TY - JOUR
T1 - Metabolic dysregulation impairs lymphocyte function during severe SARS-CoV-2 infection
AU - Gurshaney, Sanjeev
AU - Morales-Alvarez, Anamaria
AU - Ezhakunnel, Kevin
AU - Manalo, Andrew
AU - Huynh, Thien Huong
AU - Abe, Jun Ichi
AU - Le, Nhat Tu
AU - Weiskopf, Daniela
AU - Sette, Alessandro
AU - Lupu, Daniel S.
AU - Gardell, Stephen J.
AU - Nguyen, Hung
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/4/7
Y1 - 2023/4/7
N2 - Cellular metabolic dysregulation is a consequence of SARS-CoV-2 infection that is a key determinant of disease severity. However, how metabolic perturbations influence immunological function during COVID-19 remains unclear. Here, using a combination of high-dimensional flow cytometry, cutting-edge single-cell metabolomics, and re-analysis of single-cell transcriptomic data, we demonstrate a global hypoxia-linked metabolic switch from fatty acid oxidation and mitochondrial respiration towards anaerobic, glucose-dependent metabolism in CD8+Tc, NKT, and epithelial cells. Consequently, we found that a strong dysregulation in immunometabolism was tied to increased cellular exhaustion, attenuated effector function, and impaired memory differentiation. Pharmacological inhibition of mitophagy with mdivi-1 reduced excess glucose metabolism, resulting in enhanced generation of SARS-CoV-2- specific CD8+Tc, increased cytokine secretion, and augmented memory cell proliferation. Taken together, our study provides critical insight regarding the cellular mechanisms underlying the effect of SARS-CoV-2 infection on host immune cell metabolism, and highlights immunometabolism as a promising therapeutic target for COVID-19 treatment.
AB - Cellular metabolic dysregulation is a consequence of SARS-CoV-2 infection that is a key determinant of disease severity. However, how metabolic perturbations influence immunological function during COVID-19 remains unclear. Here, using a combination of high-dimensional flow cytometry, cutting-edge single-cell metabolomics, and re-analysis of single-cell transcriptomic data, we demonstrate a global hypoxia-linked metabolic switch from fatty acid oxidation and mitochondrial respiration towards anaerobic, glucose-dependent metabolism in CD8+Tc, NKT, and epithelial cells. Consequently, we found that a strong dysregulation in immunometabolism was tied to increased cellular exhaustion, attenuated effector function, and impaired memory differentiation. Pharmacological inhibition of mitophagy with mdivi-1 reduced excess glucose metabolism, resulting in enhanced generation of SARS-CoV-2- specific CD8+Tc, increased cytokine secretion, and augmented memory cell proliferation. Taken together, our study provides critical insight regarding the cellular mechanisms underlying the effect of SARS-CoV-2 infection on host immune cell metabolism, and highlights immunometabolism as a promising therapeutic target for COVID-19 treatment.
KW - Humans
KW - COVID-19
KW - SARS-CoV-2
KW - CD8-Positive T-Lymphocytes
KW - COVID-19 Drug Treatment
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UR - http://www.scopus.com/inward/citedby.url?scp=85151954220&partnerID=8YFLogxK
U2 - 10.1038/s42003-023-04730-4
DO - 10.1038/s42003-023-04730-4
M3 - Article
C2 - 37029220
AN - SCOPUS:85151954220
SN - 2399-3642
VL - 6
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 374
ER -