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Front Immunol ; 12: 799896, 2021.
Article in English | MEDLINE | ID: covidwho-1662583


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in rapid T lymphocytopenia and functional impairment of T cells. The underlying mechanism, however, remains incompletely understood. In this study, we focused on characterizing the phenotype and kinetics of T-cell subsets with mitochondrial dysfunction (MD) by multicolor flow cytometry and investigating the association between MD and T-cell functionality. While 73.9% of study subjects displayed clinical lymphocytopenia upon hospital admission, a significant reduction of CD4 or CD8 T-cell frequency was found in all asymptomatic, symptomatic, and convalescent cases. CD4 and CD8 T cells with increased MD were found in both asymptomatic and symptomatic patients within the first week of symptom onset. Lower proportion of memory CD8 T cell with MD was found in severe patients than in mild ones at the stage of disease progression. Critically, the frequency of T cells with MD in symptomatic patients was preferentially associated with CD4 T-cell loss and CD8 T-cell hyperactivation, respectively. Patients bearing effector memory CD4 and CD8 T cells with the phenotype of high MD exhibited poorer T-cell responses upon either phorbol 12-myristate-13-acetate (PMA)/ionomycin or SARS-CoV-2 peptide stimulation than those with low MD. Our findings demonstrated an MD-associated mechanism underlying SARS-CoV-2-induced T lymphocytopenia and functional impairment during the acute phase of infection.

COVID-19/complications , Lymphopenia/complications , Lymphopenia/etiology , Mitochondrial Diseases/etiology , Adult , Aged , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/drug therapy , COVID-19/immunology , Female , Humans , Immunologic Memory/immunology , Ionomycin/therapeutic use , Lymphopenia/immunology , Male , Middle Aged , Mitochondria/immunology , Mitochondrial Diseases/immunology , Phosphorylcholine/analogs & derivatives , Phosphorylcholine/therapeutic use , Polymethacrylic Acids/therapeutic use
Sci Adv ; 6(35): eaba7910, 2020 08.
Article in English | MEDLINE | ID: covidwho-760200


Targeting a universal host protein exploited by most viruses would be a game-changing strategy that offers broad-spectrum solution and rapid pandemic control including the current COVID-19. Here, we found a common YxxØ-motif of multiple viruses that exploits host AP2M1 for intracellular trafficking. A library chemical, N-(p-amylcinnamoyl)anthranilic acid (ACA), was identified to interrupt AP2M1-virus interaction and exhibit potent antiviral efficacy against a number of viruses in vitro and in vivo, including the influenza A viruses (IAVs), Zika virus (ZIKV), human immunodeficiency virus, and coronaviruses including MERS-CoV and SARS-CoV-2. YxxØ mutation, AP2M1 depletion, or disruption by ACA causes incorrect localization of viral proteins, which is exemplified by the failure of nuclear import of IAV nucleoprotein and diminished endoplasmic reticulum localization of ZIKV-NS3 and enterovirus-A71-2C proteins, thereby suppressing viral replication. Our study reveals an evolutionarily conserved mechanism of protein-protein interaction between host and virus that can serve as a broad-spectrum antiviral target.

Adaptor Proteins, Vesicular Transport/metabolism , Antiviral Agents/pharmacology , Cinnamates/pharmacology , Coronavirus Infections/drug therapy , HIV Infections/drug therapy , Influenza, Human/drug therapy , Pneumonia, Viral/drug therapy , ortho-Aminobenzoates/pharmacology , A549 Cells , Animals , Betacoronavirus/drug effects , Binding Sites/genetics , COVID-19 , Cell Line, Tumor , Chlorocebus aethiops , Coronavirus Infections/pathology , Dogs , HEK293 Cells , HIV Infections/pathology , HIV-1/drug effects , Host-Pathogen Interactions/drug effects , Humans , Influenza A virus/drug effects , Influenza, Human/pathology , Madin Darby Canine Kidney Cells , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Middle East Respiratory Syndrome Coronavirus/drug effects , Pandemics , Pneumonia, Viral/pathology , Protein Binding/genetics , Protein Transport/drug effects , RNA, Viral/genetics , Receptor, Interferon alpha-beta/genetics , SARS-CoV-2 , Transforming Growth Factor beta1/metabolism , Vero Cells , Virus Replication/drug effects , Zika Virus/drug effects , Zika Virus Infection/pathology
Immunity ; 53(4): 864-877.e5, 2020 10 13.
Article in English | MEDLINE | ID: covidwho-693493


The SARS-CoV-2 pandemic has resulted in millions of infections, yet the role of host immune responses in early COVID-19 pathogenesis remains unclear. By investigating 17 acute and 24 convalescent patients, we found that acute SARS-CoV-2 infection resulted in broad immune cell reduction including T, natural killer, monocyte, and dendritic cells (DCs). DCs were significantly reduced with functional impairment, and ratios of conventional DCs to plasmacytoid DCs were increased among acute severe patients. Besides lymphocytopenia, although neutralizing antibodies were rapidly and abundantly generated in patients, there were delayed receptor binding domain (RBD)- and nucleocapsid protein (NP)-specific T cell responses during the first 3 weeks after symptoms onset. Moreover, acute RBD- and NP-specific T cell responses included relatively more CD4 T cells than CD8 T cells. Our findings provided evidence that impaired DCs, together with timely inverted strong antibody but weak CD8 T cell responses, could contribute to acute COVID-19 pathogenesis and have implications for vaccine development.

Betacoronavirus/pathogenicity , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Coronavirus Infections/immunology , Dendritic Cells/immunology , Diabetes Mellitus/immunology , Hypertension/immunology , Pneumonia, Viral/immunology , Adult , Aged , Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , Betacoronavirus/immunology , CD4-Positive T-Lymphocytes/pathology , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/virology , COVID-19 , Convalescence , Coronavirus Infections/complications , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Dendritic Cells/pathology , Dendritic Cells/virology , Diabetes Complications , Diabetes Mellitus/diagnosis , Diabetes Mellitus/virology , Disease Progression , Female , Humans , Hypertension/complications , Hypertension/diagnosis , Hypertension/virology , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Killer Cells, Natural/virology , Lymphocyte Activation , Lymphocyte Count , Male , Middle Aged , Monocytes/immunology , Monocytes/pathology , Monocytes/virology , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , SARS-CoV-2 , Severity of Illness Index