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1.
Genome Res ; 32(2): 228-241, 2022 02.
Article in English | MEDLINE | ID: covidwho-1642462

ABSTRACT

The pathogenesis of COVID-19 is still elusive, which impedes disease progression prediction, differential diagnosis, and targeted therapy. Plasma cell-free RNAs (cfRNAs) carry unique information from human tissue and thus could point to resourceful solutions for pathogenesis and host-pathogen interactions. Here, we performed a comparative analysis of cfRNA profiles between COVID-19 patients and healthy donors using serial plasma. Analyses of the cfRNA landscape, potential gene regulatory mechanisms, dynamic changes in tRNA pools upon infection, and microbial communities were performed. A total of 380 cfRNA molecules were up-regulated in all COVID-19 patients, of which seven could serve as potential biomarkers (AUC > 0.85) with great sensitivity and specificity. Antiviral (NFKB1A, IFITM3, and IFI27) and neutrophil activation (S100A8, CD68, and CD63)-related genes exhibited decreased expression levels during treatment in COVID-19 patients, which is in accordance with the dynamically enhanced inflammatory response in COVID-19 patients. Noncoding RNAs, including some microRNAs (let 7 family) and long noncoding RNAs (GJA9-MYCBP) targeting interleukin (IL6/IL6R), were differentially expressed between COVID-19 patients and healthy donors, which accounts for the potential core mechanism of cytokine storm syndromes; the tRNA pools change significantly between the COVID-19 and healthy group, leading to the accumulation of SARS-CoV-2 biased codons, which facilitate SARS-CoV-2 replication. Finally, several pneumonia-related microorganisms were detected in the plasma of COVID-19 patients, raising the possibility of simultaneously monitoring immune response regulation and microbial communities using cfRNA analysis. This study fills the knowledge gap in the plasma cfRNA landscape of COVID-19 patients and offers insight into the potential mechanisms of cfRNAs to explain COVID-19 pathogenesis.


Subject(s)
COVID-19 , Cell-Free Nucleic Acids , RNA/blood , COVID-19/blood , COVID-19/genetics , Cell-Free Nucleic Acids/blood , Cytokine Release Syndrome , Humans , SARS-CoV-2
3.
Front Immunol ; 12: 724763, 2021.
Article in English | MEDLINE | ID: covidwho-1399141

ABSTRACT

Characterizing the serologic features of asymptomatic SARS-CoV-2 infection is imperative to improve diagnostics and control of SARS-CoV-2 transmission. In this study, we evaluated the antibody profiles in 272 plasma samples collected from 59 COVID-19 patients, consisting of 18 asymptomatic patients, 33 mildly ill patients and 8 severely ill patients. We measured the IgG against five viral structural proteins, different isotypes of immunoglobulins against the Receptor Binding Domain (RBD) protein, and neutralizing antibodies. The results showed that the overall antibody response was lower in asymptomatic infections than in symptomatic infections throughout the disease course. In contrast to symptomatic patients, asymptomatic patients showed a dominant IgG-response towards the RBD protein, but not IgM and IgA. Neutralizing antibody titers had linear correlations with IgA/IgM/IgG levels against SARS-CoV-2-RBD, as well as with IgG levels against multiple SARS-CoV-2 structural proteins, especially with anti-RBD or anti-S2 IgG. In addition, the sensitivity of anti-S2-IgG is better in identifying asymptomatic infections at early time post infection compared to anti-RBD-IgG. These data suggest that asymptomatic infections elicit weaker antibody responses, and primarily induce IgG antibody responses rather than IgA or IgM antibody responses. Detection of IgG against the S2 protein could supplement nucleic acid testing to identify asymptomatic patients. This study provides an antibody detection scheme for asymptomatic infections, which may contribute to epidemic prevention and control.


