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1.
Aging (Albany NY) ; 13(23): 24943-24962, 2021 12 04.
Article in English | MEDLINE | ID: covidwho-1622953

ABSTRACT

Ongoing pandemic and potential resurgence of Coronavirus disease 2019 (COVID-19) has prompted urgent efforts to investigate the immunological memory of convalescent patients, especially in patients with active cancers. Here we performed single-cell RNA sequencing in peripheral blood samples of 3 healthy donors (HDs), 4 COVID-19 patients (Covs) and 4 COVID-19 patients with active gynecological tumor (TCs) pre- and post- anti-tumor treatment. All Covs patients had recovered from their acute infection. Interestingly, the molecular features of PBMCs in TCs are similar to that in Covs, suggesting that convalescent COVID-19 with gynecologic tumors do not have major immunological changes and may be protected against reinfection similar to COVID-19 patients without tumors. Moreover, the chemotherapy given to these patients mainly caused neutropenia, while having little effect on the proportion and functional phenotype of T and B cells, and T cell clonal expansion. Notably, anti-PD-L1 treatment massively increased cytotoxic scores of NK cells, and T cells, and facilitated clonal expansion of T cells in these patients. It is likely that T cells could protect patients from SARS-CoV-2 virus reinfection and anti-PD-L1 treatment can enhance the anti-viral activity of the T cells.


Subject(s)
COVID-19/complications , Genital Neoplasms, Female/complications , Genital Neoplasms, Female/therapy , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy , Antibodies, Viral/immunology , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , COVID-19/immunology , COVID-19/prevention & control , Female , Genital Neoplasms, Female/immunology , Humans , Immune Checkpoint Inhibitors/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Single-Cell Analysis , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
3.
Int J Mol Sci ; 22(22)2021 Nov 19.
Article in English | MEDLINE | ID: covidwho-1524027

ABSTRACT

Severe outcomes of COVID-19 are associated with pathological response of the immune system to the SARS-CoV-2 infection. Emerging evidence suggests that an interaction may exist between COVID-19 pathogenesis and a broad range of xenobiotics, resulting in significant increases in death rates in highly exposed populations. Therefore, a better understanding of the molecular basis of the interaction between SARS-CoV-2 infection and chemical exposures may open opportunities for better preventive and therapeutic interventions. We attempted to gain mechanistic knowledge on the interaction between SARS-CoV-2 infection and chemical exposures using an in silico approach, where we identified genes and molecular pathways affected by both chemical exposures and SARS-CoV-2 in human immune cells (T-cells, B-cells, NK-cells, dendritic, and monocyte cells). Our findings demonstrate for the first time that overlapping molecular mechanisms affected by a broad range of chemical exposures and COVID-19 are linked to IFN type I/II signaling pathways and the process of antigen presentation. Based on our data, we also predict that exposures to various chemical compounds will predominantly impact the population of monocytes during the response against COVID-19.


Subject(s)
COVID-19/immunology , Immunity, Innate/drug effects , Xenobiotics/pharmacology , B-Lymphocytes/cytology , B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , COVID-19/pathology , COVID-19/virology , Humans , Interferons/metabolism , SARS-CoV-2/isolation & purification , Signal Transduction/drug effects , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism
4.
mBio ; 12(6): e0290721, 2021 12 21.
Article in English | MEDLINE | ID: covidwho-1518121

