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1.
Hum Immunol ; 2021 Nov 04.
Article in English | MEDLINE | ID: covidwho-1499900

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the pandemic of coronavirus disease 2019 (COVID-19). Great international efforts have been put into the development of prophylactic vaccines and neutralizing antibodies. However, the knowledge about the B cell immune response induced by the SARS-CoV-2 virus is still limited. Here, we report a comprehensive characterization of the dynamics of immunoglobin heavy chain (IGH) repertoire in COVID-19 patients. By using next-generation sequencing technology, we examined the temporal changes in the landscape of the patient's immunological status and found dramatic changes in the IGH within the patient's immune system after the onset of COVID-19 symptoms. Although different patients have distinct immune responses to SARS-CoV-2 infection, by employing clonotype overlap, lineage expansion, and clonotype network analyses, we observed a higher clonotype overlap and substantial lineage expansion of B cell clones 2-3 weeks after the onset of illness, which is of great importance to B-cell immune responses. Meanwhile, for preferences of V gene usage during SARS-CoV-2 infection, IGHV3-74 and IGHV4-34, and IGHV4-39 in COVID-19 patients were more abundant than those of healthy controls. Overall, we present an immunological resource for SARS-CoV-2 that could promote both therapeutic development as well as mechanistic research.

2.
J Med Virol ; 93(9): 5635-5637, 2021 09.
Article in English | MEDLINE | ID: covidwho-1208550

ABSTRACT

An outbreak of a novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had emerged in 2019 and rapidly posed a global epidemic. Here, we report the breadth of concomitant virological features of a family cluster with COVID-19. The period of virus shedding is significantly different between upper respiratory and feces samples. Even the SARS-CoV-2 virus titers were undetectable in feces, it could be positive again soon and likely related to fluctuated inflammation levels (interleukin-6, etc.) and lowered immune responses (CD4 + T lymphocyte, etc.). Our findings expand the novel understanding of the breadth of concomitant virological features during a non-severe family cluster of COVID-19.


Subject(s)
COVID-19/physiopathology , Feces/virology , SARS-CoV-2 , Virus Shedding , Adolescent , Adult , COVID-19/virology , China , Disease Outbreaks , Family , Female , Humans , Male , Middle Aged
3.
Gut Microbes ; 13(1): 1-21, 2021.
Article in English | MEDLINE | ID: covidwho-1121345

ABSTRACT

SARS-CoV-2 is the cause of the current global pandemic of COVID-19; this virus infects multiple organs, such as the lungs and gastrointestinal tract. The microbiome in these organs, including the bacteriome and virome, responds to infection and might also influence disease progression and treatment outcome. In a cohort of 13 COVID-19 patients in Beijing, China, we observed that the gut virome and bacteriome in the COVID-19 patients were notably different from those of five healthy controls. We identified a bacterial dysbiosis signature by observing reduced diversity and viral shifts in patients, and among the patients, the bacterial/viral compositions were different between patients of different severities, although these differences are not entirely distinguishable from the effect of antibiotics. Severe cases of COVID-19 exhibited a greater abundance of opportunistic pathogens but were depleted for butyrate-producing groups of bacteria compared with mild to moderate cases. We replicated our findings in a mouse COVID-19 model, confirmed virome differences and bacteriome dysbiosis due to SARS-CoV-2 infection, and observed that immune/infection-related genes were differentially expressed in gut epithelial cells during infection, possibly explaining the virome and bacteriome dynamics. Our results suggest that the components of the microbiome, including the bacteriome and virome, are affected by SARS-CoV-2 infections, while their compositional signatures could reflect or even contribute to disease severity and recovery processes.


Subject(s)
COVID-19/microbiology , COVID-19/virology , Dysbiosis/diagnosis , Gastrointestinal Microbiome , Virome , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Anti-Bacterial Agents/therapeutic use , COVID-19/therapy , Case-Control Studies , China , Disease Models, Animal , Female , Genome, Viral , Humans , Male , Mice , Mice, Inbred C57BL , MicroRNAs , Middle Aged , Transcriptome
5.
Signal Transduct Target Ther ; 6(1): 58, 2021 02 10.
Article in English | MEDLINE | ID: covidwho-1078577

