Host metabolite-cytokine correlation landscape in SARS-CoV-2 infection

Abstract The systemic cytokine release syndrome (CRS) is a major cause of the multi-organ injury and fatal outcome induced by SARS-CoV-2 infection in severe COVID-19 patients. It has been well-known that metabolism plays a role in modulating the immune responses in infectious diseases. Yet, how the host metabolism correlates with CRS in COVID-19 patients and how the perturbed metabolites affect the cytokine release remains unclear. Here, we performed both metabolomics and cytokine/chemokine profiling on serum samples from the same cohort of healthy controls, mild and severe COVID-19 patients and delineated the global metabolic and immune response landscape along disease progression. Intriguingly, the correlation analysis revealed the tight link between metabolites and proinflammatory cytokines and chemokines, such as IL-6, M-CSF, IL-1α, IL-1β, implying the potential regulatory role of arginine metabolism, tryptophan metabolism, and purine metabolism in hyperinflammation. Importantly, we demonstrated that targeting metabolism markedly modulated the proinflammatory cytokines release by PBMCs isolated from SARS-CoV-2-infected rhesus macaques ex vivo. Beyond providing a comprehensive resource of metabolism and immunology data of SARS-CoV-2 infection, our study showed that metabolic alterations can be potentially exploited to develop novel strategy for the treatment of fatal CRS in COVID-19.

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Integrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications

Nature Communications ◽

10.1038/s41467-021-21907-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Nan Xiao ◽

Meng Nie ◽

Huanhuan Pang ◽

Bohong Wang ◽

Jieli Hu ◽

...

Keyword(s):

Proinflammatory Cytokines ◽

Mononuclear Cells ◽

Inflammatory Responses ◽

Ex Vivo ◽

Rhesus Macaques ◽

Fatal Outcome ◽

Organ Injury ◽

Cytokine Release ◽

Serum Samples ◽

Peripheral Blood Mononuclear

AbstractCytokine release syndrome (CRS) is a major cause of the multi-organ injury and fatal outcome induced by SARS-CoV-2 infection in severe COVID-19 patients. Metabolism can modulate the immune responses against infectious diseases, yet our understanding remains limited on how host metabolism correlates with inflammatory responses and affects cytokine release in COVID-19 patients. Here we perform both metabolomics and cytokine/chemokine profiling on serum samples from healthy controls, mild and severe COVID-19 patients, and delineate their global metabolic and immune response landscape. Correlation analyses show tight associations between metabolites and proinflammatory cytokines/chemokines, such as IL-6, M-CSF, IL-1α, IL-1β, and imply a potential regulatory crosstalk between arginine, tryptophan, purine metabolism and hyperinflammation. Importantly, we also demonstrate that targeting metabolism markedly modulates the proinflammatory cytokines release by peripheral blood mononuclear cells isolated from SARS-CoV-2-infected rhesus macaques ex vivo, hinting that exploiting metabolic alterations may be a potential strategy for treating fatal CRS in COVID-19.

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Organ Injury and Cytokine Release Caused by Peptidoglycan Are Dependent on the Structural Integrity of the Glycan Chain

Infection and Immunity ◽

10.1128/iai.72.3.1311-1317.2004 ◽

2004 ◽

Vol 72 (3) ◽

pp. 1311-1317 ◽

Cited By ~ 19

Author(s):

Anders E. Myhre ◽

Jon Fredrik Stuestøl ◽

Maria K. Dahle ◽

Gunhild Øverland ◽

Christoph Thiemermann ◽

...

Keyword(s):

