RNA was almost identical to the pattern induced by R848. Although this awaits further investigation, our results suggest that their efficacy involves the highly efficient antiviral response pattern stimulated by the RNAs' TLR7/8 activation.


Subject(s)
Adjuvants, Immunologic/pharmacology , COVID-19/immunology , Dendritic Cells/immunology , Immunity, Cellular/drug effects , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Adolescent , Adult , Aged , Female , Humans , Imidazoles/pharmacology , Lipid A/analogs & derivatives , Lipid A/pharmacology , Male , Middle Aged , Toll-Like Receptors/immunology
7.
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
8.
PLoS Pathog ; 17(10): e1009742, 2021 10.
Article in English | MEDLINE | ID: covidwho-1456098

ABSTRACT

Disease manifestations in COVID-19 range from mild to severe illness associated with a dysregulated innate immune response. Alterations in function and regeneration of dendritic cells (DCs) and monocytes may contribute to immunopathology and influence adaptive immune responses in COVID-19 patients. We analyzed circulating DC and monocyte subsets in 65 hospitalized COVID-19 patients with mild/moderate or severe disease from acute illness to recovery and in healthy controls. Persisting reduction of all DC subpopulations was accompanied by an expansion of proliferating Lineage-HLADR+ cells lacking DC markers. Increased frequency of CD163+ CD14+ cells within the recently discovered DC3 subpopulation in patients with more severe disease was associated with systemic inflammation, activated T follicular helper cells, and antibody-secreting cells. Persistent downregulation of CD86 and upregulation of programmed death-ligand 1 (PD-L1) in conventional DCs (cDC2 and DC3) and classical monocytes associated with a reduced capacity to stimulate naïve CD4+ T cells correlated with disease severity. Long-lasting depletion and functional impairment of DCs and monocytes may have consequences for susceptibility to secondary infections and therapy of COVID-19 patients.


Subject(s)
COVID-19/immunology , Dendritic Cells/immunology , Regeneration/immunology , SARS-CoV-2/immunology , Adult , Antigens, CD/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , COVID-19/pathology , Dendritic Cells/pathology , Female , Humans , Male , Middle Aged , Monocytes/immunology , Monocytes/pathology , Programmed Cell Death 1 Receptor/immunology
9.
Front Immunol ; 12: 705646, 2021.
Article in English | MEDLINE | ID: covidwho-1450806

ABSTRACT

COVID-19 is a disease with a spectrum of clinical responses ranging from moderate to critical. To study and control its effects, a large number of researchers are focused on two substantial aims. On the one hand, the discovery of diverse biomarkers to classify and potentially anticipate the disease severity of patients. These biomarkers could serve as a medical criterion to prioritize attention to those patients with higher prone to severe responses. On the other hand, understanding how the immune system orchestrates its responses in this spectrum of disease severities is a fundamental issue required to design new and optimized therapeutic strategies. In this work, using single-cell RNAseq of bronchoalveolar lavage fluid of nine patients with COVID-19 and three healthy controls, we contribute to both aspects. First, we presented computational supervised machine-learning models with high accuracy in classifying the disease severity (moderate and severe) in patients with COVID-19 starting from single-cell data from bronchoalveolar lavage fluid. Second, we identified regulatory mechanisms from the heterogeneous cell populations in the lungs microenvironment that correlated with different clinical responses. Given the results, patients with moderate COVID-19 symptoms showed an activation/inactivation profile for their analyzed cells leading to a sequential and innocuous immune response. In comparison, severe patients might be promoting cytotoxic and pro-inflammatory responses in a systemic fashion involving epithelial and immune cells without the possibility to develop viral clearance and immune memory. Consequently, we present an in-depth landscape analysis of how transcriptional factors and pathways from these heterogeneous populations can regulate their expression to promote or restrain an effective immune response directly linked to the patients prognosis.


