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1.
EMBO J ; 41(10): e109622, 2022 May 16.
Article in English | MEDLINE | ID: covidwho-1700141

ABSTRACT

Understanding the molecular pathways driving the acute antiviral and inflammatory response to SARS-CoV-2 infection is critical for developing treatments for severe COVID-19. Here, we find decreasing number of circulating plasmacytoid dendritic cells (pDCs) in COVID-19 patients early after symptom onset, correlating with disease severity. pDC depletion is transient and coincides with decreased expression of antiviral type I IFNα and of systemic inflammatory cytokines CXCL10 and IL-6. Using an in vitro stem cell-based human pDC model, we further demonstrate that pDCs, while not supporting SARS-CoV-2 replication, directly sense the virus and in response produce multiple antiviral (interferons: IFNα and IFNλ1) and inflammatory (IL-6, IL-8, CXCL10) cytokines that protect epithelial cells from de novo SARS-CoV-2 infection. Via targeted deletion of virus-recognition innate immune pathways, we identify TLR7-MyD88 signaling as crucial for production of antiviral interferons (IFNs), whereas Toll-like receptor (TLR)2 is responsible for the inflammatory IL-6 response. We further show that SARS-CoV-2 engages the receptor neuropilin-1 on pDCs to selectively mitigate the antiviral interferon response, but not the IL-6 response, suggesting neuropilin-1 as potential therapeutic target for stimulation of TLR7-mediated antiviral protection.


Subject(s)
COVID-19 , Dendritic Cells , Toll-Like Receptor 2 , Toll-Like Receptor 7 , COVID-19/immunology , COVID-19/pathology , Cytokines/metabolism , Dendritic Cells/immunology , Dendritic Cells/pathology , Humans , Interferon Type I/immunology , Interferon-alpha/immunology , Interleukin-6/immunology , Neuropilin-1/immunology , SARS-CoV-2 , Toll-Like Receptor 2/immunology , Toll-Like Receptor 7/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.
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
4.
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
6.
Int J Mol Sci ; 22(3)2021 Jan 23.
Article in English | MEDLINE | ID: covidwho-1045411

ABSTRACT

Dendritic cells (DC) connect the innate and adaptive arms of the immune system and carry out numerous roles that are significant in the context of viral disease. Their functions include the control of inflammatory responses, the promotion of tolerance, cross-presentation, immune cell recruitment and the production of antiviral cytokines. Based primarily on the available literature that characterizes the behaviour of many DC subsets during Severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19), we speculated possible mechanisms through which DC could contribute to COVID-19 immune responses, such as dissemination of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to lymph nodes, mounting dysfunctional inteferon responses and T cell immunity in patients. We highlighted gaps of knowledge in our understanding of DC in COVID-19 pathogenesis and discussed current pre-clinical development of therapies for COVID-19.


Subject(s)
COVID-19/immunology , Dendritic Cells/immunology , SARS-CoV-2/immunology , Adaptive Immunity , Animals , COVID-19/pathology , COVID-19/therapy , Dendritic Cells/pathology , Humans , Immunity, Innate , T-Lymphocytes/immunology
7.
PLoS One ; 15(12): e0241097, 2020.
Article in English | MEDLINE | ID: covidwho-1004424

ABSTRACT

Clinical manifestations of SARS-CoV-2 infection range from mild to critically severe. The aim of the study was to highlight the immunological events associated with the severity of SARS-CoV-2 infection, with an emphasis on cells of innate immunity. Thirty COVID-19 patients with mild/moderate symptoms and 27 patients with severe/critically severe symptoms were recruited from the Clinical Center of Kragujevac during April 2020. Flow cytometric analysis was performed to reveal phenotypic and functional alterations of peripheral blood cells and to correlate them with the severity of the disease. In severe cases, the number of T and B lymphocytes, dendritic cells, NK cells, and HLA-DR-expressing cells was drastically decreased. In the monocyte population proportion between certain subsets was disturbed and cells coexpressing markers of M1 and M2 monocytes were found in intermediate and non-classical subsets. In mild cases decline in lymphocyte number was less pronounced and innate immunity was preserved as indicated by an increased number of myeloid and activated dendritic cells, NK cells that expressed activation marker at the same level as in control and by low expression of M2 marker in monocyte population. In patients with severe disease, both innate and adoptive immunity are devastated, while in patients with mild symptoms decline in lymphocyte number is lesser, and the innate immunity is preserved.