Structural Integrity ◽

Inflammatory Responses ◽

Ex Vivo ◽

Organ Injury ◽

Enzyme Linked Immunosorbent Assay ◽

Cytokine Release ◽

Ex Vivo Model ◽

Glycan Chain ◽

Tnf Α ◽

Glutamyl Transferase

ABSTRACT Several studies have implicated a role of peptidoglycan (PepG) as a pathogenicity factor in sepsis and organ injury, in part by initiating the release of inflammatory mediators. We wanted to elucidate the structural requirements of PepG to trigger inflammatory responses and organ injury. Injection of native PepG into anesthetized rats caused moderate but significant increases in the levels of alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, and bilirubin (markers of hepatic injury and/or dysfunction) and creatinine and urea (markers of renal dysfunction) in serum, whereas PepG pretreated with muramidase to digest the glycan backbone failed to do this. In an ex vivo model of human blood, PepG containing different amino acids induced similar levels of the cytokines tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), IL-8, and IL-10, as determined by plasma analyses (enzyme-linked immunosorbent assay). Hydrolysis of the Staphylococcus aureus cross-bridge with lysostaphin resulted in moderately reduced release of TNF-α, IL-6, IL-8, and IL-10, whereas muramidase digestion nearly abolished the ability to induce cytokine release and IL-6 mRNA accumulation in CD14+ monocytes compared to intact PepG. However, additional experiments showed that muramidase-treated PepG synergized with lipopolysaccharide to induce TNF-α and IL-10 release in whole blood, despite its lack of inflammatory activity when administered alone. Based on these studies, we hypothesize that the structural integrity of the glycan chain of the PepG molecule is very important for the pathogenic effects of PepG. The amino acid composition of PepG, however, does not seem to be essential for the inflammatory properties of the molecule.

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OP0224 FILGOTINIB TREATMENT LEADS TO RAPID AND SUSTAINED REDUCTIONS IN INFLAMMATORY BIOMARKERS IN PATIENTS WITH MODERATE TO SEVERE PSORIATIC ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4927 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 140.1-140

Author(s):

D. D. Gladman ◽

W. Jiang ◽

A. Hertz ◽

V. Malkov ◽

O. K. Yoon ◽

...

Keyword(s):

Psoriatic Arthritis ◽

Disease Activity ◽

Proinflammatory Cytokines ◽

Clinical Signs ◽

Signs And Symptoms ◽

Matrix Remodeling ◽

Research Support ◽

Serum Samples ◽

Cytokines And Chemokines ◽

Clinical Signs And Symptoms

Background:Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease characterized by musculoskeletal and cutaneous inflammation. In the recent EQUATOR study (NCT03101670), patients (pts) with active PsA receiving the oral, selective Janus kinase 1 (JAK1) inhibitor filgotinib (FIL) had significant and sustained improvements versus placebo (PBO) in clinical signs and symptoms. We present here updated results of the EULAR 2019 presentation of EQUATOR on circulating biomarkers in PsA.Objectives:To evaluate the impact of FIL on the levels of circulating proinflammatory cytokines and chemokines, adhesion molecules, and markers of matrix remodeling in EQUATOR pts with active PsA.Methods:EQUATOR was a 16-week, double-blind, multicenter, Phase 2 study in pts with active PsA. Pts were randomized 1:1 to FIL 200 mg (n=65) or PBO (n=66) once daily. Serum samples (FIL n=60 and PBO n=61) were collected at baseline (BL) and at Weeks 1, 4, and 16. The association of BL biomarkers with PsA disease characteristics was analyzed by Spearman’s rank-order correlation. Biomarker changes from BL were assessed in time-paired serum samples using multiplex and high sensitivity ELISA-based assays. Analytes were grouped by hierarchical clustering; treatment effect on a biomarker was defined as a difference in change from BL between pts receiving FIL versus PBO. Improvements in PsA clinical signs and symptoms were determined by assessing changes from BL in a number of clinical disease activity scores including psoriatic arthritis disease activity score (PASDAS), psoriasis area and severity index (PASI) and disease activity index for psoriatic arthritis (DAPSA) scores.Results:BL levels of numerous biomarkers were associated (p<0.05) with clinical measures of PsA. Several clusters of biomarkers were identified based on the rate and magnitude of FIL treatment response. Cluster 1 included biomarkers with substantial reductions from BL with FIL by week 1, such as the acute phase proteins CRP and SAA (>50%), and the inflammatory mediators IL-6, CXCL10, and IL-23 (>25%). Cluster 2 included biomarkers of cell adhesion (ICAM-1, VCAM1) with a 5%–15% reduction from BL with FIL by week 1. Cluster 3 included biomarkers of matrix remodeling (MMP1, SC1M) with a delayed >25% reduction from BL with FIL that was significant by Week 4. Finally, Cluster 4 included biomarkers with a modest (5%–10%) increase from BL with FIL (Eotaxin, IL-15, and adiponectin). Spearman rank correlation analyses showed that at BL, many biomarkers were positively associated with disease scores, and tended to segregate between psoriasis weighted scores such as PASI and arthritis weighted scores such as DAPSA. The observed decrease in proinflammatory cytokines were associated with on-treatment improvements from BL in disease score for pts receiving FIL.Conclusion:Compared with PBO, FIL significantly decreased BL levels of circulating biomarkers associated with PsA disease activity, including proinflammatory cytokines and chemokines, adhesion molecules, and markers of matrix remodeling. The observed decreases in circulating proinflammatory cytokines and biomarkers of both bone pathobiology and psoriatic disease suggest that FIL improves PsA clinical signs and symptoms at a molecular level. These findings are consistent with reduced disease activity in pts with PsA and suggest that FIL treatment leads to a rapid and sustained reduction of inflammation in PsA.Acknowledgments:This study was funded by Gilead Sciences, Inc. Editorial support was provided by Fishawack Communications Inc and funded by Gilead Sciences, Inc.Disclosure of Interests:Dafna D Gladman Grant/research support from: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – grant/research support, Consultant of: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – consultant, Wendy Jiang Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Angie Hertz Shareholder of: Gilead Sciences Inc, Employee of: Gilead Sciences Inc, Vlad Malkov Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Oh Kyu Yoon Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Mona Trivedi Shareholder of: Amgen and Gilead Sciences, Employee of: Gilead Sciences, Muhsen Alani Employee of: Gilead Sciences, Lene Vestergaard Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Robin Besuyen Shareholder of: Galapagos, Employee of: Galapagos, René Galien Shareholder of: Galapagos, Employee of: Galapagos, Amer M. Mirza Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Vinod Chandran Grant/research support from: Abbvie, Celgene, Consultant of: Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lily, Janssen, Novartis, Pfizer, UCB, Employee of: Spouse employed by Eli Lily

