Expression of genes belonging to the interacting TLR cascades, NADPH-oxidase and mitochondrial oxidative phosphorylation in septic patients

• Published in: PloS one Vol. 12; no. 2; p. e0172024
• Main Authors: Nucci, Laura A, Santos, Sidnéia S, Brunialti, Milena K C, Sharma, Narendra Kumar, Machado, Flavia R, Assunção, Murillo, de Azevedo, Luciano C P, Salomao, Reinaldo
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.02.2017; Public Library of Science (PLoS)
• Subjects: Aged; Aged, 80 and over; Analysis; Biology and Life Sciences; Biomarkers - metabolism; Care and treatment; Cascades; Cytokines; Degradation; Female; Gene expression; Genes; Humans; Infections; Interferon; Janus kinase; Janus Kinase 1 - genetics; Janus Kinase 1 - metabolism; Janus kinase 2; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Kinases; Male; Medicine and Health Sciences; Metabolism; Microorganisms; Middle Aged; Mitochondria; NAD(P)H oxidase; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Oxidase; Oxidative metabolism; Oxidative Phosphorylation; Oxidative stress; Patients; Phosphorylation; Physical Sciences; Pneumoviridae; Polymerase chain reaction; Risk factors; Sepsis; Sepsis - diagnosis; Sepsis - genetics; Signal Transduction; Signaling; Superoxide; Survival Analysis; Toll-Like Receptors - genetics; Toll-Like Receptors - metabolism; TYK2 Kinase - genetics; TYK2 Kinase - metabolism; Tyk2 protein
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0172024

Sepsis is a complex disease that is characterized by activation and inhibition of different cell signaling pathways according to the disease stage. Here, we evaluated genes involved in the TLR signaling pathway, oxidative phosphorylation and oxidative metabolism, aiming to assess their interactions and resulting cell functions and pathways that are disturbed in septic patients. Blood samples were obtained from 16 patients with sepsis secondary to community acquired pneumonia at admission (D0), and after 7 days (D7, N = 10) of therapy. Samples were also collected from 8 healthy volunteers who were matched according to age and gender. Gene expression of 84 genes was performed by real-time polymerase chain reactions. Their expression was considered up- or down-regulated when the fold change was greater than 1.5 compared to the healthy volunteers. A p-value of ≤ 0.05 was considered significant. Twenty-two genes were differently expressed in D0 samples; most of them were down-regulated. When gene expression was analyzed according to the outcomes, higher number of altered genes and a higher intensity in the disturbance was observed in non-survivor than in survivor patients. The canonical pathways altered in D0 samples included interferon and iNOS signaling; the role of JAK1, JAK2 and TYK2 in interferon signaling; mitochondrial dysfunction; and superoxide radical degradation pathways. When analyzed according to outcomes, different pathways were disturbed in surviving and non-surviving patients. Mitochondrial dysfunction, oxidative phosphorylation and superoxide radical degradation pathway were among the most altered in non-surviving patients. Our data show changes in the expression of genes belonging to the interacting TLR cascades, NADPH-oxidase and oxidative phosphorylation. Importantly, distinct patterns are clearly observed in surviving and non-surviving patients. Interferon signaling, marked by changes in JAK-STAT modulation, had prominent changes in both survivors and non-survivors, whereas the redox imbalance (iNOS signaling, oxidative phosphorylation and superoxide radical degradation) affecting mitochondrial functions was prominent in non-surviving patients.