Integrated analysis of plasma and single immune cells uncovers metabolic changes in individuals with COVID-19

Abstract

A better understanding of the metabolic alterations in immune cells during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may elucidate the wide diversity of clinical symptoms experienced by individuals with coronavirus disease 2019 (COVID-19). Here, we report the metabolic changes associated with the peripheral immune response of 198 individuals with COVID-19 through an integrated analysis of plasma metabolite and protein levels as well as single-cell multiomics analyses from serial blood draws collected during the first week after clinical diagnosis. We document the emergence of rare but metabolically dominant T cell subpopulations and find that increasing disease severity correlates with a bifurcation of monocytes into two metabolically distinct subsets. This integrated analysis reveals a robust interplay between plasma metabolites and cell-type-specific metabolic reprogramming networks that is associated with disease severity and could predict survival.

Development of Exhausted Memory Monocytes and Underlying Mechanisms

“…In addition to well-defined immuno-suppressive molecules mentioned above, the exhausted monocytes generated in vitro also expressed representative pathogenic inflammatory genes identified in human septic patients including S100a8, Lcn2, and Alox5 (35,38). Furthermore, we identified elevated expression of Plac8, Plaur and Ms4a3 in the exhausted monocytes, consistent with recent single cell sequencing analyses and machine learning characterization studies of monocytes from human septic patients (14,(36)(37)(38). The inductions of pathogenic inflammatory genes are consistent with both murine and human studies.…”

“…We also observed a decrease in the MFI of CD86, MHCII as well as an increase in the MFI of PD-L1 and CD38 in both Ly6C + and Ly6C ++ populations (Supplementary Figures S2A-H). Our data is consistent with emerging studies in both experimental animals and humans with sepsis and/or polymicrobial infections including COVID-19 patients, demonstrating the reduction of human non-classical monocyte population (murine Ly6C Neg monocyte equivalent) and an increase of the exhausted monocyte population (human CD14 hi , murine Ly6C hi equivalent) (7,14,16).…”

“…Next, we explored the molecular mechanisms that may lead to monocyte exhaustion. Our work and others through computational analyses suggest that STAT1 may serve as a key node for driving the polarization of inflammatory classical monocytes in murine monocytes and human monocytes with polymicrobial infections including COVID-19 (14,28). This is also consistent with additional experimental studies, reporting that STAT1 levels are upregulated in sepsis models (45); and that STAT1 deficient mice are protected from cecal-ligation and puncture-induced experimental sepsis (46).…”

“…Infiltration of Ly6C pos monocytes in early as well as late phases of sepsis has been reported in experimental murine models (5,7). Recent studies also reveal a sharp decrease of the human non-classical monocyte populations in septic patients as well as patients with severe COVID-19 (7,14,15). Despite these important phenotypic observations, mechanisms responsible for the development of pathogenic inflammatory and immuno-suppressive classical monocytes are still poorly defined.…”

Mitochondrial phenotypes in purified human immune cell subtypes and cell mixtures

“…Here we isolated and phenotyped multiple molecularly-defined immune cell subtypes and mixed PBMCs in >200 person-cell type combinations among a small diverse cohort of women and men, and in repeated weekly measures in the same participant. Our biochemical and molecular results confirm and extend previous knowledge of bioenergetic differences across human immune cell types established using extracellular flux analysis, protein and mtDNA quantification (Chacko et al, 2013;Lee et al, 2021;Maianski et al, 2004;Pyle et al, 2010). We also report preliminary evidence that mitochondrial phenotypes vary with age and sex, which PBMCs lack the sensitivity to detect.…”