ABSTRACT

Oncogenic gammaherpesviruses express viral products during latent and lytic infection that block the innate immune response. Previously, we found that Kaposi's sarcoma herpesvirus (KSHV/human herpesvirus-8) viral microRNAs (miRNAs) downregulate cholesterol biogenesis, and we hypothesized that this prevents the production of 25-hydroxycholesterol (25HC), a cholesterol derivative. 25HC blocks KSHV de novo infection of primary endothelial cells at a postentry step and decreases viral gene expression of LANA (latency-associated nuclear antigen) and RTA. Herein we expanded on this observation by determining transcriptomic changes associated with 25HC treatment of primary endothelial cells using RNA sequencing (RNA-Seq). We found that 25HC treatment inhibited KSHV gene expression and induced interferon-stimulated genes (ISGs) and several inflammatory cytokines (interleukin 8 [IL-8], IL-1α). Some 25HC-induced genes were partially responsible for the broadly antiviral effect of 25HC against several viruses. Additionally, we found that 25HC inhibited infection of primary B cells by a related oncogenic virus, Epstein-Barr virus (EBV/human herpesvirus-4) by suppressing key viral genes such as LMP-1 and inducing apoptosis. RNA-Seq analysis revealed that IL-1 and IL-8 pathways were induced by 25HC in both primary endothelial cells and B cells. We also found that the gene encoding cholesterol 25-hydroxylase (CH25H), which converts cholesterol to 25HC, can be induced by type I interferon (IFN) in human B cell-enriched peripheral blood mononuclear cells (PBMCs). We propose a model wherein viral miRNAs target the cholesterol pathway to prevent 25HC production and subsequent induction of antiviral ISGs. Together, these results answer some important questions about a widely acting antiviral (25HC), with implications for multiple viral and bacterial infections. IMPORTANCE A cholesterol derivative, 25-hydroxycholesterol (25HC), has been demonstrated to inhibit infections from widely different bacteria and viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, its mechanism of activity is still not fully understood. In this work, we look at gene expression changes in the host and virus after 25HC treatment to find clues about its antiviral activity. We likewise demonstrate that 25HC is also antiviral against EBV, a common cancer-causing virus. We compared our results with previous data from antiviral screening assays and found the same pathways resulting in antiviral activity. Together, these results bring us closer to understanding how a modified form of cholesterol works against several viruses.


Subject(s)
Cytokines/immunology , Epstein-Barr Virus Infections/immunology , Herpesvirus 4, Human/drug effects , Herpesvirus 8, Human/drug effects , Hydroxycholesterols/pharmacology , Hydroxycholesterols/therapeutic use , Inflammation/immunology , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , B-Lymphocytes/virology , Cells, Cultured , Cytokines/genetics , Endothelial Cells/drug effects , Endothelial Cells/immunology , Endothelial Cells/virology , Epstein-Barr Virus Infections/drug therapy , Gene Expression Regulation, Viral , Herpesvirus 4, Human/genetics , Herpesvirus 8, Human/genetics , Humans , Hydroxycholesterols/immunology , Sequence Analysis, RNA , Virus Latency , Virus Replication
5.
J Immunol ; 207(11): 2681-2687, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1506155

ABSTRACT

Due to limited access to vaccines, many countries have only administered a single dose of the AZD1222, whereas the dosage intervals have increased ≥4 wk. We sought to investigate the immunogenicity of a single dose of vaccine at ≥16 wk postimmunization. Severe acute respiratory syndrome coronavirus 2-specific Abs in 553 individuals and Abs to the receptor-binding domain of the Wuhan virus (wild-type) and the variants of concern, angiotensin-converting enzyme 2 receptor blocking Abs ex vivo and cultured IFN-γ T cell (Homo sapiens) responses and B cell (H. sapiens) ELISPOT responses, were investigated in a subcohort. The seropositivity rates in those >70 y of age (93.7%) was not significantly different compared with other age groups (97.7-98.2; Pearson χ2 = 7.8; p = 0.05). The Ab titers (Ab index) significantly declined (p < 0.0001) with increase in age. A total of 18 of 69 (26.1%) of individuals did not have angiotensin-converting enzyme 2 receptor-blocking Abs, whereas responses to the receptor-binding domain of wild-type (p = 0.03), B.1.1.7 (p = 0.04), and B.1.617.2 (p = 0.02) were significantly lower in those who were >60 y. Ex vivo IFN-γ T cell ELISPOT responses were seen in 10 of 66 (15.1%), whereas only a few expressed CD107a. However, >85% had a high frequency of cultured IFN-γ T cell ELISPOT responses and B cell ELISPOTs. Virus-specific Abs were maintained at ≥16 wk after receiving a single dose of AZD1222, although levels were lower to variants of concern, especially in older individuals. A single dose induced a high frequency of memory T and B cell responses.


