Immunometabolic analysis shows a distinct cyto-metabotype in Covid-19 compared to sepsis from other causes

Francesca M. Trovato; Salma Mujib; Ellen Jerome; Anna Cavazza; Phillip Morgan; John Smith; Maria Theresa Depante; Kevin O'Reilly; James Luxton; Tracey Mare; Salvatore Napoli; Mark JW McPhail

doi:10.1016/j.heliyon.2022.e09733

Immunometabolic analysis shows a distinct cyto-metabotype in Covid-19 compared to sepsis from other causes

Francesca M. Trovato^*, Salma Mujib, Ellen Jerome, Anna Cavazza, Phillip Morgan, John Smith, Maria Theresa Depante, Kevin O'Reilly, James Luxton, Tracey Mare, Salvatore Napoli, Mark JW McPhail

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

Abstract

Background: In Covid-19, profound systemic inflammatory responses are accompanied by both metabolic risk factors for severity and, separately, metabolic mechanisms have been shown to underly disease progression. It is unknown whether this reflects similar situations in sepsis or is a unique characteristic of Covid-19. Aims: Define the immunometabolic signature of Covid-19. Methods: 65 patients with Covid-19,19 patients with sepsis and 14 healthy controls were recruited and sampled for plasma, serum and peripheral blood mononuclear cells (PBMCs) through 10 days of critical illness. Metabotyping was performed using the Biocrates p180 kit and multiplex cytokine profiling undertaken. PBMCs underwent phenotyping by flow cytometry. Immune and metabolic readouts were integrated and underwent pathway analysis. Results: Phopsphatidylcholines (PC) are reduced in Covid-19 but greater than in sepsis. Compared to controls, tryptophan is reduced in Covid-19 and inversely correlated with the severity of the disease and IFN-ɣ concentrations, conversely the kyneurine and kyneurine/tryptophan ratio increased in the most severe cases. These metabolic changes were consistent through 2 pandemic waves in our centre. PD-L1 expression in CD8+ T cells, Tregs and CD14+ monocytes was increased in Covid-19 compared to controls. Conclusions: In our cohort, Covid-19 is associated with monocytopenia, increased CD14+ and Treg PD-L1 expression correlating with IFN-ɣ plasma concentration and disease severity (SOFA score). The latter is also associated with metabolic derangements of Tryptophan, LPC 16:0 and PCs. Lipid metabolism, in particular phosphatidylcholines and lysophosphatidylcolines, seems strictly linked to immune response in Covid-19. Our results support the hypothesis that IFN-ɣ -PD-L1 axis might be involved in the cytokine release syndrome typical of severe Covid-19 and the phenomenon persisted through multiple pandemic waves despite use of immunomodulation.

Original language	English
Article number	e09733
Journal	Heliyon
Volume	8
Issue number	6
DOIs	https://doi.org/10.1016/j.heliyon.2022.e09733
Publication status	Published - Jun 2022

Keywords

Covid-19
Immune checkpoint
Immunometabolism
Phosphatidylcholine
Tryptophan

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10.1016/j.heliyon.2022.e09733

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@article{288c03a3842d4ab199af5c6e157145ec,

title = "Immunometabolic analysis shows a distinct cyto-metabotype in Covid-19 compared to sepsis from other causes",

abstract = "Background: In Covid-19, profound systemic inflammatory responses are accompanied by both metabolic risk factors for severity and, separately, metabolic mechanisms have been shown to underly disease progression. It is unknown whether this reflects similar situations in sepsis or is a unique characteristic of Covid-19. Aims: Define the immunometabolic signature of Covid-19. Methods: 65 patients with Covid-19,19 patients with sepsis and 14 healthy controls were recruited and sampled for plasma, serum and peripheral blood mononuclear cells (PBMCs) through 10 days of critical illness. Metabotyping was performed using the Biocrates p180 kit and multiplex cytokine profiling undertaken. PBMCs underwent phenotyping by flow cytometry. Immune and metabolic readouts were integrated and underwent pathway analysis. Results: Phopsphatidylcholines (PC) are reduced in Covid-19 but greater than in sepsis. Compared to controls, tryptophan is reduced in Covid-19 and inversely correlated with the severity of the disease and IFN-ɣ concentrations, conversely the kyneurine and kyneurine/tryptophan ratio increased in the most severe cases. These metabolic changes were consistent through 2 pandemic waves in our centre. PD-L1 expression in CD8+ T cells, Tregs and CD14+ monocytes was increased in Covid-19 compared to controls. Conclusions: In our cohort, Covid-19 is associated with monocytopenia, increased CD14+ and Treg PD-L1 expression correlating with IFN-ɣ plasma concentration and disease severity (SOFA score). The latter is also associated with metabolic derangements of Tryptophan, LPC 16:0 and PCs. Lipid metabolism, in particular phosphatidylcholines and lysophosphatidylcolines, seems strictly linked to immune response in Covid-19. Our results support the hypothesis that IFN-ɣ -PD-L1 axis might be involved in the cytokine release syndrome typical of severe Covid-19 and the phenomenon persisted through multiple pandemic waves despite use of immunomodulation.",

keywords = "Covid-19, Immune checkpoint, Immunometabolism, Phosphatidylcholine, Tryptophan",

author = "Trovato, {Francesca M.} and Salma Mujib and Ellen Jerome and Anna Cavazza and Phillip Morgan and John Smith and Depante, {Maria Theresa} and Kevin O'Reilly and James Luxton and Tracey Mare and Salvatore Napoli and McPhail, {Mark JW}",

note = "Funding Information: MM is grateful to the NIHR Biomedical Research Council at Guys and St Thomas Hospital for salary and infrastructure support. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = jun,

doi = "10.1016/j.heliyon.2022.e09733",

language = "English",

volume = "8",

journal = "Heliyon",

issn = "2405-8440",

publisher = "Elsevier BV",

number = "6",

}

TY - JOUR

T1 - Immunometabolic analysis shows a distinct cyto-metabotype in Covid-19 compared to sepsis from other causes

AU - Trovato, Francesca M.

