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

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

doi:10.1016/j.celrep.2021.108863

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

Cell Rep. 2021 Mar 16;34(11):108863. doi: 10.1016/j.celrep.2021.108863. Epub 2021 Feb 26.

Authors

Elizabeth A Thompson¹, Katherine Cascino², Alvaro A Ordonez³, Weiqiang Zhou⁴, Ajay Vaghasia⁵, Anne Hamacher-Brady⁶, Nathan R Brady⁶, Im-Hong Sun¹, Rulin Wang⁵, Avi Z Rosenberg⁷, Michael Delannoy⁸, Richard Rothman⁹, Katherine Fenstermacher⁹, Lauren Sauer⁹, Kathyrn Shaw-Saliba⁹, Evan M Bloch⁷, Andrew D Redd¹⁰, Aaron A R Tobian⁷, Maureen Horton², Kellie Smith¹, Andrew Pekosz⁶, Franco R D'Alessio², Srinivasan Yegnasubramanian¹¹, Hongkai Ji⁴, Andrea L Cox¹², Jonathan D Powell¹³

Affiliations

¹ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
² Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
³ Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁴ Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
⁵ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁶ W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
⁷ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁸ Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁹ Department of Emergency Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹⁰ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Baltimore, MD 21205, USA.
¹¹ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹² Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA. Electronic address: acox@jhmi.edu.
¹³ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: jpowell@jhmi.edu.

Abstract

It 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.

Keywords: COVID-19; MDSCs; SARS-CoV-2; T cells; apoptosis; immunology; immunometabolism; metabolism; mitochondria.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Apoptosis / immunology
COVID-19 / immunology*
COVID-19 / metabolism*
Caspases / immunology
Caspases / metabolism
Female
Humans
Immunity / immunology*
Lymphopenia / immunology
Lymphopenia / metabolism
Male
Middle Aged
Mitochondria / immunology
Mitochondria / metabolism
Myeloid-Derived Suppressor Cells / immunology
Myeloid-Derived Suppressor Cells / metabolism
SARS-CoV-2 / immunology
T-Lymphocytes / immunology
T-Lymphocytes / metabolism
Voltage-Dependent Anion Channel 1 / metabolism
Young Adult

Substances

Voltage-Dependent Anion Channel 1
Caspases

Abstract

Publication types

MeSH terms

Substances

Grants and funding