Subject(s)
COVID-19 Vaccines/pharmacology , COVID-19/drug therapy , SARS-CoV-2/drug effects , Administration, Oral , Adult , Aged , Aged, 80 and over , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , COVID-19/immunology , COVID-19 Vaccines/administration & dosage , Female , Humans , Male , Middle Aged , SARS-CoV-2/immunology , Young Adult
6.
Immunology ; 164(4): 722-736, 2021 12.
Article in English | MEDLINE | ID: covidwho-1494730

ABSTRACT

Bruton's tyrosine kinase (BTK) is a TEC kinase with a multifaceted role in B-cell biology and function, highlighted by its position as a critical component of the B-cell receptor signalling pathway. Due to its role as a therapeutic target in several haematological malignancies including chronic lymphocytic leukaemia, BTK has been gaining tremendous momentum in recent years. Within the immune system, BTK plays a part in numerous pathways and cells beyond B cells (i.e. T cells, macrophages). Not surprisingly, BTK has been elucidated to be a driving factor not only in lymphoproliferative disorders but also in autoimmune diseases and response to infection. To extort this role, BTK inhibitors such as ibrutinib have been developed to target BTK in other diseases. However, due to rising levels of resistance, the urgency to develop new inhibitors with alternative modes of targeting BTK is high. To meet this demand, an expanding list of BTK inhibitors is currently being trialled. In this review, we synopsize recent discoveries regarding BTK and its role within different immune cells and pathways. Additionally, we discuss the broad significance and relevance of BTK for various diseases ranging from haematology and rheumatology to the COVID-19 pandemic. Overall, BTK signalling and its targetable nature have emerged as immensely important for a wide range of clinical applications. The development of novel, more specific and less toxic BTK inhibitors could be revolutionary for a significant number of diseases with yet unmet treatment needs.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/metabolism , B-Lymphocytes/enzymology , Immune System/enzymology , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Animals , Autoimmune Diseases/drug therapy , Autoimmune Diseases/enzymology , Autoimmune Diseases/immunology , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , COVID-19/drug therapy , COVID-19/enzymology , COVID-19/immunology , Humans , Immune System/drug effects , Immune System/immunology , Lymphoproliferative Disorders/drug therapy , Lymphoproliferative Disorders/enzymology , Lymphoproliferative Disorders/immunology , Molecular Targeted Therapy , Protein Kinase Inhibitors/therapeutic use , Receptors, Antigen, B-Cell/metabolism , Receptors, Chemokine/metabolism , Signal Transduction , Toll-Like Receptors/metabolism
9.
Blood ; 138(9): 811-814, 2021 09 02.
Article in English | MEDLINE | ID: covidwho-1288619
10.
Am J Hematol ; 96(8): 934-944, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1204615

ABSTRACT

Prolonged Covid-19 is an emerging issue for patients with lymphoma or immune deficiency. We aimed to examine prolonged length of in-hospital stay (LOS) due to Covid-19 among patients with lymphoma and assess its determinants and outcomes. Adult patients with lymphoma admitted for Covid-19 to 16 French hospitals in March and April, 2020 were included. Length of in-hospital stay was analyzed as a competitor vs death. The study included 111 patients. The median age was 65 years (range, 19-92). Ninety-four patients (85%) had B-cell non-Hodgkin lymphoma. Within the 12 months prior to hospitalization for Covid-19, 79 patients (71%) were treated for their lymphoma. Among them, 63 (57%) received an anti-CD20 therapy. Fourteen patients (12%) had relapsed/refractory disease. The median LOS was 14 days (range, 1-235). After a median follow-up of 191 days (3-260), the 6-month overall survival was 69%. In multivariable analyses, recent administration of anti-CD20 therapy was associated with prolonged LOS (subdistribution hazard ratio 2.26, 95% confidence interval 1.42-3.6, p < 0.001) and higher risk of death (hazard ratio 2.17, 95% confidence interval 1.04-4.52, p = 0.039). An age ≥ 70 years and relapsed/refractory lymphoma were also associated with prolonged LOS and decreased overall survival. In conclusion, an age ≥ 70 years, a relapsed/refractory lymphoma and recent administration of anti-CD20 therapy are risk factors for prolonged LOS and death for lymphoma patients hospitalized for Covid-19. These findings may contribute to guide the management of lymphoma during the pandemic, support evaluating specific therapeutic approaches, and raise questions on the efficacy and timing of vaccination of this particular population.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , B-Lymphocytes/drug effects , COVID-19/complications , Immunotherapy/adverse effects , Length of Stay/statistics & numerical data , Lymphoma, Non-Hodgkin/complications , SARS-CoV-2 , Adult , Age Factors , Aged , Aged, 80 and over , Antigens, CD20/immunology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , COVID-19/mortality , Combined Modality Therapy , Comorbidity , Drug Resistance, Neoplasm , Female , Humans , Lymphoma, Non-Hodgkin/mortality , Lymphoma, Non-Hodgkin/therapy , Male , Middle Aged , Proportional Hazards Models , Retrospective Studies , Risk Factors , Rituximab/administration & dosage , Rituximab/adverse effects , Survival Analysis , Young Adult
11.
Adv Drug Deliv Rev ; 172: 249-274, 2021 05.
Article in English | MEDLINE | ID: covidwho-1064699

