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Multi-OMICs landscape of SARS-CoV-2-induced host responses in human lung epithelial cells.
Pinto, SM, Subbannayya, Y, Kim, H, Hagen, L, Górna, MW, Nieminen, AI, Bjørås, M, Espevik, T, Kainov, D, Kandasamy, RK
iScience. 2023;(1):105895
Abstract
COVID-19 pandemic continues to remain a global health concern owing to the emergence of newer variants. Several multi-Omics studies have produced extensive evidence on host-pathogen interactions and potential therapeutic targets. Nonetheless, an increased understanding of host signaling networks regulated by post-translational modifications and their ensuing effect on the cellular dynamics is critical to expanding the current knowledge on SARS-CoV-2 infections. Through an unbiased transcriptomics, proteomics, acetylomics, phosphoproteomics, and exometabolome analysis of a lung-derived human cell line, we show that SARS-CoV-2 Norway/Trondheim-S15 strain induces time-dependent alterations in the induction of type I IFN response, activation of DNA damage response, dysregulated Hippo signaling, among others. We identified interplay of phosphorylation and acetylation dynamics on host proteins and its effect on the altered release of metabolites, especially organic acids and ketone bodies. Together, our findings serve as a resource of potential targets that can aid in designing novel host-directed therapeutic strategies.
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Legumain is upregulated in acute cardiovascular events and associated with improved outcome - potentially related to anti-inflammatory effects on macrophages.
Lunde, NN, Gregersen, I, Ueland, T, Shetelig, C, Holm, S, Kong, XY, Michelsen, AE, Otterdal, K, Yndestad, A, Broch, K, et al
Atherosclerosis. 2020;:74-82
Abstract
BACKGROUND AND AIMS We have previously found increased levels of the cysteine protease legumain in plasma and plaques from patients with carotid atherosclerosis. This study further investigated legumain during acute cardiovascular events. METHODS Circulating levels of legumain from patients and legumain released from platelets were assessed by enzyme-linked-immunosorbent assay. Quantitative PCR and immunoblotting were used to study expression, while localization was visualized by immunohistochemistry. RESULTS In the SUMMIT Malmö cohort (n = 339 with or without type 2 diabetes and/or cardiovascular disease [CVD], and 64 healthy controls), the levels of circulating legumain were associated with the presence of CVD in non-diabetics, with no relation to outcome. In symptomatic carotid plaques and in samples from both coronary and intracerebral thrombi obtained during acute cardiovascular events, legumain was co-localized with macrophages in the same regions as platelets. In vitro, legumain was shown to be present in and released from platelets upon activation. In addition, THP-1 macrophages exposed to releasate from activated platelets showed increased legumain expression. Interestingly, primary peripheral blood mononuclear cells stimulated with recombinant legumain promoted anti-inflammatory responses. Finally, in a STEMI population (POSTEMI; n = 272), patients had significantly higher circulating legumain before and immediately after percutaneous coronary intervention compared with healthy controls (n = 67), and high levels were associated with improved outcome. CONCLUSIONS Our data demonstrate for the first time that legumain is upregulated during acute cardiovascular events and is associated with improved outcome.
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Serum Omega-6 Fatty Acids and Immunology-Related Gene Expression in Peripheral Blood Mononuclear Cells: A Cross-Sectional Analysis in Healthy Children.
Christensen, JJ, Bakke, SS, Ulven, SM, Retterstøl, K, Henriksen, T, Bollerslev, J, Espevik, T, Aukrust, P, Halvorsen, B, Holven, KB
Molecular nutrition & food research. 2019;(7):e1800990
Abstract
SCOPE Some studies suggest that a high dietary intake of omega-6 fatty acids is pro-inflammatory. However, whether omega-6 fatty acids actually cause pathogenic inflammation in humans is debated. Therefore, the associations between expression of immunology-related genes in peripheral blood mononuclear cells (PBMCs) and serum total omega-6 PUFA status are investigated. METHODS AND RESULTS Serum fatty acid profile and expression of 460 immunology-related genes in PBMCs from 58 healthy children (6-13 years) is measured, and examined the expression differences between children with high or low total omega-6 PUFA status (upper vs lower tertile). Taken together, both univariate analyses and integrated omics analyses support that while high omega-6 PUFA level associated with higher expressing of genes related to innate immune responses, it also associated with lower expression of several genes related to adaptive immune responses. CONCLUSION Omega-6 PUFA status associated both positively and negatively with expression of specific immunology-related genes in PBMCs in healthy children. The results may suggest a nuanced role for omega-6 fatty acids in the interphase of lipids and inflammation, and warrants further examination in gene-environment studies and randomized controlled trials.
