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2.
Viral Immunol ; 34(5): 342-351, 2021 06.
Article in English | MEDLINE | ID: covidwho-1343608

ABSTRACT

The spectrum of coronavirus disease 2019 (COVID-19) severity, related to cellular immune functions, has not been fully clarified yet. Therefore, this study aimed to investigate the alteration of peripheral blood cells in patients with COVID-19. The flow cytometric characterization of immune cell subset was performed on 69 COVID-19 patients and 21 healthy controls. These data were evaluated based on the disease severity. A total of 69 patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were classified as asymptomatic infection (n = 14), nonsevere (n = 39), and severe (n = 16) groups. Decreased lymphocytes and increased CD14 + 4- monocytes are found in patients with severe COVID-19. Decreased CD4 expression level was observed in the monocytes of patients with severe COVID-19. The total lymphocytes, B and T lymphocytes, CD4+ cells and CD8+ cells, and natural killer (NK) and natural killer T (NKT) cells were found to be decreased in patients with severe COVID-19. The CD4+/CD8+ ratio was not significantly different between patients with COVID-19 and healthy controls. The percentage of activated T cells (CD3+HLA-DR+) and B cells (CD19+CD38+) was lower in patients with severe COVID-19. Age and CD4- monocytes were independent predictors of disease severity. The SARS-CoV-2 infection may affect lymphocyte subsets, resulting in decreased T and B cells, monocytes, and NK and NKT cells. Decreased CD4 expression level by monocytes was significantly correlated with disease severity. Further studies on the host immune response to SARS-CoV-2 infection are necessary to predict the disease severity and protect against the virus.


Subject(s)
CD4 Antigens/genetics , COVID-19/immunology , Immunity, Cellular , Lymphocyte Subsets/immunology , Monocytes/immunology , Severity of Illness Index , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/pathology , Female , Flow Cytometry , Hospitalization/statistics & numerical data , Humans , Lymphocyte Activation , Lymphocyte Count , Male , Middle Aged , Young Adult
3.
Int J Biol Sci ; 17(6): 1507-1520, 2021.
Article in English | MEDLINE | ID: covidwho-1206439

ABSTRACT

The severe cases of Coronavirus Disease 2019 (COVID-19) frequently exhibit excessive inflammatory responses, acute respiratory distress syndrome (ARDS), coagulopathy, and organ damage. The most striking immunopathology of advanced COVID-19 is cytokine release syndrome or "cytokine storm" that is attributable to the deficiencies in immune regulatory mechanisms. CD4+FoxP3+ regulatory T cells (Tregs) are central regulators of immune responses and play an indispensable role in the maintenance of immune homeostasis. Tregs are likely involved in the attenuation of antiviral defense at the early stage of infection and ameliorating inflammation-induced organ injury at the late stage of COVID-19. In this article, we review and summarize the current understanding of the change of Tregs in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and discuss the potential role of Tregs in the immunopathology of COVID-19. The emerging concept of Treg-targeted therapies, including both adoptive Treg transfer and low dose of IL-2 treatment, is introduced. Furthermore, the potential Treg-boosting effect of therapeutic agents used in the treatment of COVID-19, including dexamethasone, vitamin D, tocilizumab and sarilumab, chloroquine, hydroxychloroquine, azithromycin, adalimumab and tetrandrine, is discussed. The problems in the current study of Treg cells in COVID-19 and future perspectives are also addressed.


Subject(s)
CD4 Antigens/immunology , COVID-19/immunology , COVID-19/therapy , Forkhead Transcription Factors/immunology , T-Lymphocytes, Regulatory/immunology , COVID-19/virology , Cytokine Release Syndrome , Humans , SARS-CoV-2/isolation & purification
4.
Sci Rep ; 10(1): 22303, 2020 12 18.
Article in English | MEDLINE | ID: covidwho-989953