Subject(s)
Antibodies, Viral/blood , Asymptomatic Infections , Immunoglobulin G/blood , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Viral Structural Proteins/immunology , Adolescent , Adult , Antibodies, Neutralizing/immunology , Antibodies, Viral/physiology , Binding Sites, Antibody , Female , Humans , Immunoglobulin G/classification , Immunoglobulin M/immunology , Kinetics , Male , Middle Aged , Neutralization Tests/statistics & numerical data , SARS-CoV-2/chemistry , Young Adult
4.
Signal Transduct Target Ther ; 6(1): 155, 2021 04 15.
Article in English | MEDLINE | ID: covidwho-1189204

ABSTRACT

Disease progression prediction and therapeutic drug target discovery for Coronavirus disease 2019 (COVID-19) are particularly important, as there is still no effective strategy for severe COVID-19 patient treatment. Herein, we performed multi-platform omics analysis of serial plasma and urine samples collected from patients during the course of COVID-19. Integrative analyses of these omics data revealed several potential therapeutic targets, such as ANXA1 and CLEC3B. Molecular changes in plasma indicated dysregulation of macrophage and suppression of T cell functions in severe patients compared to those in non-severe patients. Further, we chose 25 important molecular signatures as potential biomarkers for the prediction of disease severity. The prediction power was validated using corresponding urine samples and plasma samples from new COVID-19 patient cohort, with AUC reached to 0.904 and 0.988, respectively. In conclusion, our omics data proposed not only potential therapeutic targets, but also biomarkers for understanding the pathogenesis of severe COVID-19.


Subject(s)
COVID-19/blood , COVID-19/drug therapy , Drug Discovery , Lipidomics , Proteomics , SARS-CoV-2/metabolism , Biomarkers/blood , Female , Humans , Male
5.
J Exp Med ; 218(4)2021 04 05.
Article in English | MEDLINE | ID: covidwho-1035695

ABSTRACT

Virus-specific T cells play essential roles in protection against multiple virus infections, including SARS-CoV and MERS-CoV. While SARS-CoV-2-specific T cells have been identified in COVID-19 patients, their role in the protection of SARS-CoV-2-infected mice is not established. Here, using mice sensitized for infection with SARS-CoV-2 by transduction with an adenovirus expressing the human receptor (Ad5-hACE2), we identified SARS-CoV-2-specific T cell epitopes recognized by CD4+ and CD8+ T cells in BALB/c and C57BL/6 mice. Virus-specific T cells were polyfunctional and were able to lyse target cells in vivo. Further, type I interferon pathway was proved to be critical for generating optimal antiviral T cell responses after SARS-CoV-2 infection. T cell vaccination alone partially protected SARS-CoV-2-infected mice from severe disease. In addition, the results demonstrated cross-reactive T cell responses between SARS-CoV and SARS-CoV-2, but not MERS-CoV, in mice. Understanding the role of the T cell response will guide immunopathogenesis studies of COVID-19 and vaccine design and validation.


Subject(s)
COVID-19/immunology , Epitopes, T-Lymphocyte/immunology , Host-Pathogen Interactions/physiology , T-Lymphocytes/immunology , T-Lymphocytes/virology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/blood , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/virology , Chlorocebus aethiops , Cross Reactions , Epitope Mapping , Interferon Type I/immunology , Interferon Type I/metabolism , Mice, Inbred BALB C , Mice, Inbred C57BL , Middle East Respiratory Syndrome Coronavirus/immunology , SARS Virus/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Vero Cells
6.
J Clin Invest ; 130(10): 5235-5244, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-969923

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for coronavirus 2019 (COVID-19) pneumonia. Little is known about the kinetics, tissue distribution, cross-reactivity, and neutralization antibody response in patients with COVID-19. Two groups of patients with RT-PCR-confirmed COVID-19 were enrolled in this study: 12 severely ill patients in intensive care units who needed mechanical ventilation and 11 mildly ill patients in isolation wards. Serial clinical samples were collected for laboratory detection. Results showed that most of the severely ill patients had viral shedding in a variety of tissues for 20-40 days after onset of disease (8/12, 66.7%), while the majority of mildly ill patients had viral shedding restricted to the respiratory tract and had no detectable virus RNA 10 days after onset (9/11, 81.8%). Mildly ill patients showed significantly lower IgM response compared with that of the severe group. IgG responses were detected in most patients in both the severe and mild groups at 9 days after onset, and remained at a high level throughout the study. Antibodies cross-reactive to SARS-CoV and SARS-CoV-2 were detected in patients with COVID-19 but not in patients with MERS. High levels of neutralizing antibodies were induced after about 10 days after onset in both severely and mildly ill patients which were higher in the severe group. SARS-CoV-2 pseudotype neutralization test and focus reduction neutralization test with authentic virus showed consistent results. Sera from patients with COVID-19 inhibited SARS-CoV-2 entry. Sera from convalescent patients with SARS or Middle East respiratory syndrome (MERS) did not. Anti-SARS-CoV-2 S and N IgG levels exhibited a moderate correlation with neutralization titers in patients' plasma. This study improves our understanding of immune response in humans after SARS-CoV-2 infection.


