Metabolic programs define dysfunctional immune responses in severe COVID-19 patients

Elizabeth A Thompson,Anne Hamacher-Brady,Andrea L Cox,Lauren Sauer,Andrew Pekosz,Im-Hong Sun,Katherine Cascino,Hongkai Ji,Srinivasan Yegnasubramanian,Weiqiang Zhou,Franco R D’Alessio,Nathan R Brady,Rulin Wang,Ajay Vaghasia,Andrew D Redd,Jonathan D Powell,Katherine Fenstermacher,Aaron A.R Tobian,Evan M Bloch,Avi Z Rosenberg,Kathryn Shaw-Saliba ,Kellie N Smith ,Michaël Delannoy ,Richard E Rothman ,Maureen R Horton ,Alvaro A Ordoñez

doi:10.1016/j.celrep.2021.108863

Abstract

SummaryIt is unclear why some SARS-CoV-2 patients readily resolve infection while others develop severe disease. By interrogating metabolic programs of immune cells in severe and recovered coronavirus disease 2019 (COVID-19) patients compared with other viral infections, we identify a unique population of T cells. These T cells express increased Voltage-Dependent Anion Channel 1 (VDAC1), accompanied by gene programs and functional characteristics linked to mitochondrial dysfunction and apoptosis. The percentage of these cells increases in elderly patients and correlates with lymphopenia. Importantly, T cell apoptosis is inhibited in vitro by targeting the oligomerization of VDAC1 or blocking caspase activity. We also observe an expansion of myeloid-derived suppressor cells with unique metabolic phenotypes specific to COVID-19, and their presence distinguishes severe from mild disease. Overall, the identification of these metabolic phenotypes provides insight into the dysfunctional immune response in acutely ill COVID-19 patients and provides a means to predict and track disease severity and/or design metabolic therapeutic regimens.

Highlights

SARS-CoV-2 is a coronavirus responsible for the coronavirus disease 2019 (COVID-19) pandemic, resulting in over 20 million cases worldwide
Identification of a distinct T cell subset in the peripheral blood mononuclear cells (PBMCs) of COVID-A patients The high-dimensional flow-cytometry-based assay was performed on thawed PBMCs from an institutional review board (IRB)-approved biorepository from patients admitted to Johns Hopkins Hospital (Table S2)
We initially focused on T cells within the PBMCs given their importance in viral control

Summary

Introduction

SARS-CoV-2 is a coronavirus responsible for the coronavirus disease 2019 (COVID-19) pandemic, resulting in over 20 million cases worldwide. The vast majority of infected patients experience a self-limiting viral syndrome, others develop severe disease leading to pneumonia and acute respiratory distress syndrome (ARDS), accounting for over 1 million deaths worldwide (Dong et al, 2020) At this time, it is unclear why some patients readily resolve infection while others develop severe symptoms. Preferential loss of CD8+ T cells, increased plasmablasts, neutrophil expansion, decreased plasmacytoid dendritic cells (pDCs), and differential T cell activation have been observed (Kuri-Cervantes et al, 2020; Laing et al, 2020; Mathew et al, 2020; Wilk et al, 2020) Notable, these observations are indicative of generalized inflammation and fail to distinguish specific host deficiencies in SARSCoV-2 infection versus other viral infections or inflammatory states

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Discussion

Conclusion