Subject(s)
Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , COVID-19/pathology , Lung/cytology , SARS-CoV-2/immunology , B-Lymphocytes/immunology , Biomarkers , Bronchoalveolar Lavage Fluid/chemistry , Dendritic Cells/immunology , Epithelial Cells/cytology , Epithelial Cells/virology , Humans , Killer Cells, Natural/immunology , Lung/chemistry , Machine Learning , Macrophages/immunology , Monocytes/immunology , Neutrophils/immunology , RNA, Viral/genetics , Sequence Analysis, RNA , Severity of Illness Index , Single-Cell Analysis , T-Lymphocytes/immunology
11.
Viruses ; 13(9)2021 09 15.
Article in English | MEDLINE | ID: covidwho-1411083

ABSTRACT

Type I Interferons (IFN-I) are a family of potent antiviral cytokines that act through the direct restriction of viral replication and by enhancing antiviral immunity. However, these powerful cytokines are a caged lion, as excessive and sustained IFN-I production can drive immunopathology during infection, and aberrant IFN-I production is a feature of several types of autoimmunity. As specialized producers of IFN-I plasmacytoid (p), dendritic cells (DCs) can secrete superb quantities and a wide breadth of IFN-I isoforms immediately after infection or stimulation, and are the focus of this review. Notably, a few days after viral infection pDCs tune down their capacity for IFN-I production, producing less cytokines in response to both the ongoing infection and unrelated secondary stimulations. This process, hereby referred to as "pDC exhaustion", favors viral persistence and associates with reduced innate responses and increased susceptibility to secondary opportunistic infections. On the other hand, pDC exhaustion may be a compromise to avoid IFN-I driven immunopathology. In this review we reflect on the mechanisms that initially induce IFN-I and subsequently silence their production by pDCs during a viral infection. While these processes have been long studied across numerous viral infection models, the 2019 coronavirus disease (COVID-19) pandemic has brought their discussion back to the fore, and so we also discuss emerging results related to pDC-IFN-I production in the context of COVID-19.


Subject(s)
COVID-19/metabolism , COVID-19/virology , Host-Pathogen Interactions , Interferon Type I/biosynthesis , SARS-CoV-2/physiology , Biomarkers , COVID-19/immunology , Cytokines/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate/immunology , Immunomodulation , Toll-Like Receptors/metabolism
12.
Int J Mol Sci ; 22(18)2021 Sep 16.
Article in English | MEDLINE | ID: covidwho-1409704

ABSTRACT

Autotaxin (ATX; ENPP2) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling phospholipid. Genetic and pharmacologic studies have previously established a pathologic role for ATX and LPA signaling in pulmonary injury, inflammation, and fibrosis. Here, increased ENPP2 mRNA levels were detected in immune cells from nasopharyngeal swab samples of COVID-19 patients, and increased ATX serum levels were found in severe COVID-19 patients. ATX serum levels correlated with the corresponding increased serum levels of IL-6 and endothelial damage biomarkers, suggesting an interplay of the ATX/LPA axis with hyperinflammation and the associated vascular dysfunction in COVID-19. Accordingly, dexamethasone (Dex) treatment of mechanically ventilated patients reduced ATX levels, as shown in two independent cohorts, indicating that the therapeutic benefits of Dex include the suppression of ATX. Moreover, large scale analysis of multiple single cell RNA sequencing datasets revealed the expression landscape of ENPP2 in COVID-19 and further suggested a role for ATX in the homeostasis of dendritic cells, which exhibit both numerical and functional deficits in COVID-19. Therefore, ATX has likely a multifunctional role in COVID-19 pathogenesis, suggesting that its pharmacological targeting might represent an additional therapeutic option, both during and after hospitalization.


Subject(s)
COVID-19/diagnosis , Dendritic Cells/immunology , Phosphodiesterase Inhibitors/therapeutic use , Phosphoric Diester Hydrolases/blood , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/blood , COVID-19/immunology , COVID-19/therapy , Cohort Studies , Datasets as Topic , Dendritic Cells/drug effects , Dexamethasone/pharmacology , Dexamethasone/therapeutic use , Endothelium, Vascular/immunology , Endothelium, Vascular/pathology , Female , Humans , Interleukin-6/blood , Interleukin-6/metabolism , Male , Middle Aged , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , RNA-Seq , Respiration, Artificial , SARS-CoV-2/isolation & purification , Severity of Illness Index , Signal Transduction/drug effects , Signal Transduction/immunology , Single-Cell Analysis
13.
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
14.
Viruses ; 13(9)2021 09 02.
Article in English | MEDLINE | ID: covidwho-1390789

