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1.
J Exp Med ; 218(4)2021 04 05.
Article in English | MEDLINE | ID: covidwho-1387677

ABSTRACT

SARS-CoV-2 is responsible for an ongoing pandemic that has affected millions of individuals around the globe. To gain further understanding of the immune response in recovered individuals, we measured T cell responses in paired samples obtained an average of 1.3 and 6.1 mo after infection from 41 individuals. The data indicate that recovered individuals show persistent polyfunctional SARS-CoV-2 antigen-specific memory that could contribute to rapid recall responses. Recovered individuals also show enduring alterations in relative overall numbers of CD4+ and CD8+ memory T cells, including expression of activation/exhaustion markers, and cell division.


Subject(s)
COVID-19/immunology , COVID-19/virology , Host-Pathogen Interactions/immunology , Immunity, Cellular , SARS-CoV-2/immunology , Adult , Aged , Antigens, Viral/immunology , Biomarkers , Female , Humans , Immunophenotyping , Lymphocyte Count , Male , Middle Aged , T-Cell Antigen Receptor Specificity , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Young Adult
2.
Front Cell Infect Microbiol ; 11: 646688, 2021.
Article in English | MEDLINE | ID: covidwho-1211803

ABSTRACT

The velocity of the COVID-19 pandemic spread and the variable severity of the disease course has forced scientists to search for potential predictors of the disease outcome. We examined various immune parameters including the markers of immune cells exhaustion and activation in 21 patients with COVID-19 disease hospitalised in our hospital during the first wave of the COVID-19 pandemic in Slovakia. The results showed significant progressive lymphopenia and depletion of lymphocyte subsets (CD3+, CD4+, CD8+ and CD19+) in correlation to the disease severity. Clinical recovery was associated with significant increase in CD3+ and CD3+CD4+ T-cells. Most of our patients had eosinopenia on admission, although no significant differences were seen among groups with different disease severity. Non-survivors, when compared to survivors, had significantly increased expression of PD-1 on CD4+ and CD8+ cells, but no significant difference in Tim-3 expression was observed, what suggests possible reversibility of immune paralysis in the most severe group of patients. During recovery, the expression of Tim-3 on both CD3+CD4+ and CD3+CD8+ cells significantly decreased. Moreover, patients with fatal outcome had significantly higher proportion of CD38+CD8+ cells and lower proportion of CD38+HLA-DR+CD8+ cells on admission. Clinical recovery was associated with significant decrease of proportion of CD38+CD8+ cells. The highest AUC values within univariate and multivariate logistic regression were achieved for expression of CD38 on CD8+ cells and expression of PD1 on CD4+ cells alone or combined, what suggests, that these parameters could be used as potential biomarkers of poor outcome. The assessment of immune markers could help in predicting outcome and disease severity in COVID-19 patients. Our observations suggest, that apart from the degree of depletion of total lymphocytes and lymphocytes subsets, increased expression of CD38 on CD3+CD8+ cells alone or combined with increased expression of PD-1 on CD3+CD4+ cells, should be regarded as a risk factor of an unfavourable outcome in COVID-19 patients. Increased expression of PD-1 in the absence of an increased expression of Tim-3 on CD3+CD4+ and CD3+CD8+ cells suggests potential reversibility of ongoing immune paralysis in patients with the most severe course of COVID-19.


Subject(s)
COVID-19 , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Humans , Pandemics , SARS-CoV-2
3.
AIDS Res Hum Retroviruses ; 37(8): 613-619, 2021 08.
Article in English | MEDLINE | ID: covidwho-1207226

