| 1. |
- Ahmadi, Shilan Seyed, et al.
(author)
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Risk of atrial fibrillation in persons with type 2 diabetes and the excess risk in relation to glycaemic control and renal function: a Swedish cohort study
- 2020
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In: Cardiovascular Diabetology. - : Springer Science and Business Media LLC. - 1475-2840. ; 19:1
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Journal article (peer-reviewed)abstract
- Background To examine the incidence of atrial fibrillation in individuals with type 2 diabetes compared with age- and sex-matched controls from the general population and its variation in relation to glycaemic control and renal function. Methods A total of 421,855 patients with type 2 diabetes from the Swedish National Diabetes Registry and 2,131,223 controls from the Swedish Population Registry, matched for age, sex and county, were included and followed from January 1, 2001 to December 31, 2013. Results Overall, 8.9% of individuals with type 2 diabetes and 7.0% of controls were diagnosed with atrial fibrillation during follow-up, unadjusted incidence risk ratio (IRR) 1.35 (95% 1.33-1.36). Women < 55 years old with type 2 diabetes had an IRR of 2.36 (95% CI 2.10-2.66), in relation to controls, whereas the corresponding value for men < 55 years old with type 2 diabetes was IRR 1.78 (95% CI 1.67-1.90). In the fully adjusted Cox regression, the risk of type 2 diabetes on incident atrial fibrillation was 28% greater vs controls, hazard ratio (HR) 1.28 (95% CI 1.26-1.30), p < 0.0001. The excess risk of atrial fibrillation in individuals with type 2 diabetes increased with worsening glycaemic control and renal complications. For individuals with HbA1c <= 6.9% (<= 52 mmol/mol) and normoalbuminuria the excess risk vs controls was still increased, adjusted HR 1.16 (95% CI 1.14-1.19); p < 0.0001. Conclusions Individuals with type 2 diabetes had an overall 35% higher risk of atrial fibrillation compared to age- and sex-matched controls from the general population. The excess risk for atrial fibrillation increased with renal complications or with poor glycaemic control. Individuals with type 2 diabetes with good glycaemic control and normoalbuminuria had slightly increased risk.
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| 2. |
- Ambikan, Anoop T., et al.
(author)
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Multi-omics personalized network analyses highlight progressive disruption of central metabolism associated with COVID-19 severity
- 2022
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In: Cell systems. - : Elsevier BV. - 2405-4712 .- 2405-4720. ; 13:8, s. 665-681
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Journal article (peer-reviewed)abstract
- The clinical outcome and disease severity in coronavirus disease 2019 (COVID-19) are heterogeneous, and the progression or fatality of the disease cannot be explained by a single factor like age or comorbidities. In this study, we used system-wide network-based system biology analysis using whole blood RNA sequencing, immunophenotyping by flow cytometry, plasma metabolomics, and single-cell-type metabolo-mics of monocytes to identify the potential determinants of COVID-19 severity at personalized and group levels. Digital cell quantification and immunophenotyping of the mononuclear phagocytes indicated a sub-stantial role in coordinating the immune cells that mediate COVID-19 severity. Stratum-specific and person-alized genome-scale metabolic modeling indicated monocarboxylate transporter family genes (e.g., SLC16A6), nucleoside transporter genes (e.g., SLC29A1), and metabolites such as a-ketoglutarate, succi-nate, malate, and butyrate could play a crucial role in COVID-19 severity. Metabolic perturbations targeting the central metabolic pathway (TCA cycle) can be an alternate treatment strategy in severe COVID-19.
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| 3. |
- Ambikan, Anoop T., et al.