ABSTRACT

The increasing body of literature describing the role of host factors in COVID-19 pathogenesis demonstrates the need to combine diverse, multi-omic data to evaluate and substantiate the most robust evidence and inform development of therapies. Here we present a dynamic ranking of host genes implicated in human betacoronavirus infection (SARS-CoV-2, SARS-CoV, MERS-CoV, seasonal coronaviruses). We conducted an extensive systematic review of experiments identifying potential host factors. Gene lists from diverse sources were integrated using Meta-Analysis by Information Content (MAIC). This previously described algorithm uses data-driven gene list weightings to produce a comprehensive ranked list of implicated host genes. From 32 datasets, the top ranked gene was PPIA, encoding cyclophilin A, a druggable target using cyclosporine. Other highly-ranked genes included proposed prognostic factors (CXCL10, CD4, CD3E) and investigational therapeutic targets (IL1A) for COVID-19. Gene rankings also inform the interpretation of COVID-19 GWAS results, implicating FYCO1 over other nearby genes in a disease-associated locus on chromosome 3. Researchers can search and review the gene rankings and the contribution of different experimental methods to gene rank at https://baillielab.net/maic/covid19 . As new data are published we will regularly update the list of genes as a resource to inform and prioritise future studies.


Subject(s)
COVID-19/epidemiology , COVID-19/genetics , Algorithms , CD3 Complex/genetics , CD4 Antigens/genetics , Chemokine CXCL10/genetics , Computational Biology , Cyclophilin A/genetics , Cyclosporine/pharmacology , Databases, Genetic , Genome-Wide Association Study , Genomics , Humans , Immune System , Immunogenetics , Inflammation , Interleukin-1alpha/genetics , Microtubule-Associated Proteins/genetics , Proteomics
5.
Int J Dermatol ; 60(1): 73-80, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-919217

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a systemic multi-organ viral illness. Previous studies have found that many patients had a procoagulant state and/or severe hypoxemia with relatively well-preserved lung mechanics. Mechanisms underlying the damage to vascular tissues are not well-elucidated yet. Histological data in COVID-19 patients are still limited and are mainly focused on post-mortem analysis. Given that the skin is affected by COVID-19 and the relative ease of its histological examination, we aimed to examine the histology of skin lesions in COVID-19 patients to better understand the disease's pathology. METHODS: Five skin lesions from COVID-19 adult patients were selected for a deep histological tissue examination. RESULTS: A strong vasculopathic reaction pattern based on prominent vascular endothelial and myointimal cell growth was identified. Endothelial cell distortion generated vascular lumen obliteration and striking erythrocyte and serum extravasation. Significant deposition of C4d and C3 throughout the vascular cell wall was also identified. A regenerative epidermal hyperplasia with tissue structure preservation was also observed. CONCLUSIONS: COVID-19 could comprise an obliterative microangiopathy consisting on endothelial and myointimal growth with complement activation. This mechanism, together with the increased vascular permeability identified, could contribute to obliteration of the vascular lumen and hemorrhage in COVID-19. Thus, anticoagulation by itself could not completely reverse vascular lumen obliteration, with consequent increased risk of hemorrhage. Findings of this study could contribute to a better understanding of physiopathological mechanisms underlying COVID-19 on living patients and could help further studies find potential targets for specific therapeutic interventions in severe cases.


Subject(s)
COVID-19/complications , Endothelial Cells/pathology , Myocytes, Smooth Muscle/pathology , Skin Diseases/pathology , Vascular Diseases/pathology , Aged , Blood Vessels/pathology , CD3 Complex/metabolism , CD4 Antigens/metabolism , Endothelium/metabolism , Endothelium/pathology , Humans , Hyperplasia/pathology , Hyperplasia/virology , SARS-CoV-2 , Skin/blood supply , Skin Diseases/virology , Vascular Diseases/virology
6.
J Cell Mol Med ; 24(19): 11603-11606, 2020 10.
Article in English | MEDLINE | ID: covidwho-884888

ABSTRACT

A novel pneumonia-associated respiratory syndrome named coronavirus disease-2019 (COVID-19), which was caused by SARS-CoV-2,broke out in Wuhan, China, in the end of 2019. Unfortunately, there is no specific antiviral agent or vaccine available to treat SARS-CoV-2 infections. The information regarding the immunological characteristics in COVID-19 patients remains limited. Here, we collected the blood samples from 18 healthy donors (HD) and 38 COVID-19 patients to analyze changes on γδ T cell population. In comparison with HD, the γδ T cell percentage decreased, while the activation marker CD25 expression increased in response to SARS-CoV-2 infection. Interestingly, the CD4 expression was upregulated in γδ T cells reflecting the occurrence of a specific effector cell population, which may serve as a biomarker for the assessment of SARS-CoV-2 infection.