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Faculty Opinions recommendation of Ex vivo cytokine release reflects sensitivity to occupational endotoxin exposure.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1159235.619563 ◽

2009 ◽

Author(s):

Andrea Siracusa ◽

Ilenia Folletti

Keyword(s):

Ex Vivo ◽

Cytokine Release ◽

Endotoxin Exposure

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Toll-like receptor 4-mediated cytokine synthesis and post-stroke depressive symptoms

Translational Psychiatry ◽

10.1038/s41398-021-01359-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Michal Korostynski ◽

Dzesika Hoinkis ◽

Marcin Piechota ◽

Slawomir Golda ◽

Joanna Pera ◽

...

Keyword(s):

Gene Expression ◽

Depressive Symptoms ◽

Ex Vivo ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Post Stroke ◽

Cytokines And Chemokines ◽

Patient Health ◽

Post Stroke Depression ◽

Cytokine Synthesis

AbstractAltered cytokine synthesis thought to contribute to the pathophysiology of post-stroke depression (PSD). Toll-like receptor 4 (TLR4) is a master regulator of innate immunity. The aim of this study was to explore the putative association between TLR4-mediated cytokine synthesis and subsequent symptoms of PSD. In total, 262 patients with ischemic stroke and without a history of PSD were included. Depressive symptoms were assessed using the Patient Health Questionnaire-9 in 170 patients on Day 8 and in 146 at 3 months after stroke. Blood samples taken on Day 3 after stroke were stimulated ex vivo with lipopolysaccharide (LPS). Ex vivo synthesized cytokines (TNFα, IP-10, IL-1β, IL-6, IL-8, IL-10, and IL-12p70) and circulating cytokines (TNFα, IL-6, sIL-6R, and IL-1ra) were measured using the enzyme-linked immunoassay or cytometric method. RNA sequencing was used to determine the gene expression profile of LPS-induced cytokines and chemokines. LPS-induced cytokine synthesis and the gene expression of TLR4-dependent cytokines and chemokines did not differ between patients with and without greater depressive symptoms. The plasma level of IL-6, but not TNFα, sIL-6R, and IL-1ra, was higher in patients who developed depressive symptoms at 3 months after stroke (median: 4.7 vs 3.4 pg/mL, P = 0.06). Plasma IL-6 predicted the severity of depressive symptoms at 3 months after stroke (β = 0.42, P = 0.03). In conclusion, TLR4-dependent cytokine synthesis was not associated with greater post-stroke depressive symptoms in this study. Circulating IL-6 might be associated with depressive symptoms occurring at 3 months after stroke.

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The safety and efficacy of BCG encapsulated alginate particle (BEAP) against M.tb H37Rv infection in Macaca mulatta : A pilot study

Scientific Reports ◽

10.1038/s41598-021-82614-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ashwani Kesarwani ◽

Parul Sahu ◽

Kshama Jain ◽

Prakriti Sinha ◽

K. Varsha Mohan ◽

...

