scholarly journals LPS-Induced Endotoxemia Evokes Epigenetic Alterations in Mitochondrial DNA That Impacts Inflammatory Response

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2282
Author(s):  
Björn Koos ◽  
Eva Lotta Moderegger ◽  
Katharina Rump ◽  
Hartmuth Nowak ◽  
Katrin Willemsen ◽  
...  
Keyword(s):  
Immune Response ◽  
Mitochondrial Dna ◽  
Dna Methyltransferase ◽  
Protein Import ◽  
Mononuclear Cells ◽  
Mitochondrial Protein ◽  
Mitochondrial Fraction ◽  
Protein Abundance ◽  
Peripheral Blood Mononuclear ◽  
Cellular Expression

Mitochondrial DNA (mtDNA) plays a vital role as a damage-associated molecular pattern in sepsis being able to shape the immune response. Since pathogen recognition receptors of innate immune cells are activated by demethylated DNA only, we set out to investigate the amount of DNA methyltransferase 1 (DNMT1) in mitochondria and the extent of mtDNA methylation in a human endotoxin model. Peripheral blood mononuclear cells of 20 healthy individuals were isolated from whole blood and stimulated with lipopolysaccharide (LPS) for 48 h. Subsequently, DNMT1 protein abundance was assessed in whole cells and a mitochondrial fraction. At the same time, methylation levels of mtDNA were quantified, and cytokine expression in the supernatant was measured. Despite increased cellular expression of DNMT1 after LPS stimulation, the degree of mtDNA methylation slightly decreased. Strikingly the mitochondrial protein abundance of DNMT1 was reduced by 50% in line with the lower degree of mtDNA methylation. Although only modest alterations were seen in the degree of mtDNA methylation, these strongly correlated with IL-6 and IL-10 expression. Our data may hint at a protein import problem for DNMT1 into the mitochondria under LPS stimulation and suggest a role of demethylated mtDNA in the regulation of the inflammatory immune response.

scholarly journals Reversible Inhibition of Mitochondrial Protein Synthesis during Linezolid-Related Hyperlactatemia

2006 ◽  
Vol 51 (3) ◽  
pp. 962-967 ◽  
Author(s):  
Glòria Garrabou ◽  
Alejandro Soriano ◽  
Sònia López ◽  
Jordi P. Guallar ◽  
Marta Giralt ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Protein Synthesis ◽  
Mononuclear Cells ◽  
Intact Cell ◽  
Mitochondrial Protein ◽  
Mitochondrial Rna ◽  
Mitochondrial Protein Synthesis ◽  
Peripheral Blood Mononuclear ◽  
Mitochondrial Mass ◽  
Clinical Recovery

ABSTRACT The objective of the present study was to determine the mitochondrial toxicity mechanisms of linezolid-related hyperlactatemia. Five patients on a long-term schedule of linezolid treatment were studied during the acute phase of hyperlactatemia and after clinical recovery and lactate normalization following linezolid withdrawal. Mitochondrial studies were performed with peripheral blood mononuclear cells and consisted of measurement of mitochondrial mass, mitochondrial protein synthesis homeostasis (cytochrome c oxidase [COX] activity, COX-II subunit expression, COX-II mRNA abundance, and mitochondrial DNA [mtDNA] content), and overall mitochondrial function (mitochondrial membrane potential and intact-cell oxidative capacity). During linezolid-induced hyperlactatemia, we found extremely reduced protein expression (16% of the remaining content compared to control values [100%], P < 0.001) for the mitochondrially coded, transcribed, and translated COX-II subunit. Accordingly, COX activity was also found to be decreased (51% of the remaining activity, P < 0.05). These reductions were observed despite the numbers of COX-II mitochondrial RNA transcripts being abnormally increased (297%, P = 0.10 [not significant]) and the mitochondrial DNA content remaining stable. These abnormalities persisted even after the correction for mitochondrial mass, which was mildly decreased during the hyperlactatemic phase. Most of the mitochondrial abnormalities returned to control ranges after linezolid withdrawal, lactate normalization, and clinical recovery. Linezolid inhibits mitochondrial protein synthesis, leading to decreased mitochondrial enzymatic activity, which causes linezolid-related hyperlactatemia, which resolves upon discontinuation of linezolid treatment.

scholarly journals Profiles of Peripheral Immune Cells of Uncomplicated COVID-19 Cases with Distinct Viral RNA Shedding Periods

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 514
Author(s):  
Denise Utami Putri ◽  
Cheng-Hui Wang ◽  
Po-Chun Tseng ◽  
Wen-Sen Lee ◽  
Fu-Lun Chen ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cells ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Severe Disease ◽  
Viral Rna ◽  
Disease Course ◽  
Peripheral Blood Mononuclear ◽  
Peripheral Immune Cells ◽  
Cell Profile

