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1.
Nat Microbiol ; 2022 Jan 10.
Article in English | MEDLINE | ID: covidwho-1616988

ABSTRACT

Here we compared SARS-CoV-2-specific antibody and T-cell responses between older adults (>80 years old, n = 51) and a younger control group (20-53 years old, n = 46) after receiving two doses of BNT162b2. We found that responses in older adults were generally lower, and we identified 10% low-/non-responders. After receiving a third vaccination with BNT162b2, 4 out of 5 low-/non-responders showed antibody and T-cell responses similar to those of responders after two vaccinations.

2.
Cell ; 2021 Dec 28.
Article in English | MEDLINE | ID: covidwho-1588146

ABSTRACT

Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathology, and it remains unclear whether T cells contribute to disease pathology. Here, we combined single-cell transcriptomics and single-cell proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals. We identified highly activated CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune-complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Increased generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells. Proportions of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a were associated with fatal outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.

3.
Immunity ; 54(7): 1594-1610.e11, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1281436

ABSTRACT

COVID-19 can cause severe neurological symptoms, but the underlying pathophysiological mechanisms are unclear. Here, we interrogated the brain stems and olfactory bulbs in postmortem patients who had COVID-19 using imaging mass cytometry to understand the local immune response at a spatially resolved, high-dimensional, single-cell level and compared their immune map to non-COVID respiratory failure, multiple sclerosis, and control patients. We observed substantial immune activation in the central nervous system with pronounced neuropathology (astrocytosis, axonal damage, and blood-brain-barrier leakage) and detected viral antigen in ACE2-receptor-positive cells enriched in the vascular compartment. Microglial nodules and the perivascular compartment represented COVID-19-specific, microanatomic-immune niches with context-specific cellular interactions enriched for activated CD8+ T cells. Altered brain T-cell-microglial interactions were linked to clinical measures of systemic inflammation and disturbed hemostasis. This study identifies profound neuroinflammation with activation of innate and adaptive immune cells as correlates of COVID-19 neuropathology, with implications for potential therapeutic strategies.


Subject(s)
Brain/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Microglia/immunology , Blood-Brain Barrier/immunology , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/pathology , Brain/metabolism , Brain/pathology , CD8-Positive T-Lymphocytes/metabolism , COVID-19/pathology , Cell Communication , Central Nervous System/immunology , Central Nervous System/metabolism , Central Nervous System/pathology , Humans , Immune Checkpoint Proteins/metabolism , Inflammation , Lymphocyte Activation , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Olfactory Bulb/immunology , Olfactory Bulb/metabolism , Olfactory Bulb/pathology , Respiratory Insufficiency/immunology , Respiratory Insufficiency/pathology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism
4.
Nat Med ; 27(1): 78-85, 2021 01.
Article in English | MEDLINE | ID: covidwho-1065910

ABSTRACT

Emerging data indicate that SARS-CoV-2-specific CD8+ T cells targeting different viral proteins are detectable in up to 70% of convalescent individuals1-5. However, very little information is currently available about the abundance, phenotype, functional capacity and fate of pre-existing and induced SARS-CoV-2-specific CD8+ T cell responses during the natural course of SARS-CoV-2 infection. Here, we define a set of optimal and dominant SARS-CoV-2-specific CD8+ T cell epitopes. We also perform a high-resolution ex vivo analysis of pre-existing and induced SARS-CoV-2-specific CD8+ T cells, applying peptide-loaded major histocompatibility complex class I (pMHCI) tetramer technology. We observe rapid induction, prolonged contraction and emergence of heterogeneous and functionally competent cross-reactive and induced memory CD8+ T cell responses in cross-sectionally analyzed individuals with mild disease following SARS-CoV-2 infection and three individuals longitudinally assessed for their T cells pre- and post-SARS-CoV-2 infection. SARS-CoV-2-specific memory CD8+ T cells exhibited functional characteristics comparable to influenza-specific CD8+ T cells and were detectable in SARS-CoV-2 convalescent individuals who were seronegative for anti-SARS-CoV-2 antibodies targeting spike (S) and nucleoprotein (N). These results define cross-reactive and induced SARS-CoV-2-specific CD8+ T cell responses as potentially important determinants of immune protection in mild SARS-CoV-2 infection.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/blood , Case-Control Studies , Convalescence , Coronavirus Nucleocapsid Proteins/chemistry , Cross Reactions , Cross-Sectional Studies , Epitopes, T-Lymphocyte , Flow Cytometry , HLA-B Antigens/immunology , Humans , Immunologic Memory , Longitudinal Studies , Phosphoproteins/chemistry , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry
5.
Cell ; 182(6): 1419-1440.e23, 2020 09 17.
Article in English | MEDLINE | ID: covidwho-694631

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRhiCD11chi inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DRlo monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.


Subject(s)
Coronavirus Infections/immunology , Myeloid Cells/immunology , Myelopoiesis , Pneumonia, Viral/immunology , Adult , Aged , CD11 Antigens/genetics , CD11 Antigens/metabolism , COVID-19 , Cells, Cultured , Coronavirus Infections/blood , Coronavirus Infections/pathology , Female , HLA-DR Antigens/genetics , HLA-DR Antigens/metabolism , Humans , Male , Middle Aged , Myeloid Cells/cytology , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/pathology , Proteome/genetics , Proteome/metabolism , Proteomics , Single-Cell Analysis
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