AU - Mujib, Salma

AU - Jerome, Ellen

AU - Cavazza, Anna

AU - Morgan, Phillip

AU - Smith, John

AU - Depante, Maria Theresa

AU - O'Reilly, Kevin

AU - Luxton, James

AU - Mare, Tracey

AU - Napoli, Salvatore

AU - McPhail, Mark JW

PY - 2022/6

Y1 - 2022/6

N2 - Background: In Covid-19, profound systemic inflammatory responses are accompanied by both metabolic risk factors for severity and, separately, metabolic mechanisms have been shown to underly disease progression. It is unknown whether this reflects similar situations in sepsis or is a unique characteristic of Covid-19. Aims: Define the immunometabolic signature of Covid-19. Methods: 65 patients with Covid-19,19 patients with sepsis and 14 healthy controls were recruited and sampled for plasma, serum and peripheral blood mononuclear cells (PBMCs) through 10 days of critical illness. Metabotyping was performed using the Biocrates p180 kit and multiplex cytokine profiling undertaken. PBMCs underwent phenotyping by flow cytometry. Immune and metabolic readouts were integrated and underwent pathway analysis. Results: Phopsphatidylcholines (PC) are reduced in Covid-19 but greater than in sepsis. Compared to controls, tryptophan is reduced in Covid-19 and inversely correlated with the severity of the disease and IFN-ɣ concentrations, conversely the kyneurine and kyneurine/tryptophan ratio increased in the most severe cases. These metabolic changes were consistent through 2 pandemic waves in our centre. PD-L1 expression in CD8+ T cells, Tregs and CD14+ monocytes was increased in Covid-19 compared to controls. Conclusions: In our cohort, Covid-19 is associated with monocytopenia, increased CD14+ and Treg PD-L1 expression correlating with IFN-ɣ plasma concentration and disease severity (SOFA score). The latter is also associated with metabolic derangements of Tryptophan, LPC 16:0 and PCs. Lipid metabolism, in particular phosphatidylcholines and lysophosphatidylcolines, seems strictly linked to immune response in Covid-19. Our results support the hypothesis that IFN-ɣ -PD-L1 axis might be involved in the cytokine release syndrome typical of severe Covid-19 and the phenomenon persisted through multiple pandemic waves despite use of immunomodulation.

AB - Background: In Covid-19, profound systemic inflammatory responses are accompanied by both metabolic risk factors for severity and, separately, metabolic mechanisms have been shown to underly disease progression. It is unknown whether this reflects similar situations in sepsis or is a unique characteristic of Covid-19. Aims: Define the immunometabolic signature of Covid-19. Methods: 65 patients with Covid-19,19 patients with sepsis and 14 healthy controls were recruited and sampled for plasma, serum and peripheral blood mononuclear cells (PBMCs) through 10 days of critical illness. Metabotyping was performed using the Biocrates p180 kit and multiplex cytokine profiling undertaken. PBMCs underwent phenotyping by flow cytometry. Immune and metabolic readouts were integrated and underwent pathway analysis. Results: Phopsphatidylcholines (PC) are reduced in Covid-19 but greater than in sepsis. Compared to controls, tryptophan is reduced in Covid-19 and inversely correlated with the severity of the disease and IFN-ɣ concentrations, conversely the kyneurine and kyneurine/tryptophan ratio increased in the most severe cases. These metabolic changes were consistent through 2 pandemic waves in our centre. PD-L1 expression in CD8+ T cells, Tregs and CD14+ monocytes was increased in Covid-19 compared to controls. Conclusions: In our cohort, Covid-19 is associated with monocytopenia, increased CD14+ and Treg PD-L1 expression correlating with IFN-ɣ plasma concentration and disease severity (SOFA score). The latter is also associated with metabolic derangements of Tryptophan, LPC 16:0 and PCs. Lipid metabolism, in particular phosphatidylcholines and lysophosphatidylcolines, seems strictly linked to immune response in Covid-19. Our results support the hypothesis that IFN-ɣ -PD-L1 axis might be involved in the cytokine release syndrome typical of severe Covid-19 and the phenomenon persisted through multiple pandemic waves despite use of immunomodulation.

KW - Covid-19

KW - Immune checkpoint

KW - Immunometabolism

KW - Phosphatidylcholine

KW - Tryptophan

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U2 - 10.1016/j.heliyon.2022.e09733

DO - 10.1016/j.heliyon.2022.e09733

M3 - Article

AN - SCOPUS:85132883839

SN - 2405-8440

VL - 8

JO - Heliyon

JF - Heliyon

IS - 6

M1 - e09733

ER -

Immunometabolic analysis shows a distinct cyto-metabotype in Covid-19 compared to sepsis from other causes

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