ABSTRACT

SARS-CoV-2, which causes COVID-19, was first identified in humans in late 2019 and is a coronavirus which is zoonotic in origin. As it spread around the world there has been an unprecedented effort in developing effective vaccines. Computational methods can be used to speed up the long and costly process of vaccine development. Antigen selection, epitope prediction, and toxicity and allergenicity prediction are areas in which computational tools have already been applied as part of reverse vaccinology for SARS-CoV-2 vaccine development. However, there is potential for computational methods to assist further. We review approaches which have been used and highlight additional bioinformatic approaches and PK modelling as in silico methods which may be useful for SARS-CoV-2 vaccine design but remain currently unexplored. As more novel viruses with pandemic potential are expected to arise in future, these techniques are not limited to application to SARS-CoV-2 but also useful to rapidly respond to novel emerging viruses.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Computational Biology/methods , Drug Development/methods , SARS-CoV-2/drug effects , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , COVID-19/genetics , COVID-19/immunology , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Computational Biology/trends , Drug Development/trends , Epitopes/genetics , Epitopes/immunology , Gene Expression Profiling/methods , Gene Expression Profiling/trends , Humans , SARS-CoV-2/genetics , SARS-CoV-2/metabolism
12.
Chem Commun (Camb) ; 57(4): 504-507, 2021 Jan 14.
Article in English | MEDLINE | ID: covidwho-983835

ABSTRACT

A novel STING agonist, CDGSF, ipsilaterally modified with phosphorothioate and fluorine, was synthesized. The phosphorothioate in CDGSF might be a site for covalent conjugation. Injection of CDGSF generated an immunogenic ("hot") tumor microenvironment to suppress melanoma, more efficiently than dithio CDG. In particular, immunization with SARS-CoV-2 spike protein using CDGSF as an adjuvant elicited an exceptionally high antibody titer and a robust T cell response, overcoming the drawbacks of aluminum hydroxide. These results highlighted the therapeutic potential of CDGSF for cancer immunotherapy and the adjuvant potential of the STING agonist in the SARS-CoV-2 vaccine for the first time.


Subject(s)
Adjuvants, Immunologic/administration & dosage , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Melanoma, Experimental/drug therapy , Membrane Proteins/agonists , Nucleotides, Cyclic/administration & dosage , Skin Neoplasms/drug therapy , Adjuvants, Immunologic/chemical synthesis , Aluminum Hydroxide/administration & dosage , Aluminum Hydroxide/chemistry , Animals , Antibodies, Viral/biosynthesis , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , B-Lymphocytes/virology , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/chemistry , Enzyme-Linked Immunospot Assay , Humans , Immunotherapy/methods , Interferon-gamma/biosynthesis , Melanoma, Experimental/immunology , Melanoma, Experimental/mortality , Melanoma, Experimental/pathology , Membrane Proteins/genetics , Membrane Proteins/immunology , Mice , Nucleotides, Cyclic/chemical synthesis , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Skin Neoplasms/immunology , Skin Neoplasms/mortality , Skin Neoplasms/pathology , Spike Glycoprotein, Coronavirus/administration & dosage , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Survival Analysis , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/virology , Tumor Burden/drug effects , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Vaccination/methods
13.
Bioessays ; 43(3): e2000200, 2021 03.
Article in English | MEDLINE | ID: covidwho-917077