Subject(s)
Coronavirus Infections/immunology , Pneumonia, Viral/immunology , T-Lymphocyte Subsets/immunology , Adult , Betacoronavirus/physiology , Biomarkers , CD4 Antigens/metabolism , COVID-19 , China , Flow Cytometry , Humans , Immunity, Innate , Interleukin-2 Receptor alpha Subunit/metabolism , Pandemics , SARS-CoV-2 , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/metabolism
7.
J Virol ; 94(14)2020 07 01.
Article in English | MEDLINE | ID: covidwho-823496

ABSTRACT

Mouse hepatitis virus (MHV) is a murine betacoronavirus (m-CoV) that causes a wide range of diseases in mice and rats, including hepatitis, enteritis, respiratory diseases, and encephalomyelitis in the central nervous system (CNS). MHV infection in mice provides an efficient cause-effect experimental model to understand the mechanisms of direct virus-induced neural-cell damage leading to demyelination and axonal loss, which are pathological features of multiple sclerosis (MS), the most common disabling neurological disease in young adults. Infiltration of T lymphocytes, activation of microglia, and their interplay are the primary pathophysiological events leading to disruption of the myelin sheath in MS. However, there is emerging evidence supporting gray matter involvement and degeneration in MS. The investigation of T cell function in the pathogenesis of deep gray matter damage is necessary. Here, we employed RSA59 (an isogenic recombinant strain of MHV-A59)-induced experimental neuroinflammation model to compare the disease in CD4-/- mice with that in CD4+/+ mice at days 5, 10, 15, and 30 postinfection (p.i.). Viral titer estimation, nucleocapsid gene amplification, and viral antinucleocapsid staining confirmed enhanced replication of the virions in the absence of functional CD4+ T cells in the brain. Histopathological analyses showed elevated susceptibility of CD4-/- mice to axonal degeneration in the CNS, with augmented progression of acute poliomyelitis and dorsal root ganglionic inflammation rarely observed in CD4+/+ mice. Depletion of CD4+ T cells showed unique pathological bulbar vacuolation in the brain parenchyma of infected mice with persistent CD11b+ microglia/macrophages in the inflamed regions on day 30 p.i. In summary, the current study suggests that CD4+ T cells are critical for controlling acute-stage poliomyelitis (gray matter inflammation), chronic axonal degeneration, and inflammatory demyelination due to loss of protective antiviral host immunity.IMPORTANCE The current trend in CNS disease biology is to attempt to understand the neural-cell-immune interaction to investigate the underlying mechanism of neuroinflammation, rather than focusing on peripheral immune activation. Most studies in MS are targeted toward understanding the involvement of CNS white matter. However, the importance of gray matter damage has become critical in understanding the long-term progressive neurological disorder. Our study highlights the importance of CD4+ T cells in safeguarding neurons against axonal blebbing and poliomyelitis from murine betacoronavirus-induced neuroinflammation. Current knowledge of the mechanisms that lead to gray matter damage in MS is limited, because the most widely used animal model, experimental autoimmune encephalomyelitis (EAE), does not present this aspect of the disease. Our results, therefore, add to the existing limited knowledge in the field. We also show that the microglia, though important for the initiation of neuroinflammation, cannot establish a protective host immune response without the help of CD4+ T cells.


Subject(s)
Axons/immunology , Axons/metabolism , CD4 Antigens/deficiency , Coronavirus Infections/immunology , Coronavirus Infections/virology , Murine hepatitis virus/physiology , Poliomyelitis/etiology , Animals , Axons/pathology , Brain/immunology , Brain/metabolism , Brain/pathology , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Coronavirus Infections/pathology , Cytokines/metabolism , Disease Models, Animal , Disease Susceptibility/immunology , Ganglia, Spinal/immunology , Ganglia, Spinal/metabolism , Ganglia, Spinal/pathology , Immunohistochemistry , Inflammation Mediators/metabolism , Mice
8.
N Engl J Med ; 383(16): 1544-1555, 2020 10 15.
Article in English | MEDLINE | ID: covidwho-680559