The heterogeneity of immune response to COVID-19 has been reported to correlate with disease severity and prognosis. While so, how the immune response progress along the period of viral RNA-shedding (VRS), which determines the infectiousness of disease, is yet to be elucidated. We aim to exhaustively evaluate the peripheral immune cells to expose the interplay of the immune system in uncomplicated COVID-19 cases with different VRS periods and dynamic changes of the immune cell profile in the prolonged cases. We prospectively recruited four uncomplicated COVID-19 patients and four healthy controls (HCs) and evaluated the immune cell profile throughout the disease course. Peripheral blood mononuclear cells (PBMCs) were collected and submitted to a multi-panel flowcytometric assay. CD19+-B cells were upregulated, while CD4, CD8, and NK cells were downregulated in prolonged VRS patients. Additionally, the pro-inflammatory-Th1 population showed downregulation, followed by improvement along the disease course, while the immunoregulatory cells showed upregulation with subsequent decline. COVID-19 patients with longer VRS expressed an immune profile comparable to those with severe disease, although they remained clinically stable. Further studies of immune signature in a larger cohort are warranted.

scholarly journals Single-cell multi-omics analysis of the immune response in COVID-19

2021 ◽  
Author(s):  
Emily Stephenson ◽  
◽  
Gary Reynolds ◽  
Rachel A. Botting ◽  
Fernando J. Calero-Nieto ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Single Cell ◽  
Mononuclear Cells ◽  
Severe Disease ◽  
Effector Memory ◽  
Peripheral Blood Mononuclear ◽  
Cross Sectional ◽  
Hematopoietic Stem ◽  
Symptomatic Disease

AbstractAnalysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16+C1QA/B/C+) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy.

scholarly journals Systematic evaluation of Mycobacterium tuberculosis proteins for antigenic properties identifies Rv1485 and Rv1705c as potential protective subunit vaccine candidates

2020 ◽  
pp. IAI.00585-20
Author(s):  
Yaguo Wang ◽  
Zihui Li ◽  
Shucai Wu ◽  
Joy Fleming ◽  
Chuanyou Li ◽  
...  
Keyword(s):  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
Mononuclear Cells ◽  
Protective Efficacy ◽  
Age Groups ◽  
Infectious Agent ◽  
Systematic Evaluation ◽  
Limiting Factor ◽  
Peripheral Blood Mononuclear ◽  
Antigenic Properties

Lack of efficacious vaccines against Mycobacterium tuberculosis (MTB) infection is a limiting factor in the prevention and control of tuberculosis (TB), the leading cause of death from an infectious agent. Improvement or replacement of the BCG vaccine with one that reliably protects all age-groups is urgent. Concerns exist that antigens currently being evaluated are too homogeneous. To identify new protective antigens, we screened 1781 proteins from a high-throughput proteome-wide protein purification study for antigenic activity. Forty-nine antigens (34 previously unreported) induced antigen-specific IFN-γ release from peripheral blood mononuclear cells (PBMCs) derived from 4452 TB and suspected TB patients and 167 healthy donors. Three (Rv1485, Rv1705c and Rv1802) of the 20 antigens evaluated in a BALB/c mouse challenge model showed protective efficacy, reducing lung CFU counts by 66.2%, 75.8%, and 60%, respectively. Evaluation of IgG2a:IgG1 ratios and cytokine release indicated that Rv1485 and Rv1705c induce a protective Th1 immune response. Epitope analysis of PE/PPE protein Rv1705c, the strongest candidate, identified a dominant epitope in its extreme N-terminal domain accounting for 90% of its immune response. Systematic pre-clinical assessment of antigens Rv1485 and Rv1705c is warranted.

scholarly journals Epithelial processed Mycobacterium avium subsp. paratuberculosis induced prolonged Th17 response and suppression of phagocytic maturation in bovine peripheral blood mononuclear cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hong-Tae Park ◽  
Hyun-Eui Park ◽  
Soojin Shim ◽  
Suji Kim ◽  
Min-Kyoung Shin ◽  
...  
Keyword(s):  
Immune Response ◽  
Mhc Class Ii ◽  
Mycobacterium Avium ◽  
Mononuclear Cells ◽  
Diagnostic Methods ◽  
Economic Losses ◽  
Phagocytic Cells ◽  
Peripheral Blood Mononuclear ◽  
Th17 Response ◽  
Surface Receptors

AbstractJohne’s disease (JD) caused by Mycobacterium avium subsp. paratuberculosis (MAP) is a chronic, wasting infectious disease in ruminants that causes enormous economic losses to the dairy and beef cattle industries. Understanding the mechanism of persistency of MAP is key to produce novel ideas for the development of new diagnostic methods or prevention techniques. We sought interactions between the host and MAP using epithelial passage model, which mimic initial stage of infection. From the transcriptomic analysis of bovine immune cells (PBMCs), it was suggested that infection through the epithelial cells elicited prolonged Th17-derived immune response, as indicated by upregulation of IL-17A, IL-17F and RORC until 120 h p.i., compared to directly infected PBMCs. Global downregulation of gene expression was observed after 72 h p.i., especially for genes encoding cell surface receptors of phagocytic cells, such as Toll-like receptors and MHC class II molecules. In addition, the cholesterol efflux transporters ABCA1, ABCG1, and APOE, which are regulated by the LXR/RXR pathway, were downregulated. In summary, it would be suggested that the host initiate immune response to activate Th17-derived cytokines, and MAP survives persistently by altering the host adaptive immune response by suppressing surface receptors and manipulating lipid metabolism in phagocytic cells.

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