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- Axberg Pålsson, Sandra, et al.
(författare)
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Single-Stranded Oligonucleotide-Mediated Inhibition of Respiratory Syncytial Virus Infection
- 2020
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in young children. Currently, there is no RSV vaccine or universally accessible antiviral treatment available. Addressing the urgent need for new antiviral agents, we have investigated the capacity of a non-coding single-stranded oligonucleotide (ssON) to inhibit RSV infection. By utilizing a GFP-expressing RSV, we demonstrate that the ssON significantly reduced the proportion of RSV infected A549 cells (lung epithelial cells). Furthermore, we show that ssON's antiviral activity was length dependent and that both RNA and DNA of this class of oligonucleotides have antiviral activity. We reveal that ssON inhibited RSV infection by competing with the virus for binding to the cellular receptor nucleolin in vitro. Additionally, using a recombinant RSV that expresses luciferase we show that ssON effectively blocked RSV infection in mice. Treatment with ssON in vivo resulted in the upregulation of RSV-induced interferon stimulated genes (ISGs) such as Stat1, Stat2, Cxcl10, and Ccl2. This study highlights the possibility of using oligonucleotides as therapeutic agents against RSV infection. We demonstrate that the mechanism of action of ssON is the inhibition of viral entry in vitro, likely through the binding of the receptor, nucleolin and that ssON treatment against RSV infection in vivo additionally results in the upregulation of ISGs.
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| 2. |
- Adam, Lucille, et al.
(författare)
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Early Resistance of Non-virulent Mycobacterial Infection in C57BL/6 Mice Is Associated With Rapid Up-Regulation of Antimicrobial Cathelicidin Camp
- 2018
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Early clearance of tuberculosis is the successful eradication of inhaled bacteria before the development of an adaptive immune response. We previously showed, by utilizing a non-virulent mycobacteria infection model, that C57BL/6 mice are more efficient than BALB/c in their control of bacterial growth in the lungs during the first weeks of the infection. Here, we assessed early (within 1-3 days) innate immune events locally in the lungs to identify factors that may contribute to the control of non-virulent mycobacterial burden. We confirmed that C57BL/6 mice are more resistant to infection compared with BALB/c after intranasal inoculation with mycobacterium. Transcriptomic analyses revealed a remarkably silent signature in C57BL/6 mice despite effective control of bacterial growth. In contrast, BALB/c mice up-regulated genes associated with neutrophil and myeloid cell chemotaxis and migration. Flow cytometry analyses corroborated the transcriptomic analyses and demonstrated influx of both neutrophil and myeloid cell populations in BALB/c mice, while these did not increase in C57BL/6 mice. We further detected increased release of TNF-alpha from BALB/c lung cells but limited release from C57BL/6-derived cells. However, C57BL/6 mice showed a marked early up-regulation of the Camp gene, encoding the cathelicidin CRAMP peptide, post-mycobacterial exposure. CRAMP (LL-37 in human) expression in the lungs was confirmed using immunofluorescence staining. Altogether, these findings show that C57BL/6 mice can clear the mycobacterial infection early and that this early control is associated with high CRAMP expression in the lungs without concomitant influx of immune cells. The role of CRAMP/LL-37 during mycobacterial infection may be relevant for novel protective strategies, and warrants further studies of human cohorts.
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| 5. |
- Björk, Albin, et al.
(författare)
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Protein and DNA methylation-based scores as surrogate markers for interferon system activation in patients with primary Sjögren's syndrome
- 2020
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Ingår i: RMD Open. - : BMJ PUBLISHING GROUP. - 2056-5933. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Standard assessment of interferon (IFN) system activity in systemic rheumatic diseases depends on the availability of RNA samples. In this study, we describe and evaluate alternative methods using plasma, serum and DNA samples, exemplified in the IFN-driven disease primary Sjogren's syndrome (pSS).Methods: Patients with pSS seropositive or negative for anti-SSA/SSB and controls were included. Protein-based IFN (pIFN) scores were calculated from levels of PD-1, CXCL9 and CXCL10. DNA methylation-based (DNAm) IFN scores were calculated from DNAm levels at RSAD2, IFIT1 and IFI44L. Scores were compared with mRNA-based IFN scores measured by quantitative PCR (qPCR), Nanostring or RNA sequencing (RNAseq).Results: mRNA-based IFN scores displayed strong correlations between B cells and monocytes (r=0.93 and 0.95, p<0.0001) and between qPCR and Nanostring measurements (r=0.92 and 0.92, p<0.0001). The pIFN score in plasma and serum was higher in patients compared with controls (p<0.0001) and correlated well with mRNA-based IFN scores (r=0.62-0.79, p<0.0001), as well as with each other (r=0.94, p<0.0001). Concordance of classification as 'high' or 'low' IFN signature between the pIFN score and mRNA-based IFN scores ranged from 79.5% to 88.6%, and the pIFN score was effective at classifying patients and controls (area under the curve, AUC=0.89-0.93, p<0.0001). The DNAm IFN score showed strong correlation to the RNAseq IFN score (r=0.84, p<0.0001) and performed well in classifying patients and controls (AUC=0.96, p<0.0001).Conclusions: We describe novel methods of assessing IFN system activity in plasma, serum or DNA samples, which may prove particularly valuable in studies where RNA samples are not available.
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| 7. |
- Mofors, Johannes, et al.
(författare)
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Cigarette smoking patterns preceding primary Sjögren's syndrome
- 2020
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Ingår i: RMD Open. - : BMJ Publishing Group Ltd. - 2056-5933. ; 6:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cigarette smoking is a well-established risk factor for several autoimmune diseases, but its role in primary Sjogren's syndrome (pSS) remains unclear. Here, we investigated the association between cigarette smoking and subsequent development of pSS.Methods: Information on smoking habits was collected from lifestyle habit questionnaires of patients with pSS (n=815) and a matched control group (n=4425) for a case-control study. Differences in smoking exposure were analysed by conditional logistic regression. Potential interactions between smoking and risk-associated human leucocyte antigens (HLA) were assessed by multivariate regression.Results: The fraction of patients with pSS having ever smoked prior to diagnosis was lower than in controls (OR 0.67, 95% CI 0.55 to 0.81). Current smoking at diagnosis was also less prevalent in cases (OR 0.37, 95% CI 0.26 to 0.53). However, period prevalence of smoking during early adulthood was not statistically different from controls (OR 0.89, 95% CI 0.66 to 1.22) but markedly decreased over time. This was partly due to patients being more prone to stop smoking, starting already 30 years prior to diagnosis (OR 2.01, 95% CI 1.22 to 3.30). Smoking patterns were also stratified by autoantibody status, yielding similar estimates. No interaction effects between HLA-DRB1 haplotypes and smoking were observed.Conclusion: The observed smoking patterns indicate that individuals who develop pSS smoke equally much as the general population during early life but are then more prone to stop. The data can be interpreted as smoking conferring protective effects, or reflecting early symptoms of pSS that affect smoking habits, emphasising the slow, progressive development of the disease.
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