ABSTRACT

SARS-CoV-2 uses ACE2 and TMPRSS2 to gain entry into the cell. However, recent studies have shown that SARS-CoV-2 may use additional host factors that are required for the viral lifecycle. Here we used publicly available datasets, CoV-associated genes, and machine learning algorithms to explore the SARS-CoV-2 interaction landscape in different tissues. We found that in general a small fraction of cells express ACE2 in the different tissues, including nasal, bronchi, and lungs. We show that a small fraction of immune cells (including T cells, macrophages, dendritic cells) found in tissues also express ACE2. We show that healthy circulating immune cells do not express ACE2 and TMPRSS2. However, a small fraction of circulating immune cells (including dendritic cells, monocytes, T cells) in the PBMC of COVID-19 patients express ACE2 and TMPRSS2. Additionally, we found that a large spectrum of cells (in tissues and circulation) in both healthy and COVID-19-positive patients were significantly enriched for SARS-CoV-2 factors, such as those associated with RHOA and RAB GTPases, mRNA translation proteins, COPI- and COPII-mediated transport, and integrins. Thus, we propose that further research is needed to explore if SARS-CoV-2 can directly infect tissue and circulating immune cells to better understand the virus' mechanism of action.


Subject(s)
COVID-19/etiology , Disease Susceptibility , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , SARS-CoV-2/physiology , Virus Internalization , COVID-19/blood , Dendritic Cells/immunology , Dendritic Cells/metabolism , Gene Expression Profiling , Gene Expression Regulation , High-Throughput Nucleotide Sequencing , Humans , Immune System/immunology , Immune System/metabolism , Immunity, Innate , Macrophages/immunology , Macrophages/metabolism , Single-Cell Analysis
15.
Clin Rev Allergy Immunol ; 60(2): 259-270, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1384600

ABSTRACT

Ultraviolet blood irradiation (UBI) was used with success in the 1930s and 1940s for a variety of diseases. Despite the success, the lack of understanding of the detailed mechanisms of actions, and the achievements of antibiotics, phased off the use of UBI from the 1950s. The emergence of novel viral infections, from HIV/AIDS to Ebola, from SARS and MERS, and SARS-CoV-2, bring back the attention to this therapeutical opportunity. UBI has a complex virucidal activity, mostly acting on the immune system response. It has effects on lymphocytes (T-cells and B-cells), macrophages, monocytes, dendritic cells, low-density lipoprotein (LDL), and lipids. The Knott technique was applied for bacterial infections such as tuberculosis to viral infections such as hepatitis or influenza. The more complex extracorporeal photopheresis (ECP) is also being applied to hematological cancers such as T-cell lymphomas. Further studies of UBI may help to create a useful device that may find applications for novel viruses that are resistant to known antivirals or vaccines, or also bacteria that are resistant to known antibiotics.


Subject(s)
COVID-19/therapy , Photopheresis/methods , SARS-CoV-2/radiation effects , Ultraviolet Rays , Bacteria/radiation effects , Bacterial Infections/microbiology , Bacterial Infections/therapy , COVID-19/virology , Cytokines/metabolism , Dendritic Cells/immunology , Dendritic Cells/radiation effects , Humans , Lymphocytes/immunology , Lymphocytes/radiation effects , Macrophages/immunology , Macrophages/radiation effects , Monocytes/immunology , Monocytes/radiation effects , Signal Transduction/immunology , Signal Transduction/radiation effects , Treatment Outcome
16.
Int J Mol Sci ; 22(17)2021 Aug 26.
Article in English | MEDLINE | ID: covidwho-1374426

ABSTRACT

The current spreading coronavirus SARS-CoV-2 is highly infectious and pathogenic. In this study, we screened the gene expression of three host receptors (ACE2, DC-SIGN and L-SIGN) of SARS coronaviruses and dendritic cells (DCs) status in bulk and single cell transcriptomic datasets of upper airway, lung or blood of COVID-19 patients and healthy controls. In COVID-19 patients, DC-SIGN gene expression was interestingly decreased in lung DCs but increased in blood DCs. Within DCs, conventional DCs (cDCs) were depleted while plasmacytoid DCs (pDCs) were augmented in the lungs of mild COVID-19. In severe cases, we identified augmented types of immature DCs (CD22+ or ANXA1+ DCs) with MHCII downregulation. In this study, our observation indicates that DCs in severe cases stimulate innate immune responses but fail to specifically present SARS-CoV-2. It provides insights into the profound modulation of DC function in severe COVID-19.