Subject(s)
Antibodies, Viral/blood , Betacoronavirus/metabolism , Coronavirus Infections/blood , Pneumonia, Viral/blood , Viral Load , Virus Shedding , Adult , Aged , Antibody Specificity , COVID-19 , Cross Reactions , Female , Humans , Kinetics , Male , Middle Aged , Pandemics , SARS-CoV-2 , Severity of Illness Index
7.
Cell ; 182(3): 734-743.e5, 2020 08 06.
Article in English | MEDLINE | ID: covidwho-592236

ABSTRACT

COVID-19, caused by SARS-CoV-2, is a virulent pneumonia, with >4,000,000 confirmed cases worldwide and >290,000 deaths as of May 15, 2020. It is critical that vaccines and therapeutics be developed very rapidly. Mice, the ideal animal for assessing such interventions, are resistant to SARS-CoV-2. Here, we overcome this difficulty by exogenous delivery of human ACE2 with a replication-deficient adenovirus (Ad5-hACE2). Ad5-hACE2-sensitized mice developed pneumonia characterized by weight loss, severe pulmonary pathology, and high-titer virus replication in lungs. Type I interferon, T cells, and, most importantly, signal transducer and activator of transcription 1 (STAT1) are critical for virus clearance and disease resolution in these mice. Ad5-hACE2-transduced mice enabled rapid assessments of a vaccine candidate, of human convalescent plasma, and of two antiviral therapies (poly I:C and remdesivir). In summary, we describe a murine model of broad and immediate utility to investigate COVID-19 pathogenesis and to evaluate new therapies and vaccines.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/pathology , Coronavirus Infections/prevention & control , Disease Models, Animal , Pandemics/prevention & control , Pneumonia, Viral/pathology , Pneumonia, Viral/prevention & control , Vaccination , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Chlorocebus aethiops , Coronavirus Infections/virology , Drug Evaluation, Preclinical/methods , Female , Humans , Interferon-gamma/genetics , Interferon-gamma/metabolism , Lung/pathology , Lung/virology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Receptor, Interferon alpha-beta/genetics , Receptor, Interferon alpha-beta/metabolism , SARS-CoV-2 , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/metabolism , Specific Pathogen-Free Organisms , Transduction, Genetic , Vero Cells , Viral Load , Virus Replication
8.
Emerg Microbes Infect ; 9(1): 991-993, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-133551

ABSTRACT

SARS-CoV-2 caused a major outbreak of severe pneumonia (COVID-19) in humans. Viral RNA was detected in multiple organs in COVID-19 patients. However, infectious SARS-CoV-2 was only isolated from respiratory specimens. Here, infectious SARS-CoV-2 was successfully isolated from urine of a COVID-19 patient. The virus isolated could infect new susceptible cells and was recognized by its' own patient sera. Appropriate precautions should be taken to avoid transmission from urine.


Subject(s)
Betacoronavirus/isolation & purification , Coronavirus Infections/urine , Coronavirus Infections/virology , Pneumonia, Viral/urine , Pneumonia, Viral/virology , Aged , Animals , COVID-19 , Chlorocebus aethiops , Coronavirus Infections/transmission , Genome, Viral/genetics , Humans , Male , Pandemics , Pneumonia, Viral/transmission , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2 , Vero Cells
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