ABSTRACT

Treatment of severe Coronavirus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC-MSCs) to treat severe COVID-19 patients with lung damage, based on our phase 1 data. In this randomized, double-blind, and placebo-controlled trial, we recruited 101 severe COVID-19 patients with lung damage. They were randomly assigned at a 2:1 ratio to receive either UC-MSCs (4 × 107 cells per infusion) or placebo on day 0, 3, and 6. The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28. Other imaging outcomes, 6-minute walk test (6-MWT), maximum vital capacity, diffusing capacity, and adverse events were recorded and analyzed. In all, 100 COVID-19 patients were finally received either UC-MSCs (n = 65) or placebo (n = 35). UC-MSCs administration exerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo (the median difference was -13.31%, 95% CI -29.14%, 2.13%, P = 0.080). UC-MSCs significantly reduced the proportions of solid component lesion volume compared with the placebo (median difference: -15.45%; 95% CI -30.82%, -0.39%; P = 0.043). The 6-MWT showed an increased distance in patients treated with UC-MSCs (difference: 27.00 m; 95% CI 0.00, 57.00; P = 0.057). The incidence of adverse events was similar in the two groups. These results suggest that UC-MSCs treatment is a safe and potentially effective therapeutic approach for COVID-19 patients with lung damage. A phase 3 trial is required to evaluate effects on reducing mortality and preventing long-term pulmonary disability. (Funded by The National Key R&D Program of China and others. ClinicalTrials.gov number, NCT04288102.


Subject(s)
COVID-19/therapy , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , SARS-CoV-2 , Umbilical Cord , Aged , Allografts , COVID-19/mortality , COVID-19/physiopathology , Double-Blind Method , Female , Humans , Male , Middle Aged , Treatment Outcome
6.
Signal Transduct Target Ther ; 5(1): 172, 2020 08 27.
Article in English | MEDLINE | ID: covidwho-733534

ABSTRACT

No effective drug treatments are available for coronavirus disease 2019 (COVID-19). Host-directed therapies targeting the underlying aberrant immune responses leading to pulmonary tissue damage, death, or long-term functional disability in survivors require clinical evaluation. We performed a parallel assigned controlled, non-randomized, phase 1 clinical trial to evaluate the safety of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) infusions in the treatment of patients with moderate and severe COVID-19 pulmonary disease. The study enrolled 18 hospitalized patients with COVID-19 (n = 9 for each group). The treatment group received three cycles of intravenous infusion of UC-MSCs (3 × 107 cells per infusion) on days 0, 3, and 6. Both groups received standard COVID-treatment regimens. Adverse events, duration of clinical symptoms, laboratory parameters, length of hospitalization, serial chest computed tomography (CT) images, the PaO2/FiO2 ratio, dynamics of cytokines, and IgG and IgM anti-SARS-CoV-2 antibodies were analyzed. No serious UC-MSCs infusion-associated adverse events were observed. Two patients receiving UC-MSCs developed transient facial flushing and fever, and one patient developed transient hypoxia at 12 h post UC-MSCs transfusion. Mechanical ventilation was required in one patient in the treatment group compared with four in the control group. All patients recovered and were discharged. Our data show that intravenous UC-MSCs infusion in patients with moderate and severe COVID-19 is safe and well tolerated. Phase 2/3 randomized, controlled, double-blinded trials with long-term follow-up are needed to evaluate the therapeutic use of UC-MSCs to reduce deaths and improve long-term treatment outcomes in patients with serious COVID-19.


Subject(s)
Antibodies, Viral/blood , Betacoronavirus/immunology , Cord Blood Stem Cell Transplantation/methods , Coronavirus Infections/therapy , Hematopoietic Stem Cells/virology , Mesenchymal Stem Cell Transplantation/methods , Pneumonia, Viral/therapy , Adult , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Drug Combinations , Female , Glucocorticoids/therapeutic use , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/immunology , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Lopinavir , Male , Middle Aged , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Respiration, Artificial , Ritonavir , SARS-CoV-2 , Severity of Illness Index , Treatment Outcome
7.
Immunity ; 53(3): 685-696.e3, 2020 09 15.
Article in English | MEDLINE | ID: covidwho-716745

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic poses a current world-wide public health threat. However, little is known about its hallmarks compared to other infectious diseases. Here, we report the single-cell transcriptional landscape of longitudinally collected peripheral blood mononuclear cells (PBMCs) in both COVID-19- and influenza A virus (IAV)-infected patients. We observed increase of plasma cells in both COVID-19 and IAV patients and XIAP associated factor 1 (XAF1)-, tumor necrosis factor (TNF)-, and FAS-induced T cell apoptosis in COVID-19 patients. Further analyses revealed distinct signaling pathways activated in COVID-19 (STAT1 and IRF3) versus IAV (STAT3 and NFκB) patients and substantial differences in the expression of key factors. These factors include relatively increase of interleukin (IL)6R and IL6ST expression in COVID-19 patients but similarly increased IL-6 concentrations compared to IAV patients, supporting the clinical observations of increased proinflammatory cytokines in COVID-19 patients. Thus, we provide the landscape of PBMCs and unveil distinct immune response pathways in COVID-19 and IAV patients.


Subject(s)
Coronavirus Infections/immunology , Cytokines/immunology , Influenza, Human/immunology , Leukocytes, Mononuclear/immunology , Pneumonia, Viral/immunology , Signal Transduction/immunology , Betacoronavirus/immunology , COVID-19 , Humans , Influenza A Virus, H1N1 Subtype/immunology , Pandemics , SARS-CoV-2
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