Subject(s)
COVID-19/immunology , Cell Adhesion Molecules/genetics , Dendritic Cells/immunology , Gene Expression Regulation/immunology , Lectins, C-Type/genetics , Receptors, Cell Surface/genetics , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/diagnosis , COVID-19/pathology , COVID-19/virology , Cell Adhesion Molecules/metabolism , Datasets as Topic , Dendritic Cells/metabolism , Genome-Wide Association Study , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate , Lectins, C-Type/metabolism , Lung/immunology , Lung/pathology , Lung/virology , Mendelian Randomization Analysis , Nasopharynx/immunology , Nasopharynx/pathology , Nasopharynx/virology , RNA-Seq , Receptors, Cell Surface/metabolism , Severity of Illness Index , Single-Cell Analysis
17.
Adv Mater ; 33(40): e2102528, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1358054

ABSTRACT

Dendritic cell (DC) vaccines are used for cancer and infectious diseases, albeit with limited efficacy. Modulating the formation of DC-T-cell synapses may greatly increase their efficacy. The effects of graphene oxide (GO) nanosheets on DCs and DC-T-cell synapse formation are evaluated. In particular, size-dependent interactions are observed between GO nanosheets and DCs. GOs with diameters of >1 µm (L-GOs) demonstrate strong adherence to the DC surface, inducing cytoskeletal reorganization via the RhoA-ROCK-MLC pathway, while relatively small GOs (≈500 nm) are predominantly internalized by DCs. Furthermore, L-GO treatment enhances DC-T-cell synapse formation via cytoskeleton-dependent membrane positioning of integrin ICAM-1. L-GO acts as a "nanozipper," facilitating the aggregation of DC-T-cell clusters to produce a stable microenvironment for T cell activation. Importantly, L-GO-adjuvanted DCs promote robust cytotoxic T cell immune responses against SARS-CoV-2 spike 1, leading to >99.7% viral RNA clearance in mice infected with a clinically isolated SARS-CoV-2 strain. These findings highlight the potential value of nanomaterials as DC vaccine adjuvants for modulating DC-T-cell synapse formation and provide a basis for the development of effective COVID-19 vaccines.


Subject(s)
Adjuvants, Immunologic/therapeutic use , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Dendritic Cells/immunology , Graphite/therapeutic use , Nanostructures/therapeutic use , Adjuvants, Immunologic/chemistry , Animals , COVID-19/immunology , COVID-19 Vaccines/immunology , Dendritic Cells/drug effects , Graphite/chemistry , Humans , Mice , Nanostructures/chemistry , SARS-CoV-2/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
18.
Front Immunol ; 12: 654587, 2021.
Article in English | MEDLINE | ID: covidwho-1348485

ABSTRACT

Background: SARS-CoV-2 occurs in the majority of children as COVID-19, without symptoms or with a paucisymptomatic respiratory syndrome, but a small proportion of children develop the systemic Multi Inflammatory Syndrome (MIS-C), characterized by persistent fever and systemic hyperinflammation, with some clinical features resembling Kawasaki Disease (KD). Objective: With this study we aimed to shed new light on the pathogenesis of these two SARS-CoV-2-related clinical manifestations. Methods: We investigated lymphocyte and dendritic cells subsets, chemokine/cytokine profiles and evaluated the neutrophil activity mediators, myeloperoxidase (MPO), and reactive oxygen species (ROS), in 10 children with COVID-19 and 9 with MIS-C at the time of hospital admission. Results: Patients with MIS-C showed higher plasma levels of C reactive protein (CRP), MPO, IL-6, and of the pro-inflammatory chemokines CXCL8 and CCL2 than COVID-19 children. In addition, they displayed higher levels of the chemokines CXCL9 and CXCL10, mainly induced by IFN-γ. By contrast, we detected IFN-α in plasma of children with COVID-19, but not in patients with MIS-C. This observation was consistent with the increase of ISG15 and IFIT1 mRNAs in cells of COVID-19 patients, while ISG15 and IFIT1 mRNA were detected in MIS-C at levels comparable to healthy controls. Moreover, quantification of the number of plasmacytoid dendritic cells (pDCs), which constitute the main source of IFN-α, showed profound depletion of this subset in MIS-C, but not in COVID-19. Conclusions: Our results show a pattern of immune response which is suggestive of type I interferon activation in COVID-19 children, probably related to a recent interaction with the virus, while in MIS-C the immune response is characterized by elevation of the inflammatory cytokines/chemokines IL-6, CCL2, and CXCL8 and of the chemokines CXCL9 and CXL10, which are markers of an active Th1 type immune response. We believe that these immunological events, together with neutrophil activation, might be crucial in inducing the multisystem and cardiovascular damage observed in MIS-C.