Keyword(s):

T Cells ◽

Macaca Mulatta ◽

Ex Vivo ◽

Protective Efficacy ◽

Rhesus Macaques ◽

Allergic Response ◽

Control Group ◽

Activated T Cells ◽

Primate Model ◽

Safety And Efficacy

AbstractDue to the limited utility of Bacillus Calmette–Guérin (BCG), the only approved vaccine available for tuberculosis, there is a need to develop a more effective and safe vaccine. We evaluated the safety and efficacy of a dry powder aerosol (DPA) formulation of BCG encapsulated alginate particle (BEAP) and the conventional intradermal BCG immunization in infant rhesus macaques (Macaca mulatta). The infant macaques were immunized intratracheally with DPA of BEAP into the lungs. Animals were monitored for their growth, behaviour, any adverse and allergic response. The protective efficacy of BEAP was estimated by the ex-vivo H37Rv infection method. Post-immunization with BEAP, granulocytes count, weight gain, chest radiography, levels of liver secreted enzymes, cytokines associated with inflammation like TNF and IL-6 established that BEAP is non-toxic and it does not elicit an allergic response. The T cells isolated from BEAP immunized animals’ blood, upon stimulation with M.tb antigen, secreted high levels of IFN-γ, TNF, IL-6 and IL-2. The activated T cells from BEAP group, when co-cultured with M.tb infected macrophages, eliminated largest number of infected macrophages compared to the BCG and control group. This study suggests the safety and efficacy of BEAP in Non-human primate model.

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Diagnostic Significance of Serum Galectin-3 in Hospitalized Patients with COVID-19—A Preliminary Study

Biomolecules ◽

10.3390/biom11081136 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1136

Author(s):

Beata Kuśnierz-Cabala ◽

Barbara Maziarz ◽

Paulina Dumnicka ◽

Marcin Dembiński ◽

Maria Kapusta ◽

...

Keyword(s):

Diagnostic Accuracy ◽

Hospital Stay ◽

Tissue Injury ◽

Immunological Response ◽

Organ Injury ◽

Quantitative Detection ◽

Serum Samples ◽

Diagnostic Significance ◽

Galectin 3 ◽

Preliminary Study

Severe coronavirus disease 2019 (COVID-19) is associated with hyperinflammation leading to organ injury, including respiratory failure. Galectin-3 was implicated in innate immunological response to infections and in chronic fibrosis. The aim of our preliminary study was the assessment of the diagnostic utility of serum galectin-3 in patients with COVID-19. The prospective observational study included adult patients admitted with active COVID-19 and treated in tertiary hospital between June and July 2020. The diagnosis was confirmed by the quantitative detection of nucleic acid of severe acute respiratory syndrome coronavirus 2 in nasopharyngeal swabs. Galectin-3 was measured by enzyme immunoassay in serum samples obtained during the first five days of hospital stay. We included 70 patients aged 25 to 73 years; 90% had at least one comorbidity. During the hospital stay, 32.9% were diagnosed with COVID-19 pneumonia and 12.9% required treatment in the intensive care unit (ICU). Serum galectin-3 was significantly increased in patients who developed pneumonia, particularly those who required ICU admission. Positive correlations were found between galectin-3 and inflammatory markers (interleukin-6, C-reactive protein, ferritin, pentraxin-3), a marker of endothelial injury (soluble fms-like tyrosine kinase-1), and a range of tissue injury markers. Serum galectin-3 enabled the diagnosis of pneumonia with moderate diagnostic accuracy and the need for ICU treatment with high diagnostic accuracy. Our findings strengthen the hypothesis that galectin-3 may be involved in severe COVID-19. Further studies are planned to confirm the preliminary results and to verify possible associations of galectin-3 with long-term consequences of COVID-19, including pulmonary fibrosis.

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Intestinal Permeability Is a Mechanical Rheostat in the Pathogenesis of Liver Cirrhosis

International Journal of Molecular Sciences ◽

10.3390/ijms22136921 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6921

Author(s):

Norihisa Nishimura ◽

Kosuke Kaji ◽

Koh Kitagawa ◽

Yasuhiko Sawada ◽

Masanori Furukawa ◽

...

Keyword(s):

