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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.
Mol Med ; 27(1): 162, 2021 12 27.
Article in English | MEDLINE | ID: covidwho-1582120

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel type b coronavirus responsible for the COVID-19 pandemic. With over 224 million confirmed infections with this virus and more than 4.6 million people dead because of it, it is critically important to define the immunological processes occurring in the human response to this virus and pathogenetic mechanisms of its deadly manifestation. This perspective focuses on the contribution of the recently discovered interaction of SARS-CoV-2 Spike protein with neuropilin 1 (NRP1) receptor, NRP1 as a virus entry receptor for SARS-CoV-2, its role in different physiologic and pathologic conditions, and the potential to target the Spike-NRP1 interaction to combat virus infectivity and severe disease manifestations.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Neuropilin-1/chemistry , Neuropilin-1/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/epidemiology , COVID-19/etiology , Comorbidity , Diabetes Mellitus/epidemiology , Diabetes Mellitus/virology , Female , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/immunology , Humans , Infant , Molecular Targeted Therapy/methods , Neuropilin-1/immunology , Pregnancy , Pregnancy Complications, Infectious/drug therapy , Pregnancy Complications, Infectious/virology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism
5.
Int J Mol Sci ; 22(3)2021 Jan 20.
Article in English | MEDLINE | ID: covidwho-1067752

ABSTRACT

The occurrence of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVD-19), represents a catastrophic threat to global health. Protruding from the viral surface is a densely glycosylated spike (S) protein, which engages angiotensin-converting enzyme 2 (ACE2) to mediate host cell entry. However, studies have reported viral susceptibility in intra- and extrapulmonary immune and non-immune cells lacking ACE2, suggesting that the S protein may exploit additional receptors for infection. Studies have demonstrated interactions between S protein and innate immune system, including C-lectin type receptors (CLR), toll-like receptors (TLR) and neuropilin-1 (NRP1), and the non-immune receptor glucose regulated protein 78 (GRP78). Recognition of carbohydrate moieties clustered on the surface of the S protein may drive receptor-dependent internalization, accentuate severe immunopathological inflammation, and allow for systemic spread of infection, independent of ACE2. Furthermore, targeting TLRs, CLRs, and other receptors (Ezrin and dipeptidyl peptidase-4) that do not directly engage SARS-CoV-2 S protein, but may contribute to augmented anti-viral immunity and viral clearance, may represent therapeutic targets against COVID-19.


Subject(s)
COVID-19/metabolism , COVID-19/pathology , SARS-CoV-2/physiology , Virus Internalization , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/immunology , Disease Progression , Heat-Shock Proteins/immunology , Heat-Shock Proteins/metabolism , Host-Pathogen Interactions , Humans , Lectins, C-Type/immunology , Lectins, C-Type/metabolism , Neuropilin-1/immunology , Neuropilin-1/metabolism , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Toll-Like Receptors/immunology , Toll-Like Receptors/metabolism
6.
PLoS Pathog ; 17(1): e1009153, 2021 01.
Article in English | MEDLINE | ID: covidwho-1006381

ABSTRACT

Neuropilin-1 (NRP-1), a member of a family of signaling proteins, was shown to serve as an entry factor and potentiate SARS Coronavirus 2 (SARS-CoV-2) infectivity in vitro. This cell surface receptor with its disseminated expression is important in angiogenesis, tumor progression, viral entry, axonal guidance, and immune function. NRP-1 is implicated in several aspects of a SARS-CoV-2 infection including possible spread through the olfactory bulb and into the central nervous system and increased NRP-1 RNA expression in lungs of severe Coronavirus Disease 2019 (COVID-19). Up-regulation of NRP-1 protein in diabetic kidney cells hint at its importance in a population at risk of severe COVID-19. Involvement of NRP-1 in immune function is compelling, given the role of an exaggerated immune response in disease severity and deaths due to COVID-19. NRP-1 has been suggested to be an immune checkpoint of T cell memory. It is unknown whether involvement and up-regulation of NRP-1 in COVID-19 may translate into disease outcome and long-term consequences, including possible immune dysfunction. It is prudent to further research NRP-1 and its possibility of serving as a therapeutic target in SARS-CoV-2 infections. We anticipate that widespread expression, abundance in the respiratory and olfactory epithelium, and the functionalities of NRP-1 factor into the multiple systemic effects of COVID-19 and challenges we face in management of disease and potential long-term sequelae.


Subject(s)
COVID-19/immunology , Neuropilin-1/immunology , SARS-CoV-2/immunology , Virus Internalization , COVID-19/pathology , Diabetic Nephropathies/immunology , Diabetic Nephropathies/pathology , Diabetic Nephropathies/virology , Humans , Immunologic Memory , Olfactory Bulb/immunology , Olfactory Bulb/pathology , Olfactory Bulb/virology , Respiratory Mucosa/immunology , Respiratory Mucosa/pathology , Respiratory Mucosa/virology , T-Lymphocytes/immunology , T-Lymphocytes/pathology
7.
Science ; 370(6518): 856-860, 2020 11 13.
Article in English | MEDLINE | ID: covidwho-883299

ABSTRACT

The causative agent of coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For many viruses, tissue tropism is determined by the availability of virus receptors and entry cofactors on the surface of host cells. In this study, we found that neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, an effect blocked by a monoclonal blocking antibody against NRP1. A SARS-CoV-2 mutant with an altered furin cleavage site did not depend on NRP1 for infectivity. Pathological analysis of olfactory epithelium obtained from human COVID-19 autopsies revealed that SARS-CoV-2 infected NRP1-positive cells facing the nasal cavity. Our data provide insight into SARS-CoV-2 cell infectivity and define a potential target for antiviral intervention.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/virology , Neuropilin-1/metabolism , Pneumonia, Viral/virology , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization , Angiotensin-Converting Enzyme 2 , Animals , Antibodies, Monoclonal/immunology , Betacoronavirus/genetics , COVID-19 , Caco-2 Cells , Female , HEK293 Cells , Host Microbial Interactions , Humans , Lung/metabolism , Male , Metal Nanoparticles , Mice , Mice, Inbred C57BL , Mutation , Neuropilin-1/chemistry , Neuropilin-1/genetics , Neuropilin-1/immunology , Neuropilin-2/metabolism , Olfactory Mucosa/metabolism , Olfactory Mucosa/virology , Pandemics , Peptide Fragments/metabolism , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Protein Binding , Protein Domains , Respiratory Mucosa/metabolism , SARS-CoV-2 , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/chemistry
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