ABSTRACT

People with HIV (PWH) might have a higher risk of adverse coronavirus disease 2019 (COVID-19) outcomes. Several scores were developed to predict COVID-19 progression to critical disease and are often used among PWH. We assessed the performance of two commonly used risk equations among PWH and COVID-19. Participants were identified from a multicenter cohort of 6,361 PWH on regular follow-up at 2 university hospitals. Of 99 HIV-infected individuals with confirmed SARS-CoV-2 infection, 63 had complete data and were included in this analysis. CALL and COVID-GRAM scores were calculated and participants were stratified into low-, intermediate-, and high-risk groups for each. Discrimination was assessed using receiver operating characteristic curves. Calibration was evaluated using observed versus expected (O:E) ratios and the Hosmer-Lemeshow χ2 goodness-of-fit statistic. Scores were adjusted by increasing one category level in individuals with nadir CD4 lymphocyte count <200/µL. Participants had a median nadir and current CD4 counts of 207 [interquartile range (IQR) 119-345] and 440 (IQR 280-719) cells/µL. Ten (15.9%) individuals progressed to critical disease and 4 (6.3%) died. Assessed scores showed acceptable discrimination (area under the curve 0.701-0.771) and were overall calibrated (O:E ratio 1.01). However, both overestimated the risk of progression among individuals in the low- and high-risk categories, whereas they underestimated the risk in the intermediate category (O:E 1.20-1.21). Thus, 50% of critically ill individuals were not identified as high risk. Assigning PWH with low nadir CD4 counts a higher risk of progression reduced the proportion of individuals not identified to 20%. COVID-19 risk scores had lower performance in PWH compared with that described in the general population and failed to adequately identify individuals who progressed to critical disease. Adjustment for nadir CD4 partially improved their accuracy. Risk equations incorporating HIV-related factors are needed.


Subject(s)
COVID-19/complications , COVID-19/diagnosis , Disease Progression , HIV Infections/complications , HIV Infections/diagnosis , Adult , Aged , CD4 Lymphocyte Count , Cohort Studies , Female , Hospitals, University , Humans , Male , Middle Aged , Prognosis , Risk Assessment , SARS-CoV-2 , Young Adult
4.
Thorax ; 76(10): 1010-1019, 2021 10.
Article in English | MEDLINE | ID: covidwho-1180971

ABSTRACT

BACKGROUND: Knowledge of the pathophysiology of COVID-19 is almost exclusively derived from studies that examined the immune response in blood. We here aimed to analyse the pulmonary immune response during severe COVID-19 and to compare this with blood responses. METHODS: This was an observational study in patients with COVID-19 admitted to the intensive care unit (ICU). Mononuclear cells were purified from bronchoalveolar lavage fluid (BALF) and blood, and analysed by spectral flow cytometry; inflammatory mediators were measured in BALF and plasma. FINDINGS: Paired blood and BALF samples were obtained from 17 patients, four of whom died in the ICU. Macrophages and T cells were the most abundant cells in BALF, with a high percentage of T cells expressing the ƴδ T cell receptor. In the lungs, both CD4 and CD8 T cells were predominantly effector memory cells (87·3% and 83·8%, respectively), and these cells expressed higher levels of the exhaustion marker programmad death-1 than in peripheral blood. Prolonged ICU stay (>14 days) was associated with a reduced proportion of activated T cells in peripheral blood and even more so in BALF. T cell activation in blood, but not in BALF, was higher in fatal COVID-19 cases. Increased levels of inflammatory mediators were more pronounced in BALF than in plasma. INTERPRETATION: The bronchoalveolar immune response in COVID-19 has a unique local profile that strongly differs from the immune profile in peripheral blood. Fully elucidating COVID-19 pathophysiology will require investigation of the pulmonary immune response.


Subject(s)
COVID-19/immunology , Immunity, Cellular/physiology , Inflammation Mediators/metabolism , Aged , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , COVID-19/blood , COVID-19/pathology , Critical Care , Critical Illness , Female , Flow Cytometry , Humans , Macrophages/physiology , Male , Middle Aged , T-Lymphocytes/physiology
5.
Front Immunol ; 11: 607069, 2020.
Article in English | MEDLINE | ID: covidwho-993358