ABSTRACT

BACKGROUND: Vaccines to prevent coronavirus disease 2019 (Covid-19) are urgently needed. The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines on viral replication in both upper and lower airways is important to evaluate in nonhuman primates. METHODS: Nonhuman primates received 10 or 100 µg of mRNA-1273, a vaccine encoding the prefusion-stabilized spike protein of SARS-CoV-2, or no vaccine. Antibody and T-cell responses were assessed before upper- and lower-airway challenge with SARS-CoV-2. Active viral replication and viral genomes in bronchoalveolar-lavage (BAL) fluid and nasal swab specimens were assessed by polymerase chain reaction, and histopathological analysis and viral quantification were performed on lung-tissue specimens. RESULTS: The mRNA-1273 vaccine candidate induced antibody levels exceeding those in human convalescent-phase serum, with live-virus reciprocal 50% inhibitory dilution (ID50) geometric mean titers of 501 in the 10-µg dose group and 3481 in the 100-µg dose group. Vaccination induced type 1 helper T-cell (Th1)-biased CD4 T-cell responses and low or undetectable Th2 or CD8 T-cell responses. Viral replication was not detectable in BAL fluid by day 2 after challenge in seven of eight animals in both vaccinated groups. No viral replication was detectable in the nose of any of the eight animals in the 100-µg dose group by day 2 after challenge, and limited inflammation or detectable viral genome or antigen was noted in lungs of animals in either vaccine group. CONCLUSIONS: Vaccination of nonhuman primates with mRNA-1273 induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung. (Funded by the National Institutes of Health and others.).


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/immunology , Pneumonia, Viral/prevention & control , Viral Vaccines/immunology , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Betacoronavirus/physiology , CD4 Antigens , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/pathology , Coronavirus Infections/therapy , Disease Models, Animal , Dose-Response Relationship, Immunologic , Immunization, Passive , Lung/pathology , Lung/virology , Macaca mulatta , Pneumonia, Viral/pathology , Pneumonia, Viral/therapy , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , T-Lymphocytes/immunology , Viral Load , Viral Vaccines/administration & dosage , Virus Replication
9.
Clin Chim Acta ; 508: 110-114, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-245497

ABSTRACT

BACKGROUND: We observe changes of the main lymphocyte subsets (CD16+CD56、CD19、CD3、CD4、and CD8) in COVID-19-infected patients and explore whether the changes are associated with disease severity. METHODS: One-hundred and fifty-four cases of COVID-19-infected patients were selected and divided into 3 groups (moderate group, severe group and critical group). The flow cytometry assay was performed to examine the numbers of lymphocyte subsets. RESULTS: CD3+, CD4+ and CD8 + T lymphocyte subsets were decreased in COVID-19-infected patients. Compared with the moderate group and the sever group, CD3+, CD4+ and CD8+ T cells in the critical group decreased greatly (P < 0.001, P = 0.005 or P = 0.001). CONCLUSIONS: Reduced CD3+, CD4+, CD8+ T lymphocyte counts may reflect the severity of the COVID-19. Monitoring T cell changes has important implications for the diagnosis and treatment of severe patients who may become critically ill.


Subject(s)
Betacoronavirus/pathogenicity , Cardiovascular Diseases/diagnosis , Coronavirus Infections/diagnosis , Diabetes Mellitus/diagnosis , Lung Diseases/diagnosis , Pneumonia, Viral/diagnosis , T-Lymphocyte Subsets/pathology , Aged , Aged, 80 and over , Biomarkers/analysis , CD3 Complex/genetics , CD3 Complex/immunology , CD4 Antigens/genetics , CD4 Antigens/immunology , CD8 Antigens/genetics , CD8 Antigens/immunology , COVID-19 , Cardiovascular Diseases/immunology , Cardiovascular Diseases/mortality , Cardiovascular Diseases/physiopathology , Cohort Studies , Comorbidity , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Coronavirus Infections/physiopathology , Diabetes Mellitus/immunology , Diabetes Mellitus/mortality , Diabetes Mellitus/physiopathology , Female , Gene Expression , Humans , Immunophenotyping , Lung Diseases/immunology , Lung Diseases/mortality , Lung Diseases/physiopathology , Male , Middle Aged , Pandemics , Patient Selection , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , Pneumonia, Viral/physiopathology , Prognosis , SARS-CoV-2 , Severity of Illness Index , Survival Analysis , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/virology
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