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Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin: Implications for the Progression of Atherosclerosis.
Pilely, K, Rosbjerg, A, Genster, N, Gal, P, Pál, G, Halvorsen, B, Holm, S, Aukrust, P, Bakke, SS, Sporsheim, B, et al
Journal of immunology (Baltimore, Md. : 1950). 2016;(12):5064-74
Abstract
Cholesterol crystals (CC) play an essential role in the formation of atherosclerotic plaques. CC activate the classical and the alternative complement pathways, but the role of the lectin pathway is unknown. We hypothesized that the pattern recognition molecules (PRMs) from the lectin pathway bind CC and function as an upstream innate inflammatory signal in the pathophysiology of atherosclerosis. We investigated the binding of the PRMs mannose-binding lectin (MBL), ficolin-1, ficolin-2, and ficolin-3, the associated serine proteases, and complement activation products to CC in vitro using recombinant proteins, specific inhibitors, as well as deficient and normal sera. Additionally, we examined the deposition of ficolin-2 and MBL in human carotid plaques by immunohistochemistry and fluorescence microscopy. The results showed that the lectin pathway was activated on CC by binding of ficolin-2 and MBL in vitro, resulting in activation and deposition of complement activation products. MBL bound to CC in a calcium-dependent manner whereas ficolin-2 binding was calcium-independent. No binding was observed for ficolin-1 or ficolin-3. MBL and ficolin-2 were present in human carotid plaques, and binding of MBL to CC was confirmed in vivo by immunohistochemistry, showing localization of MBL around CC clefts. Moreover, we demonstrated that IgM, but not IgG, bound to CC in vitro and that C1q binding was facilitated by IgM. In conclusion, our study demonstrates that PRMs from the lectin pathway recognize CC and provides evidence for an important role for this pathway in the inflammatory response induced by CC in the pathophysiology of atherosclerosis.
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Decreased serum lipocalin-2 levels in human immunodeficiency virus-infected patients: increase during highly active anti-retroviral therapy.
Landrø, L, Damås, JK, Flo, TH, Heggelund, L, Ueland, T, Tjønnfjord, GE, Espevik, T, Aukrust, P, Frøland, SS
Clinical and experimental immunology. 2008;(1):57-63
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Abstract
Although neutrophil gelatinase-associated lipocalin (NGAL) may play a pivotal role in the innate immune response, there are currently no data on NGAL levels in human immunodeficiency virus (HIV)-infected patients. In this study we aimed to examine the regulation of NGAL in HIV infection. The regulation of NGAL in HIV infection was examined by different experimental approaches, including studies in peripheral blood and mononuclear cells (MNC) from bone marrow aspirates before and during highly active anti-retroviral therapy (HAART). We found that: before initiating HAART, HIV-infected patients (n = 37) had significantly decreased serum NGAL levels compared with healthy controls (n = 26); (ii) during HAART, there was a gradual and significant increase in NGAL concentrations reaching levels comparable to those in healthy controls after 12 months; (iii) this increase was seen primarily in virological responders to HAART (HIV RNA level <200 copies/ml after 24 months); (iv) phytohaemagglutinin-stimulated NGAL release in MNC cells from bone marrow aspirates was decreased in untreated HIV-infected patients compared with healthy controls, but increased after 26 weeks on HAART; and (v) there was a significant positive correlation between neutrophil counts and NGAL levels at all time-points during HAART. We have shown decreased NGAL levels in HIV-infected patients, potentially reflecting decreased number and function of neutrophils as well as impaired bone marrow myelopoiesis. These abnormalities were reversed by successful HAART. Our findings underscore further the involvement of neutrophils and innate immunity in HIV-related immunodeficiency.