ABSTRACT

As the number of infections and mortalities from the SARS-CoV-2 pandemic continues to rise, the development of an effective therapy against COVID-19 becomes ever more urgent. A few reports showing a positive correlation between BCG vaccination and reduced COVID-19 mortality have ushered in some hope. BCG has been suggested to confer a broad level of nonspecific protection against several pathogens, mainly via eliciting "trained immunity" in innate immune cells. Secondly, BCG has also been proven to provide benefits in autoimmune diseases by inducing tolerogenicity. Being an acute inflammatory disease, COVID-19 requires a therapy that induces early priming of anti-viral immune responses and regulates aberrant hyperactivity of innate-immune cells. Here, we hypothesize that BCG can offer reliable spatiotemporal protection from COVID-19 by triggering trained immunity and tolerogenesis, through multiple cellular pathways. We propose further research on BCG-mediated immunoprotection, especially in vulnerable individuals, as a strategy to halt the progress of the SARS-CoV-2 pandemic. Also see the video abstract here https://youtu.be/P2D2RXfq6Vg.


Subject(s)
BCG Vaccine/therapeutic use , COVID-19/prevention & control , Cytokine Release Syndrome/prevention & control , Immune Tolerance/drug effects , Immunity, Innate/drug effects , T-Lymphocytes, Regulatory/drug effects , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , B-Lymphocytes/virology , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Cytokines/genetics , Cytokines/immunology , Gene Expression Regulation , Humans , Immunologic Memory/drug effects , Pathogen-Associated Molecular Pattern Molecules/immunology , Pathogen-Associated Molecular Pattern Molecules/metabolism , RNA, Viral/genetics , RNA, Viral/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/virology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/virology , Vaccination/methods
14.
Immunity ; 53(4): 724-732.e7, 2020 10 13.
Article in English | MEDLINE | ID: covidwho-710374

ABSTRACT

SARS-CoV-2 infection has emerged as a serious global pandemic. Because of the high transmissibility of the virus and the high rate of morbidity and mortality associated with COVID-19, developing effective and safe vaccines is a top research priority. Here, we provide a detailed evaluation of the immunogenicity of lipid nanoparticle-encapsulated, nucleoside-modified mRNA (mRNA-LNP) vaccines encoding the full-length SARS-CoV-2 spike protein or the spike receptor binding domain in mice. We demonstrate that a single dose of these vaccines induces strong type 1 CD4+ and CD8+ T cell responses, as well as long-lived plasma and memory B cell responses. Additionally, we detect robust and sustained neutralizing antibody responses and the antibodies elicited by nucleoside-modified mRNA vaccines do not show antibody-dependent enhancement of infection in vitro. Our findings suggest that the nucleoside-modified mRNA-LNP vaccine platform can induce robust immune responses and is a promising candidate to combat COVID-19.


Subject(s)
Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , Betacoronavirus/drug effects , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , RNA, Messenger/immunology , RNA, Viral/immunology , Viral Vaccines/administration & dosage , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , B-Lymphocytes/virology , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/genetics , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Disease Models, Animal , Furin/genetics , Furin/immunology , Humans , Immunity, Humoral/drug effects , Immunization/methods , Immunogenicity, Vaccine , Immunologic Memory/drug effects , Lymphocyte Activation/drug effects , Mice , Mice, Inbred BALB C , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , RNA, Messenger/genetics , RNA, Viral/genetics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic , Viral Vaccines/biosynthesis , Viral Vaccines/genetics
15.
J Dtsch Dermatol Ges ; 18(8): 795-807, 2020 08.
Article in English | MEDLINE | ID: covidwho-697169

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 has far-reaching direct and indirect medical consequences. These include both the course and treatment of diseases. It is becoming increasingly clear that infections with SARS-CoV-2 can cause considerable immunological alterations, which particularly also affect pathogenetically and/or therapeutically relevant factors. Against this background we summarize here the current state of knowledge on the interaction of SARS-CoV-2/COVID-19 with mediators of the acute phase of inflammation (TNF, IL-1, IL-6), type 1 and type 17 immune responses (IL-12, IL-23, IL-17, IL-36), type 2 immune reactions (IL-4, IL-13, IL-5, IL-31, IgE), B-cell immunity, checkpoint regulators (PD-1, PD-L1, CTLA4), and orally druggable signaling pathways (JAK, PDE4, calcineurin). In addition, we discuss in this context non-specific immune modulation by glucocorticosteroids, methotrexate, antimalarial drugs, azathioprine, dapsone, mycophenolate mofetil and fumaric acid esters, as well as neutrophil granulocyte-mediated innate immune mechanisms. From these recent findings we derive possible implications for the therapeutic modulation of said immunological mechanisms in connection with SARS-CoV-2/COVID-19. Although, of course, the greatest care should be taken with patients with immunologically mediated diseases or immunomodulating therapies, it appears that many treatments can also be carried out during the COVID-19 pandemic; some even appear to alleviate COVID-19.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/prevention & control , Cytokines/immunology , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , COVID-19/therapy , Cytokine Release Syndrome/immunology , Humans , Immunotherapy , Th1 Cells/drug effects , Th1 Cells/immunology , Th17 Cells/drug effects , Th17 Cells/immunology
16.
Nat Commun ; 11(1): 3924, 2020 08 06.
Article in English | MEDLINE | ID: covidwho-695765