(author)
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Systems-level temporal immune-metabolic profile in Crimean-Congo hemorrhagic fever virus infection
- 2023
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 120:37
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Journal article (peer-reviewed)abstract
- Crimean-Congo hemorrhagic fever (CCHF) caused by CCHF virus (CCHFV) is one of the epidemic-prone diseases prioritized by the World Health Organisation as public health emergency with an urgent need for accelerated research. The trajectory of host response against CCHFV is multifarious and remains unknown. Here, we reported the temporal spectrum of pathogenesis following the CCHFV infection using genome-wide blood transcriptomics analysis followed by advanced systems biology analysis, temporal immune-pathogenic alterations, and context-specific progressive and postinfection genome-scale metabolic models (GSMM) on samples collected during the acute (T0), early convalescent (T1), and convalescent-phase (T2). The interplay between the retinoic acid-inducible gene-I-like/nucleotide-binding oligomerization domain-like receptor and tumor necrosis factor signaling governed the trajectory of antiviral immune responses. The rearrangement of intracellular metabolic fluxes toward the amino acid metabolism and metabolic shift toward oxidative phosphorylation and fatty acid oxidation during acute CCHFV infection determine the pathogenicity. The upregulation of the tricarboxylic acid cycle during CCHFV infection, compared to the noninfected healthy control and between the severity groups, indicated an increased energy demand and cellular stress. The upregulation of glycolysis and pyruvate metabolism potentiated energy generation through alternative pathways associated with the severity of the infection. The downregulation of metabolic processes at the convalescent phase identified by blood cell transcriptomics and single-cell type proteomics of five immune cells (CD4+ and CD8+ T cells, CD14+ monocytes, B cells, and NK cells) potentially leads to metabolic rewiring through the recovery due to hyperactivity during the acute phase leading to post-viral fatigue syndrome.
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| 4. |
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| 5. |
- Ambite, Inès, et al.
(author)
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Active bacterial modification of the host environment through RNA polymerase II inhibition
- 2021
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In: Journal of Clinical Investigation. - 0021-9738. ; 131:4
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Journal article (peer-reviewed)abstract
- Unlike pathogens, which attack the host, commensal bacteria create a state of friendly coexistence. Here, we identified a mechanism of bacterial adaptation to the host niche, where they reside. Asymptomatic carrier strains were shown to inhibit RNA polymerase II (Pol II) in host cells by targeting Ser2 phosphorylation, a step required for productive mRNA elongation. Assisted by a rare, spontaneous loss-of-function mutant from a human carrier, the bacterial NlpD protein was identified as a Pol II inhibitor. After internalization by host cells, NlpD was shown to target constituents of the Pol II phosphorylation complex (RPB1 and PAF1C), attenuating host gene expression. Therapeutic efficacy of a recombinant NlpD protein was demonstrated in a urinary tract infection model, by reduced tissue pathology, accelerated bacterial clearance, and attenuated Pol II-dependent gene expression. The findings suggest an intriguing, evolutionarily conserved mechanism for bacterial modulation of host gene expression, with a remarkable therapeutic potential.
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| 6. |
- Ambite, Ines, et al.
(author)
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Bacterial suppression of RNA polymerase II-dependent host gene expression
- 2016
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In: Pathogens. - : MDPI AG. - 2076-0817. ; 5:3
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Research review (peer-reviewed)abstract
- Asymptomatic bacteriuria (ABU) is a bacterial carrier state in the urinary tract that resembles commensalism at other mucosal sites. ABU strains often lack the virulence factors that characterize uropathogenic Escherichia coli (E. coli) strains and therefore elicit weak innate immune responses in the urinary tract. In addition, ABU strains are active modifiers of the host environment, which they influence by suppressing RNA polymerase II (Pol II)-dependent host gene expression. In patients inoculated with the ABU strain E. coli 83972, gene expression was markedly reduced after 24 h (>60% of all regulated genes). Specific repressors and activators of Pol II-dependent transcription were modified, and Pol II Serine 2 phosphorylation was significantly inhibited, indicating reduced activity of the polymerase. This active inhibition included disease–associated innate immune response pathways, defined by TLR4, IRF-3 and IRF-7, suggesting that ABU strains persist in human hosts by active suppression of the antibacterial defense. In a search for the mechanism of inhibition, we compared the whole genome sequences of E. coli 83972 and the uropathogenic strain E. coli CFT073. In addition to the known loss of virulence genes, we observed that the ABU strain has acquired several phages and identified the lytic Prophage 3 as a candidate Pol II inhibitor. Intact phage particles were released by ABU during in vitro growth in human urine. To address if Prophage 3 affects Pol II activity, we constructed a Prophage 3 negative deletion mutant in E. coli 83972 and compared the effect on Pol II phosphorylation between the mutant and the E. coli 83972 wild type (WT) strains. No difference was detected, suggesting that the Pol II inhibitor is not encoded by the phage. The review summarizes the evidence that the ABU strain E. coli 83972 modifies host gene expression by inhibition of Pol II phosphorylation, and discusses the ability of ABU strains to actively create an environment that enhances their persistence.
