Cell type-specific immune dysregulation in severely ill COVID-19 patients

Abstract

Coronavirus disease 2019 (COVID-19) has quickly become the most serious pandemic since the 1918 flu pandemic. In extreme situations, patients develop a dysregulated inflammatory lung injury called acute respiratory distress syndrome (ARDS) that causes progressive respiratory failure requiring mechanical ventilatory support. Recent studies have demonstrated immunologic dysfunction in severely ill COVID-19 patients. To further delineate the dysregulated immune response driving more severe clinical course from SARS-CoV-2 infection, we used single-cell RNA sequencing (scRNAseq) to analyze the transcriptome of peripheral blood mononuclear cells (PBMC) from hospitalized COVID-19 patients having mild disease (n = 5), developing ARDS (n = 6), and recovering from ARDS (n = 6). Our data demonstrated an overwhelming inflammatory response with select immunodeficiencies within various immune populations in ARDS patients. Specifically, their monocytes had defects in antigen presentation and deficiencies in interferon responsiveness that contrasted the higher interferon signals in lymphocytes. Furthermore, cytotoxic activity was suppressed in both NK and CD8 lymphocytes whereas B cell activation was deficient, which is consistent with the delayed viral clearance in severely ill COVID-19 patients. Finally, we identified altered signaling pathways in the severe group that suggests immunosenescence and immunometabolic changes could be contributing to the dysfunctional immune response. Our study demonstrates that COVID-19 patients with ARDS have an immunologically distinct response when compared to those with a more innocuous disease course and show a state of immune imbalance in which deficiencies in both the innate and adaptive immune response may be contributing to a more severe disease course in COVID-19.

Distinctive features of SARS-CoV-2-specific T cells predict recovery from severe COVID-19

“…We also observed co-expression of PD1 with the Fas receptor CD95 involved in apoptosis, and that PD1+CD95+ T cells, within both the total and SARS-CoV-2-specific compartments, were elevated in severe relative to mild cases. These observations are in line with an upregulation of CD95 transcripts on total T cells during COVID-19 (Zhu et al, 2020), and with reports of apoptotic T cells during severe (Yao et al, 2020) and fatal (Feng et al, 2020) COVID-19, during which elevated CD95 was observed in the dying cells. Together these results suggest increased proportions of exhausted and apoptotic-prone T cells during severe COVID-19.…”

SARS-CoV-2 infection in the Syrian hamster model causes inflammation as well as type I interferon dysregulation in both respiratory and non-respiratory tissues including the heart and kidney

“…Numerous studies have demonstrated impaired type I IFN responses following SARS-CoV-2 infection in vitro16,54,[55][56][57] . The IFN dysregulation we report here has not yet been analysed in the respiratory tissue of humans with severe COVID-19, but systemic immune analyses of blood have indicated similar results16,52,53,58 . Although the mechanisms inhibiting type I interferon responses have not been fully elucidated, viral and host factors have been implicated in this dysregulation59,60 .Dysregulation of the interferon response is a strategy employed by viruses to evade hostXia et al determined this dysregulation utilized by the highly pathogenic coronaviruses extends to SARS-CoV-2 by demonstrating that all three of these beta-coronaviruses downregulate the type I interferon pathway.…”

Repurposing NASVAC, a hepatitis B therapeutic vaccine, for pre- and postexposure prophylaxis of SARS-CoV-2 infection

“…The plasmacytoid DCs, myeloid DCs, and CD14 + monocytes of COVID-19-infected individuals are less responsive to stimulation with a bacterial/viral ligand cocktail than those of healthy controls (comprising TLR-2, TLR-4 and TLR-5 ligands and TLR-3 and TLR-7/8, respectively). It is believed that the innate immune cells in the periphery of COVID-19-infected subjects have functional impairment [56,57]. PBMCinduced production of gamma IFN and other cytokines justi es the use of NASVAC as a pre-emptive therapy or pre/postexposure prophylaxis of SARS-CoV-2 to prevent infection and to arrest the progression to severe COVID-19.…”