ABSTRACT

Several studies show that the immunosuppressive drugs targeting the interleukin-6 (IL-6) receptor, including tocilizumab, ameliorate lethal inflammatory responses in COVID-19 patients infected with SARS-CoV-2. Here, by employing single-cell analysis of the immune cell composition of two severe-stage COVID-19 patients prior to and following tocilizumab-induced remission, we identify a monocyte subpopulation that contributes to the inflammatory cytokine storms. Furthermore, although tocilizumab treatment attenuates the inflammation, immune cells, including plasma B cells and CD8+ T cells, still exhibit robust humoral and cellular antiviral immune responses. Thus, in addition to providing a high-dimensional dataset on the immune cell distribution at multiple stages of the COVID-19, our work also provides insights into the therapeutic effects of tocilizumab, and identifies potential target cell populations for treating COVID-19-related cytokine storms.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Betacoronavirus/immunology , Coronavirus Infections/immunology , Cytokines/immunology , Monocytes/immunology , Pneumonia, Viral/immunology , Antibodies, Monoclonal, Humanized/administration & dosage , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , COVID-19 , Computational Biology , Coronavirus Infections/blood , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cytokines/blood , Humans , Inflammation/drug therapy , Macrophages/drug effects , Macrophages/immunology , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Receptors, Interleukin-6/immunology , SARS-CoV-2 , Single-Cell Analysis/methods
18.
Stem Cell Rev Rep ; 16(3): 434-440, 2020 06.
Article in English | MEDLINE | ID: covidwho-71853

ABSTRACT

The expressive number of deaths and confirmed cases of SARS-CoV-2 call for an urgent demand of effective and available drugs for COVID-19 treatment. CD147, a receptor on host cells, is a novel route for SARS-CoV-2 invasion. Thus, drugs that interfere in the spike protein/CD147 interaction or CD147 expression may inhibit viral invasion and dissemination among other cells, including in progenitor/stem cells. Studies suggest beneficial effects of azithromycin in reducing viral load of hospitalized patients, possibly interfering with ligand/CD147 receptor interactions; however, its possible effects on SARS-CoV-2 invasion has not yet been evaluated. In addition to the possible effect in invasion, azithromycin decreases the expression of some metalloproteinases (downstream to CD147), induces anti-viral responses in primary human bronchial epithelial infected with rhinovirus, decreasing viral replication and release. Moreover, resident lung progenitor/stem are extensively differentiated into myofibroblasts during pulmonary fibrosis, a complication observed in COVID-19 patients. This process, and the possible direct viral invasion of progenitor/stem cells via CD147 or ACE2, could result in the decline of these cellular stocks and failing lung repair. Clinical tests with allogeneic MSCs from healthy individuals are underway to enhance endogenous lung repair and suppress inflammation.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Azithromycin/therapeutic use , Basigin/genetics , Betacoronavirus/drug effects , Coronavirus Infections/therapy , Pandemics , Pneumonia, Viral/therapy , Spike Glycoprotein, Coronavirus/genetics , Stem Cell Transplantation , Angiotensin-Converting Enzyme 2 , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , B-Lymphocytes/virology , Basigin/antagonists & inhibitors , Basigin/immunology , Betacoronavirus/metabolism , Betacoronavirus/pathogenicity , COVID-19 , Clinical Trials as Topic , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Gene Expression , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/immunology , Humans , Lung/immunology , Lung/virology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Protein Binding/drug effects , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/immunology , Stem Cells/drug effects , Stem Cells/immunology , Stem Cells/virology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/virology , Viral Load/drug effects
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