Inappropriate Immune Response Hampers Viral Defense in COVID-19
Summary
SARS-CoV-2, the virus responsible for COVID-19, is controlled by natural killer (NK) cells, but their function may be altered during the disease. A decline in viral load correlates with NK cell status, and severe COVID-19 patients show defects in virus control, cytokine production and cell-mediated cytotoxicity. Single-cell RNA sequencing of NK cells shows that interferon-driven NK cell activation networks are superimposed by a dominant transforming growth factor-β (TGFβ) response signature, with reduced expression of genes related to cell–cell adhesion, granule exocytosis and cell-mediated cytotoxicity. TGFβ production is a hallmark of severe COVID-19 and may inhibit NK cell function and early control of the virus.
Research Criteria
The research idea of this article is to investigate whether natural killer (NK) cells can control SARS-CoV-2 replication by recognizing infected target cells and to determine the role of NK cells during SARS-CoV-2 infection. The article also reveals that an untimely production of transforming growth factor-β (TGFβ) is a hallmark of severe COVID-19 and may inhibit NK cell function and early control of the virus.
Fig.1 Experimental design. (Witkowski, 2021)
Sample Type
NK cells isolated from blood.
Result—Single Cell RNA Sequencing Atlas of NK Cells
Employing scRNA-seq, the investigators constructed a single-cell transcriptomic compendium of peripheral blood NK cells derived from subjects with acute COVID-19, oligosymptomatic SARS-CoV-2 afflictions, and unaffected controls, encompassing 80,325 discrete NK cell transcriptomes. Through UMAP, seven transcriptionally divergent clusters materialized, with cluster 6—containing non-NK cell contamination—omitted from subsequent examinations. Clusters 0-5 manifested conventional NK cell-specific genes, and the investigation explicated discrete cellular subpopulations: CD56bright NK cells (cluster 2), CD56dim NK cells (clusters 0, 1, and 3), transitional and adaptive NK cells (cluster 4), and proliferative NK cells (cluster 5). Appraisals of NK cell cluster occurrences across COVID-19 pathological states divulged varying NK cell differentiation patterns, typified by severe COVID-19 patients displaying augmented proliferative and terminally differentiated NK cells. Monocle pseudotime trajectory scrutiny exposed the CD56bright NK cells' differentiation into effector NK cells, culminating in terminally differentiated NK cells, with individuals afflicted by particularly acute COVID-19 exhibiting elevated proliferative NK cells and an accumulation of terminally differentiated NK cells along the progression.
Fig.2 In severe COVID-19 but not in severe influenza, NK cells are distinguished by a TGFβ response signature. (Witkowski, 2021)
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Reference
- Witkowski, M.; et al. Untimely TGFβ responses in COVID-19 limit antiviral functions of NK cells. Nature. 2021, 600(7888): 295-301.
