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
Author Information
Elizabeth A Thompson: 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.
Katherine Cascino: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Alvaro A Ordonez: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Weiqiang Zhou: Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
Ajay Vaghasia: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Anne Hamacher-Brady: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
Nathan R Brady: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
Im-Hong Sun: 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.
Rulin Wang: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Avi Z Rosenberg: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Michael Delannoy: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Richard Rothman: Department of Emergency Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Katherine Fenstermacher: Department of Emergency Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Lauren Sauer: Department of Emergency Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Kathyrn Shaw-Saliba: Department of Emergency Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Evan M Bloch: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Andrew D Redd: 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.
Aaron A R Tobian: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Maureen Horton: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Kellie Smith: 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.
Andrew Pekosz: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
Franco R D'Alessio: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Srinivasan Yegnasubramanian: 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.
Hongkai Ji: Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
Andrea L Cox: 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.
Jonathan D Powell: 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.
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.
