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1.
Front Immunol ; 13: 911859, 2022.
Article in English | MEDLINE | ID: covidwho-1952334

ABSTRACT

Safe and effective vaccines and therapeutics based on the understanding of antiviral immunity are urgently needed to end the COVID-19 pandemic. However, the understanding of these immune responses, especially cellular immune responses to SARS-CoV-2 infection, is limited. Here, we conducted a cohort study of COVID-19 patients who were followed and had blood collected to characterize the longitudinal dynamics of their cellular immune responses. Compared with healthy controls, the percentage of activation of SARS-CoV-2 S/N-specific T cells in recovered patients was significantly higher. And the activation percentage of S/N-specific CD8+ T cells in recovered patients was significantly higher than that of CD4+ T cells. Notably, SARS-CoV-2 specific T-cell responses were strongly biased toward the expression of Th1 cytokines, included the cytokines IFNγ, TNFα and IL2. Moreover, the secreted IFNγ and IL2 level in severe patients was higher than that in mild patients. Additionally, the number of IFNγ-secreting S-specific T cells in recovered patients were higher than that of N-specific T cells. Overall, the SARS-CoV-2 S/N-specific T-cell responses in recovered patients were strong, and virus-specific immunity was present until 14-16 weeks after symptom onset. Our work provides a basis for understanding the immune responses and pathogenesis of COVID-19. It also has implications for vaccine development and optimization and speeding up the licensing of the next generation of COVID-19 vaccines.


Subject(s)
COVID-19 , CD8-Positive T-Lymphocytes , COVID-19 Vaccines , Cohort Studies , Humans , Immunity, Cellular , Interleukin-2 , Pandemics , SARS-CoV-2
2.
Frontiers in immunology ; 13, 2022.
Article in English | EuropePMC | ID: covidwho-1876857

ABSTRACT

Safe and effective vaccines and therapeutics based on the understanding of antiviral immunity are urgently needed to end the COVID-19 pandemic. However, the understanding of these immune responses, especially cellular immune responses to SARS-CoV-2 infection, is limited. Here, we conducted a cohort study of COVID-19 patients who were followed and had blood collected to characterize the longitudinal dynamics of their cellular immune responses. Compared with healthy controls, the percentage of activation of SARS-CoV-2 S/N-specific T cells in recovered patients was significantly higher. And the activation percentage of S/N-specific CD8+ T cells in recovered patients was significantly higher than that of CD4+ T cells. Notably, SARS-CoV-2 specific T-cell responses were strongly biased toward the expression of Th1 cytokines, included the cytokines IFNγ, TNFα and IL2. Moreover, the secreted IFNγ and IL2 level in severe patients was higher than that in mild patients. Additionally, the number of IFNγ-secreting S-specific T cells in recovered patients were higher than that of N-specific T cells. Overall, the SARS-CoV-2 S/N-specific T-cell responses in recovered patients were strong, and virus-specific immunity was present until 14-16 weeks after symptom onset. Our work provides a basis for understanding the immune responses and pathogenesis of COVID-19. It also has implications for vaccine development and optimization and speeding up the licensing of the next generation of COVID-19 vaccines.

3.
Hum Immunol ; 83(2): 119-129, 2022 Feb.
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.


Subject(s)
Antibodies, Viral/immunology , B-Lymphocytes/immunology , COVID-19/immunology , Receptors, Antigen, B-Cell/immunology , SARS-CoV-2/immunology , Adolescent , Adult , Aged, 80 and over , Antibodies, Neutralizing/immunology , Female , Humans , Immunoglobulin Heavy Chains/immunology , Male , Middle Aged
5.
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
6.
Urine (Amst) ; 2: 1-8, 2020.
Article in English | MEDLINE | ID: covidwho-1118708

ABSTRACT

The atypical pneumonia (COVID-19) caused by SARS-CoV-2 is a serious threat to global public health. However, early detection and effective prediction of patients with mild to severe symptoms remain challenging. The proteomic profiling of urine samples from healthy individuals, mild and severe COVID-19 positive patients with comorbidities can be clearly differentiated. Multiple pathways have been compromised after the COVID-19 infection, including the dysregulation of complement activation, platelet degranulation, lipoprotein metabolic process and response to hypoxia. This study demonstrates the COVID-19 pathophysiology related molecular alterations could be detected in the urine and the potential application in auxiliary diagnosis of COVID-19.

