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Session Chair: Attila Tarnok Session Chair: Asylkhan Rakhymzhan
Combined approaches for COVID-19 Cytometry in Berlin
Speakers: Leif Erik Sander (Charité), Helena Radbruch (Charité) and Mir-Farzin Mashreghi (DRFZ and BCRT) will present data from their current Covid-19 studies
Dissecting innate immune responses to SARS-CoV-2
Leif Erik Sander
Charité Universitätsmedinzin Berlin, Germany
Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progresses to severe disease and respiratory failure. The mechanisms 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 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. Highly activated HLA-DRhiCD11chi monocytes with a strong interferon-stimulated gene (ISG) signature were elevated in mild COVID-19. In contrast, severe COVID-19 was marked by the occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, and dysfunctional mature neutrophils. Moreover, monocytes in patients with severe COVID-19 showed signs of alternative activation and expressed low levels of HLA-DR. Single cell RNA-Seq analysis of bronchoalveolar lavage and lung tissue from different disease stages, combined with Multi-epitope-ligand cartography (MELC), revealed an enrichment of alternatively activated monocyte-derived macrophages in patients with COVID-19 ARDS. Our study provides detailed insights into the innate immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19 and ARDS.
Olfactory transmucosal SARS-CoV-2 invasion as port of Central Nervous System entry in COVID-19 patients
Charité Universitätsmedizin Berlin, Germany
The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease presenting with fever, cough, and often pneumonia. Moreover, thromboembolic events throughout the body including the central nervous system (CNS) have been described. Given first indication for viral RNA presence in the brain and cerebrospinal fluid and in light of neurological symptoms in a large majority of COVID-19 patients, SARS-CoV-2-penetrance of the CNS is likely. By investigating and anatomically mapping oro- and pharyngeal regions and brains of 33 patients dying from COVID-19, we not only describe CNS infarction due to cerebral thromboembolism, but also demonstrate SARS-CoV-2 neurotropism. SARS-CoV-2 enters the nervous system via trespassing the neuro-mucosal interface in the olfactory mucosa by exploiting the close vicinity of olfactory mucosal and nervous tissue including delicate olfactory and sensitive nerve endings. Subsequently, SARS-CoV-2 follows defined neuroanatomical structures, penetrating defined neuroanatomical areas, including the primary respiratory and cardiovascular control center in the medulla oblongata.
In severe COVID-19, SARS-CoV-2 induces a chronic, TGF-β-dominated adaptive immune response
The human immune response to SARS-CoV-2 infection is highly variable, with less than 10% of infections resulting in severe COVID-19 requiring intensive care unit (ICU) treatment. Here we have analyzed the dynamics of the adaptive immune response in COVID-19 ICU patients at the level of single cell transcriptomes and B cell and T cell receptor (BCR, TCR) repertoires. Early after ICU admission, before seroconversion in response to SARS-CoV-2 spike protein, patients generate activated peripheral B cells with a type 1 interferon-induced gene expression signature. After seroconversion, patients display circulating activated B cells expressing an IL-21-induced gene expression signature and mainly IgG1 and IgA1, two isotypes induced by IL-21 and TGF-β, respectively. In sustained COVID-19, the persistent immune reaction is shifted to IgA2-expressing activated peripheral B cells, displaying somatic hypermutation, and expressing TGF-β-induced signature genes, like IgA germline transcripts. The switch from an IgG1 to an IgA2-dominated B cell response correlates with the appearance of SARS-CoV-2 reactive follicular T helper cells expressing IL-21 and/or TGF-β in the blood. Despite the continued presence of IgA2-expressing B cells and IgA antibodies in the blood of progressed COVID-19 patients, IgA2 secreting cells were scarce in the lungs of deceased COVID-19 patients. In summary, in severely affected COVID-19 patients SARS-CoV-2 triggers chronic immune reactions which are controlled by TGF-β, with most of the activated B cells being no longer specific for the SARS-CoV-2 spike protein and its receptor binding domain, nor for nucleoprotein. TGF-β may candidate as a target to ameliorate detrimental immunopathology in those patients.