ABSTRACT

Upon recognition of microbial DNA or self-DNA, the cyclic-GMP-AMP synthase (cGAS) of the host catalyzes the production of the cyclic dinucleotide cGAMP. cGAMP is the main activator of STING, stimulator of interferon genes, leading to interferon synthesis through the STING-TBK1-IRF3 pathway. STING is also a hub for activation of NF-κB and autophagy. The present review details the striking similarities between T and B cell responses in severe coronavirus disease 2019 (COVID-19) and both animal or human models of STING gain of function (SAVI syndromes: STING-associated vasculopathy with onset in infancy). Those similarities may be further clues for a delayed activation of STING in severe COVID-19 patients, due to DNA damages following severe acute respiratory syndrome coronaviruses (SARS-CoV-2) infection and unusual role of STING in SARS-CoV-2 control. In early stages, Th2 differentiation are noticed in both severe COVID-19 and SAVI syndromes; then, CD4+ and CD8+ T cells functional exhaustion/senescent patterns due to TCR hyper-responsiveness are observed. T cell delayed over-responses can contribute to pneumonitis and delayed cytokine secretion with over-production of IL-6. Last, STING over-activation induces progressive CD4+ and CD8+ T lymphopenia in SAVI syndromes, which parallels what is observed in severe COVID-19. ACE2, the main receptor of SARS-CoV-2, is rarely expressed in immune cells, and it has not been yet proven that some human lymphocytes could be infected by SARS-CoV-2 through CD147 or CD26. However, STING, expressed in humans T cells, might be triggered following excessive transfer of cGAMP from infected antigen presenting cells into activated CD4+ and CD8+ T cells lymphocytes. Indeed, those lymphocytes highly express the cGAMP importer SLC19A1. Whereas STING is not expressed in human B cells, B cells counts are much less affected, either in COVID-19 or SAVI syndromes. The recognition of delayed STING over-activation in severe COVID-19 patients could prompt to target STING with specific small molecules inhibitors already designed and/or aspirin, which inhibits cGAS.


Subject(s)
B-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Membrane Proteins/immunology , SARS-CoV-2/immunology , Th2 Cells/immunology , Angiotensin-Converting Enzyme 2/immunology , Animals , B-Lymphocytes/pathology , Basigin/immunology , CD8-Positive T-Lymphocytes/pathology , COVID-19/pathology , Dipeptidyl Peptidase 4/immunology , Humans , Interferon Regulatory Factor-3/immunology , Nucleotidyltransferases/immunology , Signal Transduction/immunology , Th2 Cells/pathology
6.
Nature ; 583(7816): 437-440, 2020 07.
Article in English | MEDLINE | ID: covidwho-326050

ABSTRACT

In December 2019, coronavirus disease 2019 (COVID-19), which is caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in Wuhan (Hubei province, China)1; it soon spread across the world. In this ongoing pandemic, public health concerns and the urgent need for effective therapeutic measures require a deep understanding of the epidemiology, transmissibility and pathogenesis of COVID-19. Here we analysed clinical, molecular and immunological data from 326 patients with confirmed SARS-CoV-2 infection in Shanghai. The genomic sequences of SARS-CoV-2, assembled from 112 high-quality samples together with sequences in the Global Initiative on Sharing All Influenza Data (GISAID) dataset, showed a stable evolution and suggested that there were two major lineages with differential exposure history during the early phase of the outbreak in Wuhan. Nevertheless, they exhibited similar virulence and clinical outcomes. Lymphocytopenia, especially reduced CD4+ and CD8+ T cell counts upon hospital admission, was predictive of disease progression. High levels of interleukin (IL)-6 and IL-8 during treatment were observed in patients with severe or critical disease and correlated with decreased lymphocyte count. The determinants of disease severity seemed to stem mostly from host factors such as age and lymphocytopenia (and its associated cytokine storm), whereas viral genetic variation did not significantly affect outcomes.


Subject(s)
Betacoronavirus/genetics , Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Coronavirus Infections/virology , Host-Pathogen Interactions/immunology , Lymphopenia/virology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Respiratory Distress Syndrome/virology , Adolescent , Adult , Aged , Aged, 80 and over , Aging , Animals , Asymptomatic Infections/epidemiology , Betacoronavirus/classification , Betacoronavirus/isolation & purification , COVID-19 , China/epidemiology , Cohort Studies , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Critical Illness/epidemiology , Disease Progression , Evolution, Molecular , Female , Genetic Variation , Genome, Viral/genetics , Hospitalization/statistics & numerical data , Humans , Inflammation Mediators/immunology , Interleukin-6/blood , Interleukin-6/immunology , Interleukin-8/blood , Interleukin-8/immunology , Lymphocyte Count , Lymphopenia/complications , Male , Middle Aged , Pandemics , Phylogeny , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , Respiratory Distress Syndrome/complications , SARS-CoV-2 , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Time Factors , Treatment Outcome , Virulence/genetics , Virus Shedding , Young Adult , Zoonoses/transmission , Zoonoses/virology
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