Abstract
COVID-19 can cause acute and chronic neurological symptoms. The underlying pathophysiological mechanisms, the involved immune cells, their spatial distribution, cellular interactions and the role of virus tropism remain largely unclear. Here, we deeply interrogated the brain stem and olfactory bulb in COVID-19 patients with imaging mass cytometry to understand the local immune response at a spatially resolved, high-dimensional single-cell level. We observed significant immune activation in the CNS and identified distinct phenotypes of T cells and microglial clusters, their presence in specific anatomical regions and context-specific cellular interactions. Microglial nodules and perivascular immune cell clusters constitute key sites of the local immune response, with viral antigen present in ACE2-expressing cells in the perivascular compartment. Disease-associated neuroinflammation is associated with astrogliosis and severe axonal damage as a structural basis for the neurologic deficits. Finally, we identify compartment- and cluster-specific immune checkpoints that can be targeted for future therapeutic interventions.Funding: This project was supported by grants from the Deutsche Forschungsgemeinschaft (DFG, GermanResearch Foundation) (SFB 992, SFB1160, SFB/TRR167, SFB/TRR179, German Excellency strategyCIBSS - EXC-2189– Project ID390939984) and special research funds from the Ministry for Science, Research and Art of Baden-Wuerttemberg dedicated to “COVID-19 research” and “Neuroinflammation”.B.B. was further supported by DFG grant BE-5496/5-1 and M.P. was further supported by the Sobek Foundation, the Ernst-Jung Foundation, the Reinhart-Koselleck-Grant and Gottfried Wilhelm Leibniz-Prize.H.E.M. was supported by DFG ME-3644/5-1.Ethical Approval: The analyses were performed with the approval of the Institutional Review Boards (Ethic Committee of the Albert-Ludwigs-University, Freiburg: 322/20, 10008/09; Ethics Committee of the Hamburg Chamber of Physicians: WF-051/20, PV7311). The study was performed in agreement with the principles expressed in the Declaration of Helsinki (2013).Conflict of Interest: None to declare.
Highlights
COVID-19 due to the SARS-CoV-2 pandemic is emerging as a multifaceted disease with multi[27] organ complications
Our results indicate that during COVID-19 encephalopathy, the adaptive as well as the central nervous system (CNS) endogenous innate immune system are concomitantly activated, and highlight disease-specific immune cell clusters that physically interact in distinct CNS compartments
Parallel manual count analysis indicated a significant immune infiltration of the brain stem from COVID-19 patients by CD8 T cells and CD4 T cells and some B cells (Figure 1D). This adaptive immune infiltration by immune cells that are largely absent in control brains occurred in the presence of significantly increased numbers of Iba1+ microglial cells as well as CD163+ perivascular macrophages (Figure 1D). Interestingly, we observed a reduction in CD3-GzmB+ NK cells in diseased patients, indicative of a ~50% depletion of brain NK cells that has been described in the periphery of COVID-19 patients and is implicated in a more severe clinical course of COVID-1915,16
Summary
COVID-19 due to the SARS-CoV-2 pandemic is emerging as a multifaceted disease with multi[27] organ complications. An immunotype with strong CD4 T cell activation, and expansion of plasmablasts was linked to highest NIH COVID severity scales[11,12]. It is currently unclear whether the immune responses assessed in the peripheral blood reflect the immune responses in the tissue and which immune populations are involved in mediating organ pathology. We utilized imaging mass cytometry (IMC) that allowed the simultaneous detection of several key immune populations, including novel disease-linked clusters of CD4 and CD8 T cells, NK cells, B cells, and numerous myeloid and brain-specific innate immune populations, their cellular interactions and importantly, their compartmentalization in distinct anatomical regions of the brain stem. Our data provide a foundation for novel therapeutic avenues aimed at reducing neuroinflammation in COVID-19 patients
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