Liver Disease ◽

Gut Microbiota ◽

Intestinal Permeability ◽

Proinflammatory Cytokines ◽

Liver Diseases ◽

Pathogenic Bacteria ◽

Necrosis Factor Alpha ◽

Cytokines And Chemokines ◽

Liver Disease Progression ◽

Cirrhotic Patients

Recent studies have suggested that an alteration in the gut microbiota and their products, particularly endotoxins derived from Gram-negative bacteria, may play a major role in the pathogenesis of liver diseases. Gut dysbiosis caused by a high-fat diet and alcohol consumption induces increased intestinal permeability, which means higher translocation of bacteria and their products and components, including endotoxins, the so-called “leaky gut”. Clinical studies have found that plasma endotoxin levels are elevated in patients with chronic liver diseases, including alcoholic liver disease and nonalcoholic liver disease. A decrease in commensal nonpathogenic bacteria including Ruminococaceae and Lactobacillus and an overgrowth of pathogenic bacteria such as Bacteroidaceae and Enterobacteriaceae are observed in cirrhotic patients. The decreased diversity of the gut microbiota in cirrhotic patients before liver transplantation is also related to a higher incidence of post-transplant infections and cognitive impairment. The exposure to endotoxins activates macrophages via Toll-like receptor 4 (TLR4), leading to a greater production of proinflammatory cytokines and chemokines including tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, which play key roles in the progression of liver diseases. TLR4 is a major receptor activated by the binding of endotoxins in macrophages, and its downstream signal induces proinflammatory cytokines. The expression of TLR4 is also observed in nonimmune cells in the liver, such as hepatic stellate cells, which play a crucial role in the progression of liver fibrosis that develops into hepatocarcinogenesis, suggesting the importance of the interaction between endotoxemia and TLR4 signaling as a target for preventing liver disease progression. In this review, we summarize the findings for the role of gut-derived endotoxemia underlying the progression of liver pathogenesis.

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Novel Strategy To Adapt Simian-Human Immunodeficiency Virus E1 Carryingenvfrom an RV144 Volunteer to Rhesus Macaques: Coreceptor Switch and Final Recovery of a Pathogenic Virus with Exclusive R5 Tropism

Journal of Virology ◽

10.1128/jvi.02222-17 ◽

2018 ◽

Vol 92 (14) ◽

Cited By ~ 1

Author(s):

Hanna B. Scinto ◽

Sandeep Gupta ◽

Swati Thorat ◽

Muhammad M. Mukhtar ◽

Anthony Griffiths ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Placebo Recipient ◽

T Cell ◽

Hiv Transmission ◽

Rhesus Macaques ◽

Phase Iii ◽

Immunodeficiency Virus ◽

Coreceptor Switch ◽

Novel Strategy ◽

Hiv Acquisition

ABSTRACTThe phase III RV144 human immunodeficiency virus (HIV) vaccine trial conducted in Thailand remains the only study to show efficacy in decreasing the HIV acquisition risk. In Thailand, circulating recombinant forms of HIV clade A/E (CRF01_AE) predominate; in such viruses,envoriginates from clade E (HIV-E). We constructed a simian-human immunodeficiency virus (SHIV) chimera carryingenvisolated from an RV144 placebo recipient in the SHIV-1157ipd3N4 backbone. The latter contains long terminal repeats (LTRs) with duplicated NF-κB sites, thus resembling HIV LTRs. We devised a novel strategy to adapt the parental infectious molecular clone (IMC), R5 SHIV-E1, to rhesus macaques: the simultaneous depletion of B and CD8+cells followed by the intramuscular inoculation of proviral DNA and repeated administrations of cell-free virus. High-level viremia and CD4+T-cell depletion ensued. Passage 3 virus unexpectedly caused acute, irreversible CD4+T-cell loss; the partially adapted SHIV had become dual tropic. Virus and IMCs with exclusive R5 tropism were reisolated from earlier passages, combined, and used to complete adaptation through additional macaques. The final isolate, SHIV-E1p5, remained solely R5 tropic. It had a tier 2 neutralization phenotype, was mucosally transmissible, and was pathogenic. Deep sequencing revealed 99% Env amino acid sequence conservation; X4-only and dual-tropic strains had evolved independently from an early branch of parental SHIV-E1. To conclude, our primate model data reveal that SHIV-E1p5 recapitulates important aspects of HIV transmission and pathobiology in humans.IMPORTANCEUnderstanding the protective principles that lead to a safe, effective vaccine against HIV in nonhuman primate (NHP) models requires test viruses that allow the evaluation of anti-HIV envelope responses. Reduced HIV acquisition risk in RV144 has been linked to nonneutralizing IgG antibodies with a range of effector activities. Definitive experiments to decipher the mechanisms of the partial protection observed in RV144 require passive-immunization studies in NHPs with a relevant test virus. We have generated such a virus by insertingenvfrom an RV144 placebo recipient into a SHIV backbone with HIV-like LTRs. The final SHIV-E1p5 isolate, grown in rhesus monkey peripheral blood mononuclear cells, was mucosally transmissible and pathogenic. Earlier SHIV-E passages showed a coreceptor switch, again mimicking HIV biology in humans. Thus, our series of SHIV-E strains mirrors HIV transmission and disease progression in humans. SHIV-E1p5 represents a biologically relevant tool to assess prevention strategies.

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