8.
EBioMedicine ; 62: 103125, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-938894

ABSTRACT

BACKGROUND: The pharmacokinetics and appropriate dose regimens of favipiravir are unknown in hospitalized influenza patients; such data are also needed to determine dosage selection for favipiravir trials in COVID-19. METHODS: In this dose-escalating study, favipiravir pharmacokinetics and tolerability were assessed in critically ill influenza patients. Participants received one of two dosing regimens; Japan licensed dose (1600 mg BID on day 1 and 600 mg BID on the following days) and the higher dose (1800 mg/800 mg BID) trialed in uncomplicated influenza. The primary pharmacokinetic endpoint was the proportion of patients with a minimum observed plasma trough concentration (Ctrough) ≥20 mg/L at all measured time points after the second dose. RESULTS: Sixteen patients were enrolled into the low dose group and 19 patients into the high dose group of the study. Favipiravir Ctrough decreased significantly over time in both groups (p <0.01). Relative to day 2 (48 hrs), concentrations were 91.7% and 90.3% lower in the 1600/600 mg group and 79.3% and 89.5% lower in the 1800/800 mg group at day 7 and 10, respectively. In contrast, oseltamivir concentrations did not change significantly over time. A 2-compartment disposition model with first-order absorption and elimination described the observed favipiravir concentration-time data well. Modeling demonstrated that less than 50% of patients achieved Ctrough ≥20 mg/L for >80% of the duration of treatment of the two dose regimens evaluated (18.8% and 42.1% of patients for low and high dose regimen, respectively). Increasing the favipravir dosage predicted a higher proportion of patients reaching this threshold of 20 mg/L, suggesting that dosing regimens of ≥3600/2600 mg might be required for adequate concentrations. The two dosing regimens were well-tolerated in critical ill patients with influenza. CONCLUSION: The two dosing regimens proposed for uncomplicated influenza did not achieve our pre-defined treatment threshold.


Subject(s)
Amides , Influenza, Human/drug therapy , Oseltamivir , Pyrazines , Aged , Amides/administration & dosage , Amides/pharmacokinetics , Drug Therapy, Combination , Female , Humans , Influenza, Human/blood , Male , Middle Aged , Oseltamivir/administration & dosage , Oseltamivir/pharmacokinetics , Pyrazines/administration & dosage , Pyrazines/pharmacokinetics , Severity of Illness Index
9.
Int Immunopharmacol ; 89(Pt A): 107031, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-785793

ABSTRACT

Clearance of COVID-19 from the human body has not been established. Our study collected the laboratory test results from patients and analyzed the correlation between early changes in serum indices and the virus clearance by univariable and multivariable COX regression models, with an aim to explore the risk factors for prolonged viral clearance. The study included 61 patients with COVID-19 treated at the Fifth Medical Center of PLA General Hospital in Beijing from 20 January 2020 to 20 February 2020. We set the total observation of the disease course to 20 days and the patients were divided into two groups (prolonged group, > 20d vs. normal group, ≤ 20d). The 48 patients with COVID-19 included in this study, 13 remained positive for viral nucleic acid monitoring 20 days after onset. The median for virus clearance was 16 days (range, 6-35 days). The results showed that hypertension, a lactate dehydrogenase level > 211.5 U/L, an interleukin 6 (IL-6) level > 12.5 pg/ml, and a NK lymphocyte percentage > 0.5% were associated with prolonged viral clearance. Therefore, we showed that a history of hypertension, an elevated IL-6 level, and an elevated percentage of NK cells were risk factors for prolonged viral clearance.


Subject(s)
COVID-19/virology , RNA, Viral/analysis , SARS-CoV-2/isolation & purification , Virus Shedding , Adult , Aged , COVID-19/immunology , Female , Humans , Killer Cells, Natural/immunology , Male , Middle Aged , Proportional Hazards Models , Prospective Studies , Risk Factors
10.
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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