Subject(s)
Adaptive Immunity , COVID-19/immunology , Dendritic Cells/immunology , Immunity, Innate , Monocytes/immunology , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , Antigens, Differentiation/immunology , COVID-19/pathology , Dendritic Cells/pathology , Female , Flow Cytometry , HLA-DR Antigens/immunology , Humans , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Male , Middle Aged , Monocytes/pathology
8.
J Clin Invest ; 130(12): 6290-6300, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-962340

ABSTRACT

SARS-CoV-2 is responsible for the development of coronavirus disease 2019 (COVID-19) in infected individuals, who can either exhibit mild symptoms or progress toward a life-threatening acute respiratory distress syndrome (ARDS). Exacerbated inflammation and dysregulated immune responses involving T and myeloid cells occur in COVID-19 patients with severe clinical progression. However, the differential contribution of specific subsets of dendritic cells and monocytes to ARDS is still poorly understood. In addition, the role of CD8+ T cells present in the lung of COVID-19 patients and relevant for viral control has not been characterized. Here, we have studied the frequencies and activation profiles of dendritic cells and monocytes present in the blood and lung of COVID-19 patients with different clinical severity in comparison with healthy individuals. Furthermore, these subpopulations and their association with antiviral effector CD8+ T cell subsets were also characterized in lung infiltrates from critical COVID-19 patients. Our results indicate that inflammatory transitional and nonclassical monocytes and CD1c+ conventional dendritic cells preferentially migrate from blood to lungs in patients with severe COVID-19. Thus, this study increases the knowledge of specific myeloid subsets involved in the pathogenesis of COVID-19 disease and could be useful for the design of therapeutic strategies for fighting SARS-CoV-2 infection.


Subject(s)
Antigens, CD1/immunology , COVID-19/immunology , Cell Movement/immunology , Glycoproteins/immunology , Lung/immunology , Monocytes/immunology , Respiratory Distress Syndrome/immunology , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , COVID-19/pathology , Dendritic Cells/immunology , Dendritic Cells/pathology , Female , Humans , Lung/pathology , Male , Middle Aged , Monocytes/classification , Monocytes/pathology , Severity of Illness Index
9.
Immunology ; 161(4): 345-353, 2020 12.
Article in English | MEDLINE | ID: covidwho-738708

ABSTRACT

SARS-CoV-2 is responsible for a new infectious disease (COVID-19) in which individuals can either remain asymptomatic or progress from mild to severe clinical conditions including acute respiratory distress syndrome and multiple organ failure. The immune mechanisms that potentially orchestrate the pathology in SARS-CoV-2 infection are complex and only partially understood. There is still paucity of data on the features of myeloid cells involved in this viral infection. For this reason, we investigated the different activation status profiles and the subset distribution of myeloid cells and their correlation with disease progression in 40 COVID-19 patients at different stages of disease. COVID-19 patients showed a decrease in the absolute number of plasmacytoid and myeloid dendritic cells, different subset distribution of monocytes and different activation patterns of both monocytes and neutrophils, coupled to a significant reduction of HLA-DR monocyte levels. We found that some of these alterations are typical of all COVID-19 patients, while some others vary at different stages of the disease and correlate with biochemical parameters of inflammation. Collectively, these data suggest that not only the lymphoid, but also the myeloid compartment, is severely affected by SARS-CoV-2 infection.


Subject(s)
COVID-19/immunology , Dendritic Cells/immunology , Myeloid Cells/immunology , Adult , Aged , COVID-19/pathology , Dendritic Cells/pathology , Female , Flow Cytometry , Humans , Intensive Care Units , Male , Myeloid Cells/pathology
10.
Immunity ; 53(4): 864-877.e5, 2020 10 13.
Article in English | MEDLINE | ID: covidwho-693493

ABSTRACT

The SARS-CoV-2 pandemic has resulted in millions of infections, yet the role of host immune responses in early COVID-19 pathogenesis remains unclear. By investigating 17 acute and 24 convalescent patients, we found that acute SARS-CoV-2 infection resulted in broad immune cell reduction including T, natural killer, monocyte, and dendritic cells (DCs). DCs were significantly reduced with functional impairment, and ratios of conventional DCs to plasmacytoid DCs were increased among acute severe patients. Besides lymphocytopenia, although neutralizing antibodies were rapidly and abundantly generated in patients, there were delayed receptor binding domain (RBD)- and nucleocapsid protein (NP)-specific T cell responses during the first 3 weeks after symptoms onset. Moreover, acute RBD- and NP-specific T cell responses included relatively more CD4 T cells than CD8 T cells. Our findings provided evidence that impaired DCs, together with timely inverted strong antibody but weak CD8 T cell responses, could contribute to acute COVID-19 pathogenesis and have implications for vaccine development.


Subject(s)
Betacoronavirus/pathogenicity , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Coronavirus Infections/immunology , Dendritic Cells/immunology , Diabetes Mellitus/immunology , Hypertension/immunology , Pneumonia, Viral/immunology , Adult , Aged , Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , Betacoronavirus/immunology , CD4-Positive T-Lymphocytes/pathology , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/virology , COVID-19 , Convalescence , Coronavirus Infections/complications , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Dendritic Cells/pathology , Dendritic Cells/virology , Diabetes Complications , Diabetes Mellitus/diagnosis , Diabetes Mellitus/virology , Disease Progression , Female , Humans , Hypertension/complications , Hypertension/diagnosis , Hypertension/virology , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Killer Cells, Natural/virology , Lymphocyte Activation , Lymphocyte Count , Male , Middle Aged , Monocytes/immunology , Monocytes/pathology , Monocytes/virology , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , SARS-CoV-2 , Severity of Illness Index
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