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| 7. |
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| 8. |
- Ambite, Ines, et al.
(author)
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Fimbriae reprogram host gene expression - Divergent effects of P and type 1 fimbriae
- 2019
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In: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 15:6, s. 1007671-1007671
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Journal article (peer-reviewed)abstract
- Pathogens rely on a complex virulence gene repertoire to successfully attack their hosts. We were therefore surprised to find that a single fimbrial gene reconstitution can return the virulence-attenuated commensal strain Escherichia coli 83972 to virulence, defined by a disease phenotype in human hosts. E. coli 83972pap stably reprogrammed host gene expression, by activating an acute pyelonephritis-associated, IRF7-dependent gene network. The PapG protein was internalized by human kidney cells and served as a transcriptional agonist of IRF-7, IFN-β and MYC, suggesting direct involvement of the fimbrial adhesin in this process. IRF-7 was further identified as a potent upstream regulator (-log (p-value) = 61), consistent with the effects in inoculated patients. In contrast, E. coli 83972fim transiently attenuated overall gene expression in human hosts, enhancing the effects of E. coli 83972. The inhibition of RNA processing and ribosomal assembly indicated a homeostatic rather than a pathogenic end-point. In parallel, the expression of specific ion channels and neuropeptide gene networks was transiently enhanced, in a FimH-dependent manner. The studies were performed to establish protective asymptomatic bacteriuria in human hosts and the reconstituted E. coli 83972 variants were developed to improve bacterial fitness for the human urinary tract. Unexpectedly, P fimbriae were able to drive a disease response, suggesting that like oncogene addiction in cancer, pathogens may be addicted to single super-virulence factors.
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| 9. |
- Ambite, Ines, et al.
(author)
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Molecular Basis of Acute Cystitis Reveals Susceptibility Genes and Immunotherapeutic Targets
- 2016
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In: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 12:10
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Journal article (peer-reviewed)abstract
- Tissue damage is usually regarded as a necessary price to pay for successful elimination of pathogens by the innate immune defense. Yet, it is possible to distinguish protective from destructive effects of innate immune activation and selectively attenuate molecular nodes that create pathology. Here, we identify acute cystitis as an Interleukin-1 beta (IL-1β)-driven, hyper-inflammatory condition of the infected urinary bladder and IL-1 receptor blockade as a novel therapeutic strategy. Disease severity was controlled by the mechanism of IL-1β processing and mice with intact inflammasome function developed a moderate, self-limiting form of cystitis. The most severe form of acute cystitis was detected in mice lacking the inflammasome constituents ASC or NLRP-3. IL-1β processing was hyperactive in these mice, due to a new, non-canonical mechanism involving the matrix metalloproteinase 7- (MMP-7). ASC and NLRP-3 served as transcriptional repressors of MMP7 and as a result, Mmp7 was markedly overexpressed in the bladder epithelium of Asc-/- and Nlrp3-/- mice. The resulting IL-1β hyper-activation loop included a large number of IL-1β-dependent pro-inflammatory genes and the IL-1 receptor antagonist Anakinra inhibited their expression and rescued susceptible Asc-/- mice from bladder pathology. An MMP inhibitor had a similar therapeutic effect. Finally, elevated levels of IL-1β and MMP-7 were detected in patients with acute cystitis, suggesting a potential role as biomarkers and immunotherapeutic targets. The results reproduce important aspects of human acute cystitis in the murine model and provide a comprehensive molecular framework for the pathogenesis and immunotherapy of acute cystitis, one of the most common infections in man. Trial Registration: The clinical studies were approved by the Human Ethics Committee at Lund University (approval numbers LU106-02, LU236-99 and Clinical Trial Registration RTP-A2003, International Committee of Medical Journal Editors, www.clinicaltrials.gov).