Subject(s)
COVID-19/immunology , Chemokine CXCL10/immunology , Chemokine CXCL9/immunology , Dendritic Cells/immunology , Interferon-gamma/immunology , Plasma Cells/immunology , SARS-CoV-2/immunology , Systemic Inflammatory Response Syndrome/immunology , Child , Child, Preschool , Female , Humans , Infant , Male , Retrospective Studies
19.
Front Immunol ; 12: 679344, 2021.
Article in English | MEDLINE | ID: covidwho-1325528

ABSTRACT

Recently, mRNA vaccines have become a significant type of therapeutic and have created new fields in the biopharmaceutical industry. mRNA vaccines are promising next-generation vaccines that have introduced a new age in vaccinology. The recent approval of two COVID-19 mRNA vaccines (mRNA-1273 and BNT162b2) has accelerated mRNA vaccine technology and boosted the pharmaceutical and biotechnology industry. These mRNA vaccines will help to tackle COVID-19 pandemic through immunization, offering considerable hope for future mRNA vaccines. Human trials with data both from mRNA cancer vaccines and mRNA infectious disease vaccines have provided encouraging results, inspiring the pharmaceutical and biotechnology industries to focus on this area of research. In this article, we discuss current mRNA vaccines broadly in two parts. In the first part, mRNA vaccines in general and COVID-19 mRNA vaccines are discussed. We presented the mRNA vaccine structure in general, the different delivery systems, the immune response, and the recent clinical trials for mRNA vaccines (both for cancer mRNA vaccines and different infectious diseases mRNA vaccines). In the second part, different COVID-19 mRNA vaccines are explained. Finally, we illustrated a snapshot of the different leading mRNA vaccine developers, challenges, and future prospects of mRNA vaccines.


Subject(s)
COVID-19 Vaccines/therapeutic use , Cancer Vaccines/therapeutic use , Drug Development , Vaccines, Synthetic/therapeutic use , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Cancer Vaccines/genetics , Cancer Vaccines/immunology , Dendritic Cells/immunology , Drug Delivery Systems , Humans , Immunity , Neoplasms/immunology , Neoplasms/therapy , SARS-CoV-2/immunology , Vaccination , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology
20.
Cell Mol Immunol ; 18(9): 2128-2139, 2021 09.
Article in English | MEDLINE | ID: covidwho-1320227

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection induces an exacerbated inflammation driven by innate immunity components. Dendritic cells (DCs) play a key role in the defense against viral infections, for instance plasmacytoid DCs (pDCs), have the capacity to produce vast amounts of interferon-alpha (IFN-α). In COVID-19 there is a deficit in DC numbers and IFN-α production, which has been associated with disease severity. In this work, we described that in addition to the DC deficiency, several DC activation and homing markers were altered in acute COVID-19 patients, which were associated with multiple inflammatory markers. Remarkably, previously hospitalized and nonhospitalized patients remained with decreased numbers of CD1c+ myeloid DCs and pDCs seven months after SARS-CoV-2 infection. Moreover, the expression of DC markers such as CD86 and CD4 were only restored in previously nonhospitalized patients, while no restoration of integrin ß7 and indoleamine 2,3-dyoxigenase (IDO) levels were observed. These findings contribute to a better understanding of the immunological sequelae of COVID-19.


Subject(s)
COVID-19/immunology , Dendritic Cells/immunology , SARS-CoV-2/immunology , Cells, Cultured , Female , Humans , Immunity, Innate/immunology , Inflammation/immunology , Interferon-alpha/immunology , Leukocytes, Mononuclear/immunology , Male , Severity of Illness Index
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