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/metabolismABSTRACT
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.