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| 10. |
- Ambite, Ines
(author)
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Molecular determinants of disease severity in urinary tract infection
- 2019
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Doctoral thesis (other academic/artistic)abstract
- In the urinary tract, Escherichia coli infection may result in life-threatening disease, or asymptomatic bacterial carriage, comparable to bacterial commensalism in the gut. Pathogenic strains trigger a disease provoking host response which differs depending on the infected organ. The diversity of the response reflects the virulence repertoire of the infecting strain and by the susceptibility of the host. During asymptomatic bacteriuria (ABU), the lack of clinical symptoms has been attributed to the loss of virulence by the strains. ABU strains have a reduced genome size and carry point mutations or deletions in virulence genes. In the prototype strain E. coli 83972 fimbrial gene clusters are affected by multiple point mutations (the papG adhesin gene) or large deletions (the fim gene cluster). As a result, the innate immune response to ABU strains is reduced. In addition, we made the discovery that asymptomatic carrier strains actively inhibit RNA Polymerase II (Pol II) Ser2 phosphorylation. Pol II is the enzyme required for the transcription of all mRNA in eukaryotes and its function is tightly regulated. E. coli 83972 suppresses Pol II-dependent host gene expression, including genes involved in immune activation. Compared to a broad chemical inhibitor, DRB, inhibition was more limited, suggesting a degree of specificity for a certain repertoire of host genes. Through this suppression of transcription, ABU strains may promote tissue integrity while inhibiting potentially destructive immune activation. NlpD was identified as a protein released by asymptomatic carrier strains with potent host gene expression inhibitory capacity. NlpD targeted the Pol II phosphorylation machinery by interacting with the biggest Pol II subunit, RPB1, and PAF1C in host cells. In treated mice, NlpD inhibited the destructive arm of innate immune activation and reduced bacterial loads. Our findings suggest that molecules of bacterial origin may be explored as therapies to reproduce the beneficial effects associated with ABU.The symptoms of acute cystitis, in contrast, are caused by an exaggerated inflammatory response triggered by infection. We now define acute cystitis as an IL-1β-driven, hyper-inflammatory disorder with atypical IL-1β processing through MMP-7. The results also suggest a genetic susceptibility factor in patients with severe and chronic cystitis, through mutations affecting ASC or NLRP3 expression. ASC and NLRP-3 were identified as negative regulators of MMP-7 expression and the identified molecular determinants and IL-1β and MMP-7 as novel targets for immunomodulatory therapy with potent effects in vivo as well as biomarkers for acute cystitis.In contrast to acute cystitis, acute pyelonephritis is a severe, sometimes life-threatening kidney infection with systemic involvement and risk of developing bacteremia. Uropathogenic E. coli strains initiate tissue attack of the renal pelvis thus starting disease pathogenesis. A normally protective innate immune signalling cascade, controlled by toll like receptor (TLR)4, is exaggerated explaining the acute disease and sometimes destructive, long-term effects. The response is determined, in part, by bacterial P fimbriae, their receptors and the quality of the signalling cascade that they activate, including several transcription factors. The transcription factor IRF-3 controls the protective arm of the innate immune response to kidney infection, and as a result, mice lacking Irf3 develop severe infection accompanied by urosepsis and renal abscess formation. We identify IRF-7 as a driving force for the disease response in Irf3-/- mice and development of renal pathology. We also define Irf7 as an immuno-therapeutic target that can be controlled with small interfering RNA (siRNA) to restore the balance of resistance versus pathology and prevent kidney damage.Finally, we show that P fimbriae influence the IRF-7 expression and the repertoire of downstream genes associated with acute pyelonephritis (APN). Specifically, P fimbriae were shown to act as IRF-7 agonists. The expression of functional P fimbriae was sufficient to reprogram host gene expression, through effects of PapG on the transcriptional machinery of the host. Paradoxically, the results suggest that a single “super virulence” factor may be sufficient to tilt the balance from peaceful coexistence to disease and for the host to recognize and respond